Boyi Zong
Fengzhi Yu1,2,3
Xiaoyou Zhang
Lin Li- 1College of Physical Education and Health, East China Normal University, Shanghai, China
- 2Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, China
- 3School of Exercise and Health, Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- 4School of Physical Education, Hubei University, Wuhan, China
- 5College of Physical Education and Health Sciences, Zhejiang Normal University, Jinhua, China
Multiple sclerosis (MS) is a prevalent neuroimmunological illness that leads to neurological disability in young adults. Although the etiology of MS is heterogeneous, it is well established that aberrant activity of adaptive and innate immune cells plays a crucial role in its pathogenesis. Several immune cell abnormalities have been described in MS and its animal models, including T lymphocytes, B lymphocytes, dendritic cells, neutrophils, microglia/macrophages, and astrocytes, among others. Physical exercise offers a valuable alternative or adjunctive disease-modifying therapy for MS. A growing body of evidence indicates that exercise may reduce the autoimmune responses triggered by immune cells in MS. This is partially accomplished by restricting the infiltration of peripheral immune cells into the central nervous system (CNS) parenchyma, curbing hyperactivation of immune cells, and facilitating a transition in the balance of immune cells from a pro-inflammatory to an anti-inflammatory state. This review provides a succinct overview of the correlation between physical exercise, immune cells, and MS pathology, and highlights the potential benefits of exercise as a strategy for the prevention and treatment of MS.
1 Introduction
Multiple sclerosis (MS) is a disease characterized by neuroinflammation, demyelination, and axonal damage, with lesions that involve both the brain and spinal cord. It is estimated that MS affects approximately 2.8 million individuals worldwide, with a higher prevalence in women (1). Symptoms of MS, such as vision loss, numbness, tingling, motor paralysis, cognitive impairment, and bladder dysfunction, significantly diminish the quality of life for patients (2, 3). In general, the course of MS disease manifests in three main forms: primary progressive MS (PPMS), secondary progressive MS (SPMS), and relapsing-remitting MS (RRMS) (4). Initially, most patients with MS (PwMS) experience the neurological symptoms of RRMS. Within a decade of disease onset, approximately 30-40% of PwMS transition into SPMS, which is characterized by an irreversible and progressive accumulation of neurological disability (3). The disability status of PwMS can be assessed on a scale of zero to ten using the Expanded Disability Status Scale (EDSS), with zero representing a normal neurological examination, and ten representing MS-caused death (5). There is evidence that the disease is associated with genetic, lifestyle and environmental risk factors (6, 7), but the exact cause of MS remains unclear.
The myelin sheath is a protective lipoprotein coating that surrounds axons and is composed mainly of oligodendroglial cell membranes, which help to protect nerves and ensure the normal conduction of nerve impulses. The normal formation of myelin depends on the process of myelination (8). Oligodendrocytes (OLs) are glial cells responsible for myelination, and these cells differentiate from oligodendrocyte progenitor cells (OPCs) (9). However, in MS, dysfunction of OLs and pathology of myelin lead to severe demyelination, impaired remyelination, and axonal degeneration (10). Over the years, the interactions between the immune cell, glial cell, and neuronal cell in the pathology of MS have been extensively studied. In the early stages, pathogenesis is primarily driven by peripheral immune cell responses targeting the CNS (11–13). The peripheral immune cells, such as T cells, B cells, and myeloid cells, infiltrate the CNS and interact with microglia and astrocytes, causing damage to OLs and inhibiting myelin formation (14–19). In the progressive stages, immune responses mediated by CNS-resident microglia and astrocytes predominate (20). In the inflammatory state, microglia generate pro-inflammatory cytokines and chemokines, and increase the expression of costimulatory molecules that facilitate the recruitment and activation of peripheral leukocytes (21, 22). Furthermore, microglia stimulate pro-inflammatory and neurotoxic responses in astrocytes that exacerbate demyelination, neurodegeneration, and atrophy of both grey and white matter (23, 24) (Figure 1). The autoimmune response directed against neuronal axons or synapses interferes with proper neurotransmission, resulting in a variety of motor and non-motor symptoms (25, 26).
Figure 1 Schematic diagram of immune cells-driven multiple sclerosis pathology. In multiple sclerosis, peripheral immune cells, including lymphocytes and monocytes, infiltrate into the central nervous system and secrete pro-inflammatory and neurotoxic substances. These cells, particularly T lymphocytes, possess the ability to interact with CNS-resident microglia and astrocytes, leading to microglial and astrocyte activation and the subsequent release of pro-inflammatory and neurotoxic substances. These substances contribute to the demyelination and neuronal damage, and erode oligodendrocytes, preventing them from forming myelin. Meanwhile, some of the pro-inflammatory substances released by microglia and astrocytes promote the recruitment, infiltration and activation of peripheral immune cells, further enhancing the autoimmune response in the CNS. The figure was created using BioRender. BBB, blood-brain barrier; CCL, chemokine (C-C motif) ligand; CNS, central nervous system; CXCL, chemokine (C-X-C motif) ligand; GM-CSF, granulocyte-macrophage colony stimulating factor; IFN-γ, interferon-γ; IL, interleukin; MMP, matrix metallopeptidase; NO, nitric oxide; OPC, oligodendrocyte progenitor cell; RNS, reactive nitrogen species; ROS, reactive oxygen species; Th, T helper cells; TNF-α, tumor necrosis factor-α.
Nowadays, pharmacotherapy is considered the primary treatment for MS; however, its efficacy falls short for a significant number of patients. Furthermore, the side effects and exorbitant costs linked with pharmacotherapy may result in reduced patient compliance (27). Non-pharmacological treatments, such as physical exercise, have gained attention as potential disease-modifying therapies for PwMS (28, 29). Physical exercise has been shown to be effective in rehabilitating PwMS, effectively alleviating symptoms, enhancing functionality, improving quality of life, and increasing engagement in daily activities (30–32). Mechanistically, physical exercise provides some protection to the CNS from disease-related atrophy and dysfunction. Structurally, objective research has demonstrated that several months of exercise in PwMS can preserve cortical thickness (33), pallidum (34) and hippocampal volume (35), as well as the microstructural integrity of the insula (36) and motor-related tracts and nuclei (37). Functionally, research has found that exercise can improve functional connectivity between the caudate and the left inferior parietal, bilateral frontal, and right insula regions (38). In addition, exercise can also increase functional connectivity within the hippocampus and the default-mode network (39). Notably, the utilization of animal models is of great value in investigating cellular and molecular mechanisms. Commonly used models include myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and toxin and/or virus-induced demyelination models, such as cuprizone (CPZ) and lysophospholipid, among others (40). In animal studies, there is evidence that regular exercise training can effectively promote the process of remyelination, alleviate demyelination, and enhance neuroplasticity by modulating the activity and function of OLs and neurons (41–45), and exert neuroprotective effects by reducing oxidative stress (46–49), maintaining the integrity and permeability of the blood-brain barrier (BBB) (48, 50), and adjusting the physiological levels of various exercise metabolites (51, 52). Moreover, it is imperative to recognize the anti-inflammatory benefits of physical exercise, as it not only regulates OLs and neurons, but also influences numerous immune cell types. This review will focus on the effect of physical exercise on neuroimmune regulation in MS, specifically regarding T cells, B cells, dendritic cells, neutrophils, macrophages, microglia, and astrocytes.
2 Effect of physical exercise on immune cells in multiple sclerosis
2.1 Adaptive immune cells
2.1.1 T cells and B cells
Lymphocytes, particularly T cells and B cells, are integral components of the adaptive immune system and are required for immune surveillance of the CNS. They can induce significant immunopathological responses in the presence of viral infections and autoimmune disorders (53, 54). T cells are mainly classified into CD4+ T cells and CD8+ T cells based on distinct cell surface differentiation antigens (55). Aberrant activation of autoreactive CD4+ T cells is considered a primary factor in the development of MS (56, 57). Upon activation, naive CD4+ T cells differentiate into different T helper (Th) cell subsets, including Th1, Th2, Th17, and T regulatory (Treg) cells. These subsets have distinct cytokine profiles and effector functions (58). Th17 cells can release several pro-inflammatory cytokines, such as interleukin 17A (IL-17A), interferon γ (IFN-γ), and IL-22 (57). In EAE, the number of peripheral Th1/Th17 cells increases significantly, as do the levels of IFN-γ and IL-17. These immune cells and their associated cytokines, infiltrate the CNS to exacerbate autoimmune neuroinflammation (59). In addition to neuroinflammation, excessive inflammatory cytokines (such as members of the IL-17 family) can initiate other malignant events. Within the CNS of the EAE model, IL-17 is involved in pain modulation as an upstream regulator of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) (60). During EAE, overexpression of IL-17A results in impaired long-term potentiation (LTP) and synaptic plasticity in the hippocampus. This leads to cognitive decline through activation of the IL-17A receptor and the p38 mitogen-activated protein kinase (MAPK) signaling pathway, as reported by Di Filippo et al. (26). In contrast, Treg cells possess the ability to release anti-inflammatory cytokines such as IL-10, transforming growth factor β (TGF-β), and IL-35 (61). The beneficial effects of natural Treg cells, which express CD4+ forkhead box protein 3 (FoxP3), and T regulatory type 1 (Tr1) cells, which produce IL-10, on autoimmune neuroinflammation have been demonstrated in both MS patients (62, 63) and experimental animal models (64, 65). A crucial aspect contributing to tissue inflammation in CNS autoimmunity is the impaired functionality of Th17 and Treg cells. It is noteworthy that modulation of the Th17/Treg balance, as well as the functional state of the intrasubsets, can attenuate CNS autoimmunity (66, 67). Different substances, compound 21 (68) and ACDT (69), have demonstrated inhibition of the infiltration of pathogenic Th1/Th17 cells into the CNS in the EAE model. Furthermore, the administration of propionic acid to PwMS resulted in a significant and sustained increase in functional Treg and a significant decrease in Th1/Th17 cells (70). Ultimately, the disease severity of EAE is minimized, or the clinical symptoms of PwMS are reduced.
Alongside CD4+ T cells, some of the cytotoxic CD8+ T cells, such as IL-17-producing CD8+ T (Tc17) cells, have been identified as possible drivers of localized autoimmune damage to the CNS in the EAE model (71). Intriguingly, while in most animal models this is not the case, studies examining human patients have revealed that CD8+ T cells are the main type of T cells present in the CNS of these individuals (72–74). Inflammatory active lesions in MS are populated by CD8+ tissue-resident memory T cells, exhibiting indications of reactivation and infiltration into the brain parenchyma (73). The CD8+ T cells could serve various functions, as they have been assigned both pathogenic and regulatory roles. On one hand, CD8+ T cells could act as pathogenic effectors that lead to the breakdown of the BBB (75) and promote pathogenic CD4+ T cell activity (71), damage OLs (76) and OPCs (77), and/or direct damage axons (78). On the other hand, CD8+ T cells may regulate pathogenic CD4+ T cells by directly modulating antigen-presenting cells and/or through releasing immunoregulatory cytokines such as IL-10, IFN-γ, and TGF-β (79, 80). Moreover, the efficacy of several therapeutic interventions that selectively deplete B cells (rituximab, ocrelizumab and ofatumumab) highlights the importance of B cells in the pathogenesis of the disease (81). B cells contribute to the pathology of MS through multiple mechanisms. They present antigens to T cells, driving the auto-proliferation of brain-homing T cells (82). Additionally, B cells secrete pro-inflammatory cytokines, such as TNF-α, IL-6, IL-15, and granulocyte-macrophage colony stimulating factor (GM-CSF) (83), and produce extracellular vesicles and antibodies (84). It should be noted that there are distinct functional differences within subpopulations of CD8+ T cells and B cells, emphasising the need for the development and implementation of therapies that target specific pathogenic cell subsets.
Physical exercise has been proven to improve systemic autoimmune inflammation mediated by lymphocytes, in addition to pharmacological treatment, and is generally secure for individuals with autoimmune disorders like systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel diseases and MS, among others (85). Since 2018, numerous studies conducted by Einsteina et al. have investigated the effect of different exercise programs on T cell-mediated autoimmunity from the proteolipid protein (PLP)-induced transfer EAE model in animals. By transferring T cells from lymph nodes (LN-T cells) obtained from mice that underwent six weeks of treadmill running, or from sedentary donor mice, to naive recipients and recipient mice that were either trained prior to EAE induction or sedentary, researchers confirmed that physical exercise limits immune responses to an auto-antigen to weaken EAE, instead of suppressing the immune system in general (86). Further studies have confirmed the superior effect of high-intensity continuous training (HICT) in preventing T cell-induced autoimmunity in EAE through treadmill running, compared to moderate-intensity continuous training (MICT) (87). Remarkly, variations were found in the mechanisms by which continuous and intermittent exercise, performed at the same high intensity, alleviated systemic autoimmunity and T cell encephalitogenicity. Specifically, HICT impeded PLP-induced T cell proliferation without affecting T cell differentiation, while high-intensity intermittent exercise (HIIT) had no noticeable impact on T cell proliferation but hindered T cell polarization into Th1 and Th17 pro-inflammatory phenotypes (88). Taken together, because of the significant variation observed across different disease trajectories, it is essential to implement effective intervention programs that are customized to suit the specific characteristics of each phase of the disease.
In other previous animal studies, mice that underwent regular swimming exercise before EAE induction showed suppressed infiltration of CD4+ T cells, CD8+ T cells, and B cells into the spinal cord. Meanwhile, the proliferation of antigen-specific T cells was halted and the proliferation of Treg cells was promoted, while restricting the secretion of IFN-γ and IL-17 and enhancing the secretion of IL-10 and TGF-β. Furthermore, regular swimming exercise also alleviated damage to myelin and axons and reduced clinical scores (89, 90). Notably, research suggests that high-intensity swimming (4% body weight) may prove more effective than moderate-intensity swimming (0% body weight) (90). It seems that swimming exercise represents a noteworthy non-pharmacological intervention for improving chronic inflammation or autoimmunity; however, the success of this intervention could be modified by the intensity of the exercise. In addition, it is probable that the efficacy of exercise interventions is also reliant on the type of exercise employed. Over a four-week period, it was observed that both strength and endurance training programs impeded the development and progression of disease, improved genomic antioxidant defense-nuclear factor erythroid 2-related factor (Nrf2)/antioxidant response elements (ARE) pathway, lowered the production of IFN-γ, IL-17, and IL-1β, reduced the expression of adhesion molecules, such as platelet and endothelial cell adhesion molecule 1 (PECAM-1), and reinstated the expression of tight junction proteins such as occludin and claudin-4 in the spinal cord after EAE induction. However, only strength training significantly increased the expression of Treg cell markers, specifically CD25 and IL-10, obtained from spleen cells, and inhibited the production of IL-6, monocyte chemotactic protein 1 (MCP-1), and TNF-α (48). Further analyses revealed that while endurance exercise was superior in delaying disease progression and lowering clinical scores as well as antioxidants, strength training was more effective in improving immune system function. Voluntary wheel running, as a rehabilitation approach, has been demonstrated as an effective intervention for promoting motor recovery. Regular voluntary wheel running had a significant positive effect on demyelination and axonal damage in EAE mice, in comparison to their sedentary counterparts. However, the impact of lymphocyte infiltration was insignificant (47, 91). Additionally, gender of the subjects must be taken into consideration as it may have an influence on the exercise intervention’s efficacy (47, 92). Further, a study has investigated the potential of combined interventions and has discovered a substantial positive interaction between exercise and galantamine medication. The outcome of this interaction led to a notable rise in the quantity of Foxp3+ T cells in the brainstem of rats affected by EAE (93). The animal studies’ collective findings suggest that physical exercise could potentially suppress lymphocyte infiltration, including CD4+ T cells, CD8+ T cells, and B cells. Additionally, it could modulate the Th cell phenotype and regulate related cytokine levels, eventually leading to a reduction in autoimmune responses in the CNS, an improvement in MS pathology, and a decrease in disease severity (Table 1). Nonetheless, the effects of exercise may be impacted by different aspects of the exercise intervention, such as the type and intensity of the exercise, as well as the heterogeneity of the subjects.
Table 1 Effect of exercise on adaptive immune cells in animal models and human patients of MS.
In human studies, lymphocyte proliferation has been observed to be suppressed after acute exercise in healthy individuals. This effect is more pronounced during exercise sessions exceeding an hour in duration, regardless of exercise intensity (100). However, some studies have reported inconsistent findings. For example, individuals who are healthy controls and those with PwMS receiving alemtuzumab, fingolimod, or natalizumab displayed an increase in the absolute number of lymphocytes and specific subsets following exercise. The degree of response was impacted by the intensity of the exercise program (99). In Deckx’s study, naturally occurring CD25hiFoxp3+ Treg cells and antigen-induced IL-10-producing Tr1 cells increased in the peripheral blood of patients with chronically progressive MS and RRMS following a single session of moderate-to-high-intensity endurance with resistance exercise. The number of Tr1 cells remained elevated for up to two hours after exercise (95). This increase in Treg cells may serve as a negative feedback mechanism to the immune system’s capacity to elicit tissue damage and inflammation when responding to exercise. Moreover, the findings of regular exercise intervention studies require careful observation. A four-week experiment of treadmill running in normoxic conditions (rather than hypoxic conditions) caused modifications in circulating Treg subpopulations among patients with RRMS. These alterations comprised of an increase in CD39+ Treg cells and a decrease in CD31+ Treg cells, as well as a reduction in IL-17A-producing CD4+ T cells. These results imply that treadmill running has a vital function in adjusting the adaptive immune response in MS through impacting distinct T cell subsets (98). Remarkably, conflicting results have also emerged. As early as 2012, a cross-sectional study revealed that there were no discernible differences in the proportions of circulating CD4+ T cells (including Foxp3+ Treg cells), CD8+ T cells, and B cells in the peripheral blood between physically active and inactive PwMS, and no correlation with physical performance parameters (101). These findings suggest that prolonged physical activity may not have a significant impact on the adaptive immune cells in PwMS. In accordance with this, Deckx et al. (96) discovered that 12 weeks of endurance and strength training had no effect on the circulating Treg subsets, including CD25hiFoxp3+, Tr1, and Th3 cells in PwMS. These inconsistent findings in human patients have significant implications for experimental and clinical research, particularly regarding the development of interventions to address autoimmune factors in MS.
The BBB is a dynamic interface linking the blood with the brain parenchyma. It comprises capillary endothelial cells (ECs) from the brain and spinal cord, and perivascular cells including smooth muscle cells, microglia, pericytes, and astrocytes. Of note, the ECs have adherens junctions and tight junctions between cells and lack fenestration (102). It has been suggested that the destruction of BBB integrity and permeability may be the initial pathological features of MS. This results in the infiltration of immune cells from the periphery into the brain parenchyma (103). This is indicated by changes in biomarker levels, such as enzymes gelatinase A/MMP-2 (104), gelatinase B/MMP-9 (105), S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE) (106), among others. Although it is unclear whether the destruction of the BBB is the cause or the result of MS, several studies have confirmed that MS-related neuroinflammation has an impact on the structure and function of the BBB (107). Physical exercise has been shown to regulate BBB permeability through various pathways, including systemic inflammation, the brain renin-angiotensin and noradrenergic systems, central autonomic function, and the kynurenine pathway (108). In human studies, Mokhtarzade et al. (106) found that acute cycling causes a significant increase in circulating S100B, but has no effect on NSE in RRMS patients. Proschinger et al. (109) showed that a 12-month combination of functional resistance and endurance training programs reduce serum MMP-2 concentration in RRMS patients. Furthermore, Zimmer et al. (104) discovered that patients with RRMS or SPMS who participated in HIIT or MICT programs for three weeks reported a significant decrease in serum MMP-2 levels, while the level of MMP-9 remained stable. Therefore, exercise can partially ameliorate the disruption of the BBB in PwMS, as evidenced by circulating biomarkers. Tight junction proteins, consisting mainly of transmembrane and cytoplasmic proteins, are essential components of the BBB. The transmembrane structure of tight junctions is comprised primarily of three classical proteins: claudins, occludins, and junction adherence molecules. Furthermore, the support structure of tight junctions is established by cytoplasmic attachment proteins such as zonula occludens (ZO) and cingulin, among others (110). During the development of neuroinflammation, certain chemokines and cytokines may induce the expression of EC adhesion molecules, specifically intercellular cell adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, and PECAM-1, among others. As a result, peripheral immune cells could cross the BBB (111). Abnormal expression of tight junction proteins has been observed in animal models of MS and in human studies. For instance, the permeability of the BBB to Evans blue in the brain homogenate of mice with EAE significantly increased, accompanied by a reduction in claudin-5, occludin and ZO-1, while ICAM-1 and VCAM-1 expression increased (112). Similar findings were attained by other researchers in their evaluation of the degree of loss or redistribution of tight junction proteins, and the expression of ICAM-1 and VCAM-1 in the brains of EAE models (113). Another animal research demonstrated that after four weeks of strength or endurance training programs, the expression levels of tight junction proteins, including occludin and claudin-4, were restored in the CNS, and the expression of PECAM-1 was significantly suppressed, thus preserving the BBB from injury in EAE (48). A recent study conducted by Hamdi et al. (114) has implemented a PLP-induced transfer EAE model. The results show that HICT has an impact on T cell migration and invasion and is linked to a decrease in interactions between very late antigen 4 (VLA-4)/VCAM-1 and lymphocyte function antigen 1 (LFA-1)/ICAM-1. Thus, physical exercise could indirectly regulate lymphocyte infiltration by modifying BBB integrity and permeability.
In light of emerging evidence on the disruption of gut microbiota in PwMS, the mechanism by which gut microbiota disorder exacerbates the condition is progressively becoming more apparent (115–118). Studies have shown that the intestinal microbiome can promote the development of CNS-reactive pathogenic T cells in both EAE (119, 120) and MS (121). Aberrant alterations in colony patterns were noted in PwMS. These changes were accompanied by an increase in Desulfovibrionaceae, Akkermansia muciniphila, and Acinetobacter calcoacetius levels, among others, as well as a decrease in Faecalibacterium prausnitzii, Parabacteroides, Prevotella, and Bacteroides fragilis (122). There is an increasing body of evidence that suggests physical exercise could positively influence the composition and function of the gut microbiota (123–125). The implementation of a four-week strength training program, performed six times per week, led to significant outcomes in EAE. Specifically, this intervention resulted in increased abundance and diversity of gut microbiota, a decrease in the Firmicutes to Bacteroidetes ratio, and improvement in intestinal mucosal permeability. Various bacteria including Akkermansia, Clostridium, Parabacteroides, Christensenella, Dorea, Roseburia, and Paraprevotella can produce short-chain fatty acids (SCFAs). The training program efficiently decreased Th17 responses and increased Treg responses in lymphoid tissues of the small intestine. It is noteworthy that after completing four weeks of strength training, with each session lasting up to 60 minutes, there was a significant improvement in disease severity and neuropathology in EAE. Moreover, the microbiome fecal transplantation of trained mice into microbiota-depleted mice alleviated disease severity and neuropathology scores in microbiota-depleted mice relative to controls. However, shorter training durations, either 20 or 40 minutes per session, do not appear to affect T cell-mediated autoimmunity in EAE (94). These observational data indicate that the modulation of gut microbiota through exercise represents a mechanism that can improve T cell-mediated autoimmunity in MS. The beneficial effects of exercise on the pathology of EAE mice may be affected by the duration of training sessions, except for exercise type and intensity. For human patients, a brief high-impact multidimensional rehabilitation program that incorporates physical activity in a leisurely setting has demonstrated a decrease in proportions of pathobionts, such as Collinsella and Ruminococcus, while increasing amounts of SCFA producers, such as Coprococcus, Bacteroides, and Oscillospira. The alterations in the colony were associated with a reduction in the quantity of pro-inflammatory T lymphocyte subpopulations, especially CD4+/IFN-γ+ Th1 cells and CD4+/ROR-γ+ and CD4+/IL-17+ Th17 cells, as well as a decrease in circulating lipopolysaccharide (LPS). Simultaneously, the rehabilitation program also improved physical performance and relieved fatigue (126). In a separate study, a six-month home-based exercise training program held with a frequency of five sessions per week exhibited a significant increase in Prevotella populations and a reduction in Akkermansia muciniphila populations among PwMS. Furthermore, this intervention had a positive effect on adverse psychological states such as anxiety and depression. However, no substantial influence was observed on fatigue, Faecalibacterium prausnitzii and Bacteroides counts, or the presence of anti-inflammatory cytokines in the serum. Nonetheless, changes in Akkermansia muciniphila, Prevotella, and Bacteroides counts in response to the intervention were correlated with changes in IL-10 (127). The above results strongly indicate that exercise can elicit neuroimmunomodulatory effects by regulating the gut microbiome.
2.2 Innate immune cells
2.2.1 Dendritic cells
Dendritic cells (DCs) are specialized antigen-presenting cells and are vital regulators of innate and adaptive immune responses (128). They have the ability to express many molecules associated with antigen presentation that interact with T cells, including major histocompatibility complex-I (MHC-I), MHC-II, and CD1, as well as co-stimulatory molecules, including CD80, CD86, and CD40 (129). Moreover, upon activation, DCs also produce multiple cytokines, such as GM-CSF, IL-23 (130, 131), and IL-27 (132), which direct the differentiation of naive T cells. A human study compared the phenotypes and cytokine secretion of DCs among PwMS, individuals with other neurological disorders, and healthy controls. The research discovered that the number, morphology, and phenotype of DCs were comparable in PwMS and healthy controls. The phenotypic features included immature myeloid lineages such as CD1a+ and CD11c+. However, PwMS showed a higher proportion of CD1a+ DCs and a lower proportion of CD86+ DCs compared to controls (133). It is evident that alterations in the surface molecules of DCs, which have functional significance, are related to MS. In the EAE model, dysfunctional or deficient DC genes result in abnormal responses from effector T cells. For instance, researchers have identified that mammalian sterile 20-like kinase 1 (MST1) to be an essential regulator of EAE, promoting Th17 differentiation depending on DCs. The absence of MST1 in DCs causes CD4+ T cells to produce higher quantities of IL-17, whereas the amplification of MST1 in DCs restrains IL-17 production. Mechanically, activation of p38 MAPK signaling occurs in DCs lacking MST1, resulting in increased IL-6 secretion in Th17 differentiation induction and the activation of IL-6 receptor α/β and signal transducer and activator of transcription 3 (STAT3) in CD4+ T cells (134). Additional in vivo research with rodents revealed worsened autoimmune neuroinflammation with increased Th17 cell polarization during EAE induction in REGγ-deficient mice. Moreover, ex vivo experiments have confirmed that a REGγ deficit enhances integrin αvβ8 expression in DCs, which stimulates TGF-β1 maturation and promotes Th17 cell development. The process is supported by REGγ proteasome-dependent degradation of IRF8 (135). DCs play an important role in immune regulation initiation and maintenance of inflammatory events. It is essential to conduct further research on DC genes that affect T cell-mediated pathology in MS. This will improve our basic understanding of MS pathogenesis and support the creation of more effective treatments for this disease. Bilirubin nanomedicine (136), urolithin A (137), and optineurin (138) have already been demonstrated to be effective in impacting disease progression by regulating the activity and function of DCs.
Furthermore, it should be noted that DCs may also exhibit heterogeneity in the pathogenesis of MS. DCs are generally classified into two main subsets, referred to as myeloid/conventional DCs (cDCs) and plasmacytoid DCs (pDCs). Interestingly, cDCs and pDCs obtained from PwMS manifested significant tolerogenic (139) or regulatory effects (140) in comparison with control groups. The cDCs are further categorized into cDC1 and cDC2 cells, which exhibit distinct ontogenies, surface markers, localizations, and immunological functions (141). In a stable condition, the cDCs commonly reside in the meninges, brain, and spinal cord of the CNS. They are capable of stimulating the activation and secretion of pro-inflammatory cytokines directly ex vivo from naive, effector, myelin-specific T cells. The population of cDCs increases in the meninges and CNS parenchyma during the development of EAE. Upon selective depletion of cDCs, the quantity of myelin-primed donor T cells in the CNS decreased, resulting in a 50% reduction in the incidence of clinical presentation (142). The pDCs can be subdivided into pDC1 and pDC2. The former displays increased levels of CD123 expression, while demonstrating decreased expression of CD86 and Toll-like receptor 2 (TLR2). It also facilitates the secretion of IFN-α and IL-10. Conversely, the latter subtype, pDC2, exhibits reduced expression of CD123 but higher expression of CD86 and TLR2. It promotes the secretion of TNF-α and IL-6 (143). Thewissen et al. (144) reported that circulating DCs in PwMS demonstrate a pro-inflammatory state and possess a migratory phenotype. DCs derived from MS patients exhibited increased production of IL-12p70 following TLR ligation. Additionally, these DCs had heightened expression levels of the migratory molecules C-C chemokine receptor 5 (CCR5) and CCR7, as well as improved in vitro chemotaxis when compared to healthy controls. Another study showed a significant alteration in the pDC1/pDC2 ratio, with a ratio of approximately 4.4:1 observed in healthy controls and 0.69:1 observed in PwMS. This shift towards pDC2 may contribute to the preferential activation of IL-17-secreting cells in MS, over IL-10-secreting CD4+ T cells (145). The concurrent occurrence of various DC subpopulations suggests their dual function in MS pathology.
In 2007, research conducted on DCs in Sprague-Dawley rats showed that progressive endurance exercise for five weeks modified the development of DCs and directed them towards a more mature state (146). However, in studies of animal disease models, Mackenzie et al. (147) found that four weeks of treadmill running led to a reduction in DC activation. This was shown by a decrease in production of the inflammatory markers IL-6, chemokine (C-X-C motif) ligand 1 (CXCL1)/KC, IL-12p70, and TNF-α, as well as a decrease in MHC-II expression, indicating a decrease in DC maturation (147). It also appears that the effects of exercise on different DC subtypes may vary considerably. In a study of an asthma model, a four-week treadmill exercise program led to a reduction of co-stimulatory molecules, CD80, CD86, and inducible T-cell costimulator ligand (ICOSL), in cDCs located in the lymph nodes that drained from the affected areas, and an increase in ICOSL expression in pDCs (148). Human studies have demonstrated that acute exercise causes a transient increase in DCs in the blood and a greater mobilization of pDCs than cDCs (149). In patients suffering from chronically progressive MS or RRMS, an increase in the numbers of cDC and pDC, along with the expression of the cell adhesion molecule CD62 ligand (CD62L) and CCR5, were noticed after a session of endurance and resistance training, and most of the markers did not return to their resting state within two hours of exercising. This increase may be mediated by FMS-like tyrosine kinase 3 ligand (FLT3L)- and MMP-9-dependent DCs mobilization. Acute exercise can potentially reduce the responsiveness of circulating DCs to TLR, thus establishing a negative feedback regulatory mechanism to counteract the heightened inflammatory state resulting from acute exercise (95). In the chronic exercise intervention program, a 12-week training program that combining endurance with resistance exercise significantly increased the absolute number of pDCs in patients with chronically progressive or RRMS. This increase was observed specifically in those pDCs expressing CD80 and CD62L, whereas there were no significant changes in cDCs. Further analysis demonstrated a positive correlation between the quantity of CD80+ pDCs and IL-10-producing Tr1 cells. These findings suggest that regular exercise may enhance the immunomodulatory function of circulating pDCs. Moreover, the exercise program suppressed the production of TNF-α and MMP-9 by DCs in response to TLR activation, indicating that the program could reduce inflammation in individuals (96). Although acute exercise resulted in an elevation of cDCs and pDCs, that is not indicative of an exercise-induced response of DCs contributing to the advancement of an inflammatory state. Additionally, a regular exercise program in PwMS can result in an increase in activated pDCs, and is associated with the occurrence of Tr1 cells. However, only two human investigations have studied the influence of exercise on DCs in MS; further research is necessary on this issue.
2.2.2 Neutrophils
Neutrophils, which originate from the bone marrow, are the most prevalent leukocyte in peripheral blood and are crucial for non-specific host defense. They are responsible for phagocytosis of microbial, bacterial, and viral pathogens, while also producing and releasing cytokines that regulate T cell and B cell activities (150). Several studies have shown that neutrophils in PwMS exhibit a higher quantity and activated phenotype compared to healthy controls. This phenotype is distinguished by an elevated surface expression of TLR-2, N-Formyl-methionyl-leucyl-phenylalanine (fMLP) receptor, IL-8 receptor, and CD43, an increased granule release and oxidative burst, and also higher serum levels of neutrophil extracellular traps (NETs) (151–153). Multiple mechanisms exist through which neutrophils promote MS, including the secretion of inflammatory mediators and enzymes such as IL-1β (154, 155), myeloperoxidase (156), and various proteinases (157, 158), the production of reactive oxygen species (ROS) (159, 160), and antigen presentation to T cells (161). In EAE, a lineage tracing study has demonstrated a significant increase in myelopoiesis in the bone marrow resulting in the enhanced production and subsequent invasion of neutrophils in the CNS (162). The regulation of neutrophil-associated factors, specifically granulocyte colony-stimulating factor (G-CSF) and CXCL1, plays a crucial role in this process (163). Deficiency of the G-CSF receptor and obstruction of CXCL1 lessened myeloid cell accumulation in the bloodstream and ameliorated the clinical outcomes of mice that received injections of myelin-reactive Th17 cells (163). Additionally, the presence of CXCL1, CXCL2, and CXCL6 was essential for the recruitment of neutrophils in the CNS. These chemokines exert their effects via activation of the G protein-coupled receptor CXCR2, which is predominantly expressed on mature neutrophils (164). The existence of neutrophils positive for CXCR2 has been shown to contribute to the process of inflammatory demyelination in demyelination models, such as EAE and CPZ intoxication. In contrast, CXCR2-deficient mice exhibit greater resistance to CPZ-induced demyelination (165). It can be inferred that CXCR2 may be a pivotal molecular target for MS therapy. Additionally, the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) are frequently observed in clinical practice as dependable indicators of inflammation related to various pathologies (166, 167). In PwMS, the NLR has been proposed as a marker of disease activity, with elevated levels displaying a positive association with the severity of MS symptoms (168, 169). Therefore, it may be crucial to monitor neutrophil activity and function to gain understanding of the progression of MS.
The evidence clearly shows that acute exercise affects neutrophil response. At the gene expression level, a study discovered that a brief bout of intense exercise modifies neutrophil gene expression, including the janus kinase (Jak)/STAT pathway involved in apoptosis, and genes linked to inflammation, such as IL-32, TNF receptor superfamily member 8 (TNFSF8), CCR5 and Annexin A1 (ANXA1), in addition to genes related to growth and repair, such as Amphiregulin (AREG) and fibroblast growth factor receptor 2 (FGFR2) genes (170, 171). In terms of activity and function, physical exercise typically induces an initial activation of neutrophils. This is demonstrated through the release of enzymes (172, 173) and subsequent changes in crucial effector functions, including phagocytosis and respiratory burst activity (174, 175). Acute exercise has been shown to attenuate neutrophil apoptosis, possibly by its action on the inducible nitric oxide synthase (iNOS)-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-myeloid cell leukemia 1 (Mcl-1) pathway (176), as well as calcium and redox signaling (177). Furthermore, although acute aerobic exercise was able to increase the number of total circulating neutrophils, the number of neutrophils expressing CXCR2 decreased during the recovery period (178). Previous research indicates that regular, chronic exercise can have a positive impact on neutrophil-mediated immune function in both physiological and pathological conditions. A cross-sectional study involving older adults found that increasing habitual physical activity can potentially enhance neutrophil-mediated immunity (179). Moreover, several months of exercise training not only reduce individual neutrophil chemotaxis and lower IL-8 and noradrenaline concentrations (180), but also enhance deoxyribonuclease (DNase) activity, increasing the ability to degrade NETs (181). In the case of EAE and MS, one study conducted with animals suggested that EAE mice that underwent six weeks of voluntary wheel running prior to the disease had a lower rate of neutrophil infiltration in the spinal cord and lesser severity of EAE in the chronic period (49). Furthermore, three weeks of HIIT programs during inpatient rehabilitation of patients with RRMS or SPMS resulted in a greater decrease of NLR compared to MICT. This could be attributed to the repetitive inflammatory status and compensatory anti-inflammatory balance after each high-intensity exercise, as suggested by Joisten et al. (182). The research shows that regular exercise has the potential to ameliorate the clinical symptoms of MS by modulating the activity of neutrophils.
2.2.3 Microglia/macrophages
Microglia and macrophages are integral components of the mononuclear phagocytic system. They accumulate at the sites of active demyelination and neurodegeneration in the CNS of MS and are believed to be central to the disease process. Evidence suggests an increase in macrophage infiltration into the CNS and exaggerated activation of resident microglia and pathological microgliosis (183, 184). Microglia and macrophages can be classified into two subtypes: the classically activated M1 phenotype, which is associated with inflammatory and degenerative processes, and the alternatively activated M2 phenotype, which has protective properties. In addition to these two subtypes, there may exist intermediate polarization phenotypes (185). Classical activation can be induced by various stimuli such as IFN-γ and LPS. This activation results in the increased expression of antigen presentation related molecules, specifically CD80, CD86, and CD40, which demonstrate a significant ability to present antigens. Furthermore, M1 microglia/macrophages can produce pro-inflammatory cytokines like TNF-α and IL-6, and chemokines such as CCL2 and CCL3, as well as neurotoxic NO. In contrast, M2 microglia/macrophages lack cytotoxicity and can be stimulated by IL-4 and IL-13. They could exhibit raised levels of CD14 and CD163, among other markers, and release anti-inflammatory cytokines such as IL-10 and TGF-β (21, 186). It should be noted that microglia and macrophages play a dual role in the pathology of MS. In the early stages of demyelination and neurodegeneration present in active lesions, microglia with a pro-inflammatory phenotype were observed. They expressed molecules involved in phagocytosis, oxidative injury, antigen presentation, and T cell co-stimulation. In later stages, the microglia and macrophages in active lesions shifted to a phenotype that was intermediate between pro- and anti-inflammatory activation (187). Activated microglia have the ability to directly drive demyelination and are necessary for it (188). Conversely, microglia and monocyte-derived macrophages play a significant role in facilitating efficient remyelination by secreting growth factors and eliminating inhibitory myelin debris (189). Genetic fate mapping and multiphoton live imaging demonstrate that administering niacin at therapeutically relevant doses to demyelinated aged mice assists in clearing myelin debris in lesions through the action of both peripherally-derived macrophages and microglia (190). Moreover, M2 microglia and macrophages were found to drive OLs differentiation during CNS remyelination (191). Notably, the triggering receptor expressed on myeloid cells 2 (TREM2) is believed to play a significant part in the remyelination process. Research indicates that TREM2 is highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of PwMS. Gene expression research indicates that macrophages in individuals with genetic deficiency in TREM2 lack phagocytic pathways (192). Additionally, when TREM2 is deficient, the capability of microglia to phagocytose myelin debris is significantly diminished. These microglia also display impaired mobility and are unable to metabolize cholesterol, leading to deficient remyelination in TREM2-deficient mice (193). However, TREM2 activation in microglia led to increased OPC density in demyelinated regions, contributed to the development of mature OL, which subsequently improved remyelination and axonal integrity (192). Furthermore, regulation of neuroinflammation can be attained by adjusting the dynamic alterations in two phenotypes of microglia/macrophages. It has been recommended that to alleviate clinical symptoms in EAE mice, M1 microglia/macrophage polarization should be suppressed and shifted towards the protective M2 phenotype (194–196). As a result, the regulation of the activation and polarization of microglia/macrophages may be an effective approach to MS pathology.
Accumulated evidence over the past decades suggests that exercise have a considerable impact on macrophage chemotaxis, antigen presentation, phagocytosis, inflammatory cytokine release, antiviral capability, and antitumor activity (197–202). These effects could be attributed to exercise’s regulation of immunometabolism and macrophage polarization. Murugathasan et al. (203) conducted a study which revealed bone marrow-derived macrophages (BMDMs) obtained from mice that underwent eight weeks of moderate-intensity treadmill running exhibited reduced LPS-induced NF-κB activation, decreased expression of pro-inflammatory genes (such as Il-1β and Tnfα), and increased M2-like-associated genes (such as Arg1 and Hmox-1) in contrast to BMDMs from sedentary mice. This was linked to improved mitochondrial quality and higher dependence on oxidative phosphorylation, accompanied by reduced mitochondrial ROS production. Similarly, physical exercise has a wide range of effects on microglia activity and function by modulating the expression of cytokines and their receptors (204) and attenuating oxidative stress (205). Recently, mounting evidence has confirmed the influence of exercise on microglia in the physiology of the CNS and various conditions, such as AD (206–208), PD (209), and cerebral ischemia (210). In MS, the effects of physical exercise on microglia/macrophages can be summarized in three key ways: (i) inhibiting macrophage infiltration into the CNS, (ii) constraining atypical microglia activation and microgliosis at lesion sites, and (iii) inhibiting M1 polarization and promoting M2 polarization. Specifically, the results of a pre-training program, involving either a three-week voluntary wheel running or six-week treadmill running, demonstrated the capacity to restrain the infiltration of macrophages into the spinal cord, which was induced by EAE (49, 211). Regarding CNS-resident microglia, Rizzo et al. (212) showed that engaging in voluntary wheel running for three weeks alleviated microgliosis and reduced the expression of TNF-α and IL-1β in the hippocampal CA1 area of EAE mice. In CPZ-induced mice, six weeks of voluntary wheel running alleviated microgliosis in the striatum and corpus callosum (42). Additionally, regular exercise may lower the number of neurotoxic M1-like phenotype cells while increasing the number of M2-like phenotype cells. Before the induction of EAE by injecting PLP-reactive T-cells, the mice underwent six weeks of HICT, which reduced the number of neurotoxic microglia expressing the ionized calcium binding adapter molecule 1 (Iba1+) and the M1-like marker inducible nitric oxide synthase (iNOS+). The content of pro-inflammatory cytokines IL-6 and MCP-1 secreted by microglia in response to PLP and LPS stimulations also decreased (213). Meanwhile, a daily one-hour voluntary exercise on a wheel reduces the number of Iba1+ microglia/macrophages expressing iNOS in the spinal cord of EAE mice (46). In mice with lysolecithin-induced demyelination, voluntary wheel running for a duration of time augments the M2-like phenotype in the myelin lesions and enhances the phagocytic function of myelin fragments. This reduction in inhibitory lipid debris likely facilitates the prolonged proliferation of OPCs with exercise to produce increased numbers of OLs, ultimately promoting the remyelination process (214). However, other studies have reported negative and contradictory results regarding macrophage infiltration and microgliosis (47, 51, 91) (Table 2). Although there is no data available for humans, research on animals confirms that exercise elicits a response in MS-afflicted microglia/macrophages. In addition, it is noteworthy that several studies have demonstrated the impact of exercise on microglia activation, microglial glucose metabolism, and morphological plasticity by modifying the TREM2 pathway (207, 218). Xu et al. (219) propose that physical exercise can assist in the regeneration of OLs to protect against white matter damage after a stroke. This is primarily achieved by increasing TREM2 and microglia-generated factors. Due to TREM2’s regulatory function in microglia, and its impact on myelin regeneration and neuroinflammation, it is imperative to investigate whether TREM2 can assist physical exercise in mitigating MS pathology in an animal model of MS.
Table 2 Effect of exercise on innate immune cells in animal models and human patients of MS.
2.2.4 Astrocytes
Astrocytes represent the most prevalent type of glial cells in the mammalian brain and perform various physiological functions, including regulating ion homeostasis, neurotransmitter clearance, synapse formation and removal, and neurovascular coupling, among others (220–222). It is noteworthy that astrocyte dysfunction can lead to the development of MS, including neuroinflammation and demyelination. In MS/EAE, the excess activation of astrocytes may foster innate inflammation and neurodegeneration via the production of cytokines such as IL-6, IL-15, and TNF-α, chemokines such as CXCL1, CXCL10, CCL2, and CCL20, and neurotoxic metabolites such as NO (19). Despite being neither immune progenitors nor strictly classified as innate immune cells, astrocytes can perceive inflammatory signals and regulate neuroinflammation. Some studies have suggested a possible connection between abnormal gene expression in astrocytes or metabolic abnormalities and increased neuroinflammation (223–225). Wheeler et al. (226) utilized single-cell RNA sequencing combined with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing, chromatin immunoprecipitation with sequencing, genome-wide analysis of DNA methylation and in vivo CRISPR-Cas9-based genetic perturbations to examine astrocytes in MS and EAE. The results showed that astrocytes in both EAE and MS exhibit reduced expression of Nrf2 and an upregulation of V-maf musculoaponeurotic fibrosarcoma oncogene homolog G (MAFG). MAFG collaborates with methionine adenosyltransferase II alpha (MAT2α) to propagate DNA methylation and impede antioxidant and anti-inflammatory transcriptional programs. GM-CSF signaling in astrocytes induces the expression of MAFG and MAT2α, as well as pro-inflammatory transcriptional modules, which potentially lead to CNS pathology in both EAE and MS. In general, astrocytes experience persistent and extensive activation in response to pathological stimuli, resulting in a reactive state that encompasses two subtypes: A1, characterized by a pro-inflammatory function, and A2, which exerts a protective effect (227). Additionally, numerous studies have identified the beneficial and detrimental roles performed by astrocytes in the process of remyelination. Molina-Gonzalez et al. (228) employed unbiased RNA sequencing, functional manipulation, and rodent models in vivo/ex vivo/in vitro, as well as human brain lesion analyses, to investigate the interaction between astrocytes and OLs during remyelination. The investigation has revealed that astrocytes can promote the survival of regenerating OLs by suppressing the Nrf2 pathway and stimulating the cholesterol biosynthesis pathway. This finding highlights the importance of astrocyte-OL interaction in myelin repair. In contrast, demyelinating lesions exhibit an augmented degree of reactive astrogliosis. Such reactive astrocytes present a hypertrophic phenotype and generate astroglial scars that can create an inhibitory milieu, ultimately obstructing tissue repair (229). Moreover, it has been discovered that irregular copper transportation in astrocytes may lead to demyelination in MS (230). The regulation of reactive astrocytes could hold significant therapeutic potential in the context of inflammation and myelin damage associated with MS.
Similar to microglia and OLs, the effect of physical exercise on the activity and function of astrocytes in the CNS has been widely researched. Appropriate exercise can alter astrocyte activation (231), phenotype (232, 233), remodeling (234, 235), tropic factor release (236), and energy metabolism (237), among others. Furthermore, it can regulate astrocyte-mediated neuroinflammatory responses (234) and intercellular interactions of astrocytes with other cells (238). In mouse models of MS, Bernardes et al. (211) found that a pre-exercise program involving six weeks of treadmill running contributed to a further reduction in astrocyte responses in the dorsal horn of the spinal cord, induced by GA drug therapy in EAE mice after the first relapse. This reduction was demonstrated using glial fibrillary acidic protein (GFAP) immunofluorescence. In addition, simultaneous voluntary wheel running during CPZ-induced demyelination alleviated astrogliosis in the striatum and corpus callosum, while decreasing CXCL10 expression and ameliorating axonal pathology in CPZ-treated mice (42). These findings imply that physical exercise has the potential to mitigate the pathophysiological features of MS through the reduction of the astrocytic response. However, it is important to acknowledge that the human studies have yet to provide concrete evidence for the consistency of these findings. GFAP is released into the cerebrospinal fluid and blood in disorders associated with astrocyte activation and astrogliosis following inflammation and neurodegeneration and therefore is highly expressed in MS lesions (239). In 2021, Ercan et al. (216) conducted a study observing a decrease in serum levels of GFAP and neurofilament light (NFL) after eight weeks of cycling in patients with RRMS. However, a subsequent investigation by Gravesteijn et al. (217) found no statistically significant changes in serum levels of GFAP, brain-derived neurotrophic factor (BDNF), and NFL in PwMS following a 16-week cycling intervention. The amount of relevant research available is restricted and there is a lack of consistency in the results obtained from human trials. Additional research is necessary to obtain a more comprehensive understanding of this issue.
3 Conclusions and perspectives
Both peripheral and CNS immunity are essential for maintaining the proper CNS function. Physical exercise provides direct neuroprotective benefits and induces immunomodulatory effects. However, additional research is necessary to fully understand the impact of physical exercise on autoimmune diseases. In animal models and PwMS, the aberrant functioning of immune cells has been identified as a significant pathological mechanism. The implementation of a moderate exercise program has been shown to effectively limit the infiltration of various peripheral immune cell types, including T lymphocytes, B lymphocytes, neutrophils, dendritic cells, and macrophages, into the CNS. This physiological phenomenon can be attributed to the fact that physical exercise can modify the quantity, functionality, and migratory potential of immune cells and contribute to the establishment of immune cell homeostasis from a pro-inflammatory phenotype to an anti-inflammatory phenotype. For instance, studies have indicated that exercise can promote the differentiation of Treg cells, while inhibiting the differentiation of Th1/Th17 cells, thereby leading to a reduction in IFN-γ and IL-17 production, and an increase in IL-10 and TGF-β production. Additionally, physical exercise has been observed to modulate the structure of the BBB, consequently improving integrity and decreasing permeability. In addition, physical exercise has an impact on resident innate immune cells, specifically microglia and astrocytes in the CNS. This impact mainly manifests as a reduction in the activation of microglia and astrocytes induced by pathological stimuli, as well as a decrease in microgliosis and astrogliosis and the synthesis of pro-inflammatory cytokines (Figure 2). The immunomodulatory responses elicited by exercise may constitute a vital mechanism by which exercise ameliorates myelin and axonal damage, alleviates disease symptoms, and abates clinical scores.
Figure 2 Schematic diagram of the effect of exercise on immune cells in multiple sclerosis. In human patients with MS or animal models, moderate exercise inhibits infiltration of peripheral immune cells including lymphocytes and monocytes, increases anti-inflammatory Th cell differentiation, decreases pro-inflammatory Th cell differentiation, promotes pDC mobilization, and induces macrophage polarization toward the M2 anti-inflammatory phenotype. In addition, exercise also inhibits microglia and astrocyte hyperactivation in the CNS, limits microgliosis and astrogliosis, and promotes microglia polarization toward the M2 anti-inflammatory phenotype. The figure was created using BioRender. pDC, plasmacytoid dendritic cell; Th, T helper cells; Treg, regulatory T cells.
The regulation of immune cells in MS through exercise has attracted growing attention. However, some immune cells, including γ-δT cells, MAIT cells, and natural killer cells, among others, have not yet been investigated. Additionally, current research has some potential limitations. Firstly, so far, most studies have only described alterations in cellular phenotype. Few studies have been undertaken regarding the molecular mechanisms that underlie the effects of exercise on immune cells in MS. Although it has been proposed that exercise could modulate immune cell function by altering immunometabolism in MS (240), the current evidence is insufficient. Furthermore, many transcription factors, including peroxisome proliferator-activated receptor γ (PPAR-γ) (241), and regulators of signaling pathways, such as nuclear factor kappa-B (NF-κB) (242) are involved in regulating immune cell plasticity but have not been explored in MS. Secondly, it is essential to give more consideration to the interaction between the immunomodulatory mechanisms linked to exercise improvement and other mechanisms, such as the release of neurotrophic factors, mitochondrial dysfunction, and oxidative stress. Thirdly, exploration of the disparities in immunomodulatory mechanisms induced by varied experimental protocols in animal studies, such as disease prevention via pre-training, disease progression inhibition via concurrent training, functional improvement through training during remission, presents a fascinating future research topic. Additionally, the effects of exercise alone and exercise combined with other interventions should be actively explored. Finally, despite extensive research and notable advancements in studying animal models, it is important to acknowledge that these models cannot fully replicate the entire spectrum of MS and its clinical manifestations due to significant heterogeneity observed in various disease courses. Therefore, further empirical studies are imperative to validate the efficacy of exercise interventions in ameliorating the disease across diverse types, durations, intensities, and cycles. During the clinical translational phase, it is crucial to provide personalized exercise programs to PwMS to improve functional recovery.
Author contributions
BZ: Writing – original draft, Writing – review & editing, Conceptualization, Funding acquisition, Investigation. FY: Writing – original draft, Writing – review & editing. XZ: Investigation, Writing – review & editing. WZ: Investigation, Writing – review & editing. SL: Writing – review & editing. LL: Writing – review & editing.
Funding
The authors declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Academic Innovation Ability Improvement Program for Outstanding Doctoral Students of East China Normal University [grant number YBNLTS2022-034]; Fundamental Research Funds for the Central Universities [grant number 43800-20102-222000/003/015]; Key Laboratory Construction Project of Adolescent Health Assessment and Exercise Intervention of the Ministry of Education [grant number 40500-22203-542500/001/007/003].
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
1. Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA, et al. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult Scler (2020) 26(14):1816–21. doi: 10.1177/1352458520970841
2. Brownlee WJ, Hardy TA, Fazekas F, Miller DH. Diagnosis of multiple sclerosis: progress and challenges. Lancet (2017) 389(10076):1336–46. doi: 10.1016/S0140-6736(16)30959-X
3. McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and treatment of multiple sclerosis: A review. JAMA (2021) 325(8):765–79. doi: 10.1001/jama.2020.26858
4. Bierhansl L, Hartung HP, Aktas O, Ruck T, Roden M, Meuth SG. Thinking outside the box: non-canonical targets in multiple sclerosis. Nat Rev Drug Discovery (2022) 21(8):578–600. doi: 10.1038/s41573-022-00477-5
5. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology (1983) 33(11):1444–52. doi: 10.1212/wnl.33.11.1444
6. Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O. Multiple sclerosis. Lancet (2018) 391(10130):1622–36. doi: 10.1016/S0140-6736(18)30481-1
7. Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol (2017) 13(1):25–36. doi: 10.1038/nrneurol.2016.187
8. Nave KA. Myelination and support of axonal integrity by glia. Nature (2010) 468(7321):244–52. doi: 10.1038/nature09614
9. Stadelmann C, Timmler S, Barrantes-Freer A, Simons M. Myelin in the central nervous system: structure, function, and pathology. Physiol Rev (2019) 99(3):1381–431. doi: 10.1152/physrev.00031.2018
10. Faissner S, Plemel JR, Gold R, Yong VW. Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nat Rev Drug Discovery (2019) 18(12):905–22. doi: 10.1038/s41573-019-0035-2
11. Charabati M, Wheeler MA, Weiner HL, Quintana FJ. Multiple sclerosis: Neuroimmune crosstalk and therapeutic targeting. Cell (2023) 186(7):1309–27. doi: 10.1016/j.cell.2023.03.008
12. Rodriguez Murua S, Farez MF, Quintana FJ. The immune response in multiple sclerosis. Annu Rev Pathol (2022) 17:121–39. doi: 10.1146/annurev-pathol-052920-040318
13. Prinz M, Priller J. The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci (2017) 20(2):136–44. doi: 10.1038/nn.4475
14. Liu C, Zhu J, Mi Y, Jin T. Impact of disease-modifying therapy on dendritic cells and exploring their immunotherapeutic potential in multiple sclerosis. J Neuroinflammation (2022) 19(1):298. doi: 10.1186/s12974-022-02663-z
15. Pierson ER, Wagner CA, Goverman JM. The contribution of neutrophils to CNS autoimmunity. Clin Immunol (2018) 189:23–8. doi: 10.1016/j.clim.2016.06.017
16. Kamma E, Lasisi W, Libner C, Ng HS, Plemel JR. Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics. J Neuroinflammation (2022) 19(1):45. doi: 10.1186/s12974-022-02408-y
17. Comi G, Bar-Or A, Lassmann H, Uccelli A, Hartung HP, Montalban X, et al. Expert panel of the 27th annual meeting of the european charcot F. Role of B cells in multiple sclerosis and related disorders. Ann Neurol (2021) 89(1):13–23. doi: 10.1002/ana.25927
18. Dong Y, Yong VW. When encephalitogenic T cells collaborate with microglia in multiple sclerosis. Nat Rev Neurol (2019) 15(12):704–17. doi: 10.1038/s41582-019-0253-6
19. Brambilla R. The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol (2019) 137(5):757–83. doi: 10.1007/s00401-019-01980-7
20. Healy LM, Stratton JA, Kuhlmann T, Antel J. The role of glial cells in multiple sclerosis disease progression. Nat Rev Neurol (2022) 18(4):237–48. doi: 10.1038/s41582-022-00624-x
21. Voet S, Prinz M, van Loo G. Microglia in central nervous system inflammation and multiple sclerosis pathology. Trends Mol Med (2019) 25(2):112–23. doi: 10.1016/j.molmed.2018.11.005
22. Jie Z, Ko CJ, Wang H, Xie X, Li Y, Gu M, et al. Microglia promote autoimmune inflammation via the noncanonical NF-kappaB pathway. Sci Adv (2021) 7(36):eabh0609. doi: 10.1126/sciadv.abh0609
23. Absinta M, Maric D, Gharagozloo M, Garton T, Smith MD, Jin J, et al. A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature (2021) 597(7878):709–14. doi: 10.1038/s41586-021-03892-7
24. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature (2017) 541(7638):481–7. doi: 10.1038/nature21029
25. Patejdl R, Zettl UK. Spasticity in multiple sclerosis: Contribution of inflammation, autoimmune mediated neuronal damage and therapeutic interventions. Autoimmun Rev (2017) 16(9):925–36. doi: 10.1016/j.autrev.2017.07.004
26. Di Filippo M, Mancini A, Bellingacci L, Gaetani L, Mazzocchetti P, Zelante T, et al. Interleukin-17 affects synaptic plasticity and cognition in an experimental model of multiple sclerosis. Cell Rep (2021) 37(10):110094. doi: 10.1016/j.celrep.2021.110094
27. Derfuss T, Mehling M, Papadopoulou A, Bar-Or A, Cohen JA, Kappos L. Advances in oral immunomodulating therapies in relapsing multiple sclerosis. Lancet Neurol (2020) 19(4):336–47. doi: 10.1016/S1474-4422(19)30391-6
28. Gilio L, Fresegna D, Gentile A, Guadalupi L, Sanna K, De Vito F, et al. Preventive exercise attenuates IL-2-driven mood disorders in multiple sclerosis. Neurobiol Dis (2022) 172:105817. doi: 10.1016/j.nbd.2022.105817
29. Langeskov-Christensen M, Hvid LG, Nygaard MKE, Ringgaard S, Jensen HB, Nielsen HH, et al. Efficacy of high-intensity aerobic exercise on brain MRI measures in multiple sclerosis. Neurology (2021) 96(2):E203–13. doi: 10.1212/Wnl.0000000000011241
30. Motl RW, Sandroff BM, Kwakkel G, Dalgas U, Feinstein A, Heesen C, et al. Exercise in patients with multiple sclerosis. Lancet Neurol (2017) 16(10):848–56. doi: 10.1016/S1474-4422(17)30281-8
31. Motl RW, Pilutti LA. The benefits of exercise training in multiple sclerosis. Nat Rev Neurol (2012) 8(9):487–97. doi: 10.1038/nrneurol.2012.136
32. De la Rosa A, Olaso-Gonzalez G, Arc-Chagnaud C, Millan F, Salvador-Pascual A, Garcia-Lucerga C, et al. Physical exercise in the prevention and treatment of Alzheimer's disease. J Sport Health Sci (2020) 9(5):394–404. doi: 10.1016/j.jshs.2020.01.004
33. Kjolhede T, Siemonsen S, Wenzel D, Stellmann JP, Ringgaard S, Pedersen BG, et al. Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis? Mult Scler (2018) 24(10):1356–65. doi: 10.1177/1352458517722645
34. Feys P, Moumdjian L, Van Halewyck F, Wens I, Eijnde BO, Van Wijmeersch B, et al. Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis. Mult Scler (2019) 25(1):92–103. doi: 10.1177/1352458517740211
35. Sandroff BM, Wylie GR, Baird JF, Jones CD, Diggs MD, Genova H, et al. Effects of walking exercise training on learning and memory and hippocampal neuroimaging outcomes in MS: A targeted, pilot randomized controlled trial. Contemp Clin Trials (2021) 110:106563. doi: 10.1016/j.cct.2021.106563
36. Albergoni M, Storelli L, Preziosa P, Rocca MA, Filippi M. The insula modulates the effects of aerobic training on cardiovascular function and ambulation in multiple sclerosis. J Neurol (2023) 270(3):1672–81. doi: 10.1007/s00415-022-11513-0
37. Riemenschneider M, Hvid LG, Ringgaard S, Nygaard MKE, Eskildsen SF, Gaemelke T, et al. Investigating the potential disease-modifying and neuroprotective efficacy of exercise therapy early in the disease course of multiple sclerosis: The Early Multiple Sclerosis Exercise Study (EMSES). Mult Scler (2022) 28(10):1620–9. doi: 10.1177/13524585221079200
38. Akbar N, Sandroff BM, Wylie GR, Strober LB, Smith A, Goverover Y, et al. Progressive resistance exercise training and changes in resting-state functional connectivity of the caudate in persons with multiple sclerosis and severe fatigue: A proof-of-concept study. Neuropsychol Rehabil (2020) 30(1):54–66. doi: 10.1080/09602011.2018.1449758
39. Huiskamp M, Moumdjian L, van Asch P, Popescu V, Schoonheim MM, Steenwijk MD, et al. A pilot study of the effects of running training on visuospatial memory in MS: A stronger functional embedding of the hippocampus in the default-mode network? Mult Scler (2020) 26(12):1594–8. doi: 10.1177/1352458519863644
40. Lassmann H, Bradl M. Multiple sclerosis: experimental models and reality. Acta Neuropathol (2017) 133(2):223–44. doi: 10.1007/s00401-016-1631-4
41. Pryor WM, Freeman KG, Larson RD, Edwards GL, White LJ. Chronic exercise confers neuroprotection in experimental autoimmune encephalomyelitis. J Neurosci Res (2015) 93(5):697–706. doi: 10.1002/jnr.23528
42. Mandolesi G, Bullitta S, Fresegna D, De Vito F, Rizzo FR, Musella A, et al. Voluntary running wheel attenuates motor deterioration and brain damage in cuprizone-induced demyelination. Neurobiol Dis (2019) 129:102–17. doi: 10.1016/j.nbd.2019.05.010
43. Kim JY, Yi ES, Lee H, Kim JS, Jee YS, Kim SE, et al. Swimming exercise ameliorates symptoms of MOG-induced experimental autoimmune encephalomyelitis by inhibiting inflammation and demyelination in rats. Int Neurourol J (2020) 24(Suppl 1):S39–47. doi: 10.5213/inj.2040156.078
44. Farahmand F, Nourshahi M, Soleimani M, Rajabi H, Power KE. The effect of 6 weeks of high intensity interval training on myelin biomarkers and demyelination in experimental autoimmune encephalomyelitis model. J Neuroimmunol (2020) 346:577306. doi: 10.1016/j.jneuroim.2020.577306
45. Kim TW, Sung YH. Regular exercise promotes memory function and enhances hippocampal neuroplasticity in experimental autoimmune encephalomyelitis mice. Neuroscience (2017) 346:173–81. doi: 10.1016/j.neuroscience.2017.01.016
46. Benson C, Paylor JW, Tenorio G, Winship I, Baker G, Kerr BJ. Voluntary wheel running delays disease onset and reduces pain hypersensitivity in early experimental autoimmune encephalomyelitis (EAE). Exp Neurol (2015) 271:279–90. doi: 10.1016/j.expneurol.2015.05.017
47. Mifflin KA, Frieser E, Benson C, Baker G, Kerr BJ. Voluntary wheel running differentially affects disease outcomes in male and female mice with experimental autoimmune encephalomyelitis. J Neuroimmunol (2017) 305:135–44. doi: 10.1016/j.jneuroim.2017.02.005
48. Souza PS, Goncalves ED, Pedroso GS, Farias HR, Junqueira SC, Marcon R, et al. Physical exercise attenuates experimental autoimmune encephalomyelitis by inhibiting peripheral immune response and blood-brain barrier disruption. Mol Neurobiol (2017) 54(6):4723–37. doi: 10.1007/s12035-016-0014-0
49. Saffar Kohneh Quchan AH, Kordi MR, Namdari H, Shabkhiz F. Voluntary wheel running stimulates the expression of Nrf-2 and interleukin-10 but suppresses interleukin-17 in experimental autoimmune encephalomyelitis. Neurosci Lett (2020) 738:135382. doi: 10.1016/j.neulet.2020.135382
50. Razi O, Parnow A, Rashidi I, Pakravan N, Nedaei SE, Motl RW. Aerobic training improves blood-brain barrier and neuronal apoptosis in experimental autoimmune encephalomyelitis. Iran J Basic Med Sci (2022) 25(2):245–53. doi: 10.22038/IJBMS.2022.61671.13645
51. Naghibzadeh M, Ranjbar R, Tabandeh MR, Habibi A. Effects of two training programs on transcriptional levels of neurotrophins and glial cells population in hippocampus of experimental multiple sclerosis. Int J Sports Med (2018) 39(8):604–12. doi: 10.1055/a-0608-4635
52. Sajedi D, Shabani R, Elmieh A. Changes in leptin, serotonin, and cortisol after eight weeks of aerobic exercise with probiotic intake in a cuprizone-induced demyelination mouse model of multiple sclerosis. Cytokine (2021) 144:155590. doi: 10.1016/j.cyto.2021.155590
53. Korn T, Kallies A. T cell responses in the central nervous system. Nat Rev Immunol (2017) 17(3):179–94. doi: 10.1038/nri.2016.144
54. Sabatino JJ Jr., Probstel AK, Zamvil SS. B cells in autoimmune and neurodegenerative central nervous system diseases. Nat Rev Neurosci (2019) 20(12):728–45. doi: 10.1038/s41583-019-0233-2
55. Sun L, Su Y, Jiao A, Wang X, Zhang B. T cells in health and disease. Signal Transduct Target Ther (2023) 8(1):235. doi: 10.1038/s41392-023-01471-y
56. Zuroff L, Rezk A, Shinoda K, Espinoza DA, Elyahu Y, Zhang B, et al. Immune aging in multiple sclerosis is characterized by abnormal CD4 T cell activation and increased frequencies of cytotoxic CD4 T cells with advancing age. EBioMedicine (2022) 82:104179. doi: 10.1016/j.ebiom.2022.104179
57. Bronge M, Ruhrmann S, Carvalho-Queiroz C, Nilsson OB, Kaiser A, Holmgren E, et al. Myelin oligodendrocyte glycoprotein revisited-sensitive detection of MOG-specific T-cells in multiple sclerosis. J Autoimmun (2019) 102:38–49. doi: 10.1016/j.jaut.2019.04.013
58. Dong C. Cytokine regulation and function in T cells. Annu Rev Immunol (2021) 39:51–76. doi: 10.1146/annurev-immunol-061020-053702
59. Murphy AC, Lalor SJ, Lynch MA, Mills KH. Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun (2010) 24(4):641–51. doi: 10.1016/j.bbi.2010.01.014
60. Hu X, Huang F, Wang ZJ. CaMKIIalpha mediates the effect of IL-17 to promote ongoing spontaneous and evoked pain in multiple sclerosis. J Neurosci (2018) 38(1):232–44. doi: 10.1523/JNEUROSCI.2666-17.2017
61. Scheinecker C, Goschl L, Bonelli M. Treg cells in health and autoimmune diseases: New insights from single cell analysis. J Autoimmun (2020) 110:102376. doi: 10.1016/j.jaut.2019.102376
62. Carbone F, De Rosa V, Carrieri PB, Montella S, Bruzzese D, Porcellini A, et al. Regulatory T cell proliferative potential is impaired in human autoimmune disease. Nat Med (2014) 20(1):69–74. doi: 10.1038/nm.3411
63. Farez MF, Mascanfroni ID, Mendez-Huergo SP, Yeste A, Murugaiyan G, Garo LP, et al. Melatonin contributes to the seasonality of multiple sclerosis relapses. Cell (2015) 162(6):1338–52. doi: 10.1016/j.cell.2015.08.025
64. Thome R, Casella G, Lotfi N, Ishikawa LWL, Wang Q, Ciric B, et al. Primaquine elicits Foxp3(+) regulatory T cells with a superior ability to limit CNS autoimmune inflammation. J Autoimmun (2020) 114:102505. doi: 10.1016/j.jaut.2020.102505
65. Ma A, Xiong Z, Hu Y, Qi S, Song L, Dun H, et al. Dysfunction of IL-10-producing type 1 regulatory T cells and CD4(+)CD25(+) regulatory T cells in a mimic model of human multiple sclerosis in Cynomolgus monkeys. Int Immunopharmacol (2009) 9(5):599–608. doi: 10.1016/j.intimp.2009.01.034
66. Wagner A, Wang C, Fessler J, DeTomaso D, Avila-Pacheco J, Kaminski J, et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell (2021) 184(16):4168–4185 e21. doi: 10.1016/j.cell.2021.05.045
67. Aso K, Kono M, Kanda M, Kudo Y, Sakiyama K, Hisada R, et al. Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming. Nat Commun (2023) 14(1):984. doi: 10.1038/s41467-023-36594-x
68. Zhao Z, Bao XQ, Zhang Z, Li F, Liu H, Zhang D. Novel phloroglucinol derivative Compound 21 protects experimental autoimmune encephalomyelitis rats via inhibiting Th1/Th17 cell infiltration. Brain Behav Immun (2020) 87:751–64. doi: 10.1016/j.bbi.2020.03.009
69. Kuo PC, Brown DA, Scofield BA, Paraiso HC, Wang PY, Yu IC, et al. Dithiolethione ACDT suppresses neuroinflammation and ameliorates disease severity in experimental autoimmune encephalomyelitis. Brain Behav Immun (2018) 70:76–87. doi: 10.1016/j.bbi.2018.03.010
70. Duscha A, Gisevius B, Hirschberg S, Yissachar N, Stangl GI, Eilers E, et al. Propionic acid shapes the multiple sclerosis disease course by an immunomodulatory mechanism. Cell (2020) 180(6):1067–1080 e16. doi: 10.1016/j.cell.2020.02.035
71. Huber M, Heink S, Pagenstecher A, Reinhard K, Ritter J, Visekruna A, et al. IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis. J Clin Invest (2013) 123(1):247–60. doi: 10.1172/JCI63681
72. Kaskow BJ, Baecher-Allan C. Effector T cells in multiple sclerosis. Cold Spring Harb Perspect Med (2018) 8(4):a029025. doi: 10.1101/cshperspect.a029025
73. Fransen NL, Hsiao CC, van der Poel M, Engelenburg HJ, Verdaasdonk K, Vincenten MCJ, et al. Tissue-resident memory T cells invade the brain parenchyma in multiple sclerosis white matter lesions. Brain (2020) 143(6):1714–30. doi: 10.1093/brain/awaa117
74. MaChado-Santos J, Saji E, Troscher AR, Paunovic M, Liblau R, Gabriely G, et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain (2018) 141(7):2066–82. doi: 10.1093/brain/awy151
75. Aydin S, Pareja J, Schallenberg VM, Klopstein A, Gruber T, Page N, et al. Antigen recognition detains CD8(+) T cells at the blood-brain barrier and contributes to its breakdown. Nat Commun (2023) 14(1):3106. doi: 10.1038/s41467-023-38703-2
76. Saxena A, Bauer J, Scheikl T, Zappulla J, Audebert M, Desbois S, et al. Cutting edge: Multiple sclerosis-like lesions induced by effector CD8 T cells recognizing a sequestered antigen on oligodendrocytes. J Immunol (2008) 181(3):1617–21. doi: 10.4049/jimmunol.181.3.1617
77. Kirby L, Jin J, Cardona JG, Smith MD, Martin KA, Wang J, et al. Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination. Nat Commun (2019) 10(1):3887. doi: 10.1038/s41467-019-11638-3
78. Sauer BM, Schmalstieg WF, Howe CL. Axons are injured by antigen-specific CD8(+) T cells through a MHC class I- and granzyme B-dependent mechanism. Neurobiol Dis (2013) 59:194–205. doi: 10.1016/j.nbd.2013.07.010
79. Mangalam AK, Luckey D, Giri S, Smart M, Pease LR, Rodriguez M, et al. Two discreet subsets of CD8 T cells modulate PLP(91-110) induced experimental autoimmune encephalomyelitis in HLA-DR3 transgenic mice. J Autoimmun (2012) 38(4):344–53. doi: 10.1016/j.jaut.2012.02.004
80. York NR, Mendoza JP, Ortega SB, Benagh A, Tyler AF, Firan M, et al. Immune regulatory CNS-reactive CD8+T cells in experimental autoimmune encephalomyelitis. J Autoimmun (2010) 35(1):33–44. doi: 10.1016/j.jaut.2010.01.003
81. Cencioni MT, Mattoscio M, Magliozzi R, Bar-Or A, Muraro PA. B cells in multiple sclerosis - from targeted depletion to immune reconstitution therapies. Nat Rev Neurol (2021) 17(7):399–414. doi: 10.1038/s41582-021-00498-5
82. Jelcic I, Al Nimer F, Wang J, Lentsch V, Planas R, Jelcic I, et al. Memory B cells activate brain-homing, autoreactive CD4(+) T cells in multiple sclerosis. Cell (2018) 175(1):85–100 e23. doi: 10.1016/j.cell.2018.08.011
83. Li R, Patterson KR, Bar-Or A. Reassessing B cell contributions in multiple sclerosis. Nat Immunol (2018) 19(7):696–707. doi: 10.1038/s41590-018-0135-x
84. Bhargava P, Hartung HP, Calabresi PA. Contribution of B cells to cortical damage in multiple sclerosis. Brain (2022) 145(10):3363–73. doi: 10.1093/brain/awac233
85. Sharif K, Watad A, Bragazzi NL, Lichtbroun M, Amital H, Shoenfeld Y. Physical activity and autoimmune diseases: Get moving and manage the disease. Autoimmun Rev (2018) 17(1):53–72. doi: 10.1016/j.autrev.2017.11.010
86. Einstein O, Fainstein N, Touloumi O, Lagoudaki R, Hanya E, Grigoriadis N, et al. Exercise training attenuates experimental autoimmune encephalomyelitis by peripheral immunomodulation rather than direct neuroprotection. Exp Neurol (2018) 299(Pt A):56–64. doi: 10.1016/j.expneurol.2017.10.008
87. Fainstein N, Tyk R, Touloumi O, Lagoudaki R, Goldberg Y, Agranyoni O, et al. Exercise intensity-dependent immunomodulatory effects on encephalomyelitis. Ann Clin Transl Neurol (2019) 6(9):1647–58. doi: 10.1002/acn3.50859
88. Goldberg Y, Fainstein N, Zaychik Y, Hamdi L, Segal S, Nabat H, et al. Continuous and interval training attenuate encephalomyelitis by separate immunomodulatory mechanisms. Ann Clin Transl Neurol (2021) 8(1):190–200. doi: 10.1002/acn3.51267
89. Bernardes D, Brambilla R, Bracchi-Ricard V, Karmally S, Dellarole A, Carvalho-Tavares J, et al. Prior regular exercise improves clinical outcome and reduces demyelination and axonal injury in experimental autoimmune encephalomyelitis. J Neurochem (2016) 136 Suppl 1:63–73. doi: 10.1111/jnc.13354
90. Xie Y, Li Z, Wang Y, Xue X, Ma W, Zhang Y, et al. Effects of moderate- versus high- intensity swimming training on inflammatory and CD4(+) T cell subset profiles in experimental autoimmune encephalomyelitis mice. J Neuroimmunol (2019) 328:60–7. doi: 10.1016/j.jneuroim.2018.12.005
91. Rossi S, Furlan R, De Chiara V, Musella A, Lo Giudice T, Mataluni G, et al. Exercise attenuates the clinical, synaptic and dendritic abnormalities of experimental autoimmune encephalomyelitis. Neurobiol Dis (2009) 36(1):51–9. doi: 10.1016/j.nbd.2009.06.013
92. Mifflin KA, Yousuf MS, Thorburn KC, Huang J, Perez-Munoz ME, Tenorio G, et al. Voluntary wheel running reveals sex-specific nociceptive factors in murine experimental autoimmune encephalomyelitis. Pain (2019) 160(4):870–81. doi: 10.1097/j.pain.0000000000001465
93. El-Emam MA, El Achy S, Abdallah DM, El-Abhar HS, Gowayed MA. Neuroprotective role of galantamine with/without physical exercise in experimental autoimmune encephalomyelitis in rats. Life Sci (2021) 277:119459. doi: 10.1016/j.lfs.2021.119459
94. Chen H, Shen L, Liu Y, Ma X, Long L, Ma X, et al. Strength exercise confers protection in central nervous system autoimmunity by altering the gut microbiota. Front Immunol (2021) 12:628629. doi: 10.3389/fimmu.2021.628629
95. Deckx N, Wens I, Nuyts AH, Lee WP, Hens N, Koppen G, et al. Rapid exercise-induced mobilization of dendritic cells is potentially mediated by a Flt3L- and MMP-9-dependent process in multiple sclerosis. Mediators Inflamm (2015) 2015:158956. doi: 10.1155/2015/158956
96. Deckx N, Wens I, Nuyts AH, Hens N, De Winter BY, Koppen G, et al. 12 weeks of combined endurance and resistance training reduces innate markers of inflammation in a randomized controlled clinical trial in patients with multiple sclerosis. Mediators Inflamm (2016) 2016:6789276. doi: 10.1155/2016/6789276
97. Alvarenga-Filho H, Sacramento PM, Ferreira TB, Hygino J, Abreu JEC, Carvalho SR, et al. Combined exercise training reduces fatigue and modulates the cytokine profile of T-cells from multiple sclerosis patients in response to neuromediators. J Neuroimmunol (2016) 293:91–9. doi: 10.1016/j.jneuroim.2016.02.014
98. Mahler A, Balogh A, Csizmadia I, Klug L, Kleinewietfeld M, Steiniger J, et al. Metabolic, mental and immunological effects of normoxic and hypoxic training in multiple sclerosis patients: A pilot study. Front Immunol (2018) 9:2819. doi: 10.3389/fimmu.2018.02819
99. Proschmann U, Shalchi-Amirkhiz P, Andres P, Haase R, Inojosa H, Ziemssen T, et al. Influence of exercise on quantity and deformability of immune cells in multiple sclerosis. Front Neurol (2023) 14:1148106. doi: 10.3389/fneur.2023.1148106
100. Siedlik JA, Benedict SH, Landes EJ, Weir JP, Vardiman JP, Gallagher PM. Acute bouts of exercise induce a suppressive effect on lymphocyte proliferation in human subjects: A meta-analysis. Brain Behav Immun (2016) 56:343–51. doi: 10.1016/j.bbi.2016.04.008
101. Waschbisch A, Wenny I, Tallner A, Schwab S, Pfeifer K, Maurer M. Physical activity in multiple sclerosis: a comparative study of vitamin D, brain-derived neurotrophic factor and regulatory T cell populations. Eur Neurol (2012) 68(2):122–8. doi: 10.1159/000337904
102. Liebner S, Dijkhuizen RM, Reiss Y, Plate KH, Agalliu D, Constantin G. Functional morphology of the blood-brain barrier in health and disease. Acta Neuropathol (2018) 135(3):311–36. doi: 10.1007/s00401-018-1815-1
103. Spencer JI, Bell JS, DeLuca GC. Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier. J Neurol Neurosurg Psychiatry (2018) 89(1):42–52. doi: 10.1136/jnnp-2017-316011
104. Zimmer P, Bloch W, Schenk A, Oberste M, Riedel S, Kool J, et al. High-intensity interval exercise improves cognitive performance and reduces matrix metalloproteinases-2 serum levels in persons with multiple sclerosis: A randomized controlled trial. Mult Scler (2018) 24(12):1635–44. doi: 10.1177/1352458517728342
105. Gerwien H, Hermann S, Zhang X, Korpos E, Song J, Kopka K, et al. Imaging matrix metalloproteinase activity in multiple sclerosis as a specific marker of leukocyte penetration of the blood-brain barrier. Sci Transl Med (2016) 8(364):364ra152. doi: 10.1126/scitranslmed.aaf8020
106. Mokhtarzade M, Motl R, Negaresh R, Zimmer P, Khodadoost M, Baker JS, et al. Exercise-induced changes in neurotrophic factors and markers of blood-brain barrier permeability are moderated by weight status in multiple sclerosis. Neuropeptides (2018) 70:93–100. doi: 10.1016/j.npep.2018.05.010
107. Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med (2007) 13(10):1173–5. doi: 10.1038/nm1651
108. Malkiewicz MA, Szarmach A, Sabisz A, Cubala WJ, Szurowska E, Winklewski PJ. Blood-brain barrier permeability and physical exercise. J Neuroinflammation (2019) 16(1):15. doi: 10.1186/s12974-019-1403-x
109. Proschinger S, Joisten N, Rademacher A, Schlagheck ML, Walzik D, Metcalfe AJ, et al. Influence of combined functional resistance and endurance exercise over 12 weeks on matrix metalloproteinase-2 serum concentration in persons with relapsing-remitting multiple sclerosis - a community-based randomized controlled trial. BMC Neurol (2019) 19(1):314. doi: 10.1186/s12883-019-1544-7
110. Lochhead JJ, Yang J, Ronaldson PT, Davis TP. Structure, function, and regulation of the blood-brain barrier tight junction in central nervous system disorders. Front Physiol (2020) 11:914. doi: 10.3389/fphys.2020.00914
111. Marchetti L, Engelhardt B. Immune cell trafficking across the blood-brain barrier in the absence and presence of neuroinflammation. Vasc Biol (2020) 2(1):H1–H18. doi: 10.1530/VB-19-0033
112. Wang D, Li SP, Fu JS, Zhang S, Bai L, Guo L. Resveratrol defends blood-brain barrier integrity in experimental autoimmune encephalomyelitis mice. J Neurophysiol (2016) 116(5):2173–9. doi: 10.1152/jn.00510.2016
113. Huang J, Han S, Sun Q, Zhao Y, Liu J, Yuan X, et al. Kv1.3 channel blocker (ImKTx88) maintains blood-brain barrier in experimental autoimmune encephalomyelitis. Cell Biosci (2017) 7:31. doi: 10.1186/s13578-017-0158-2
114. Hamdi L, Nabat H, Goldberg Y, Fainstein N, Segal S, Mediouni E, et al. Exercise training alters autoimmune cell invasion into the brain in autoimmune encephalomyelitis. Ann Clin Transl Neurol (2022) 9(11):1792–806. doi: 10.1002/acn3.51677
115. i MCEasbue, i MC. Gut microbiome of multiple sclerosis patients and paired household healthy controls reveal associations with disease risk and course. Cell (2022) 185(19):3467–3486 e16. doi: 10.1016/j.cell.2022.08.021
116. Correale J, Hohlfeld R, Baranzini SE. The role of the gut microbiota in multiple sclerosis. Nat Rev Neurol (2022) 18(9):544–58. doi: 10.1038/s41582-022-00697-8
117. Thirion F, Sellebjerg F, Fan Y, Lyu L, Hansen TH, Pons N, et al. The gut microbiota in multiple sclerosis varies with disease activity. Genome Med (2023) 15(1):1. doi: 10.1186/s13073-022-01148-1
118. Cantoni C, Lin Q, Dorsett Y, Ghezzi L, Liu Z, Pan Y, et al. Alterations of host-gut microbiome interactions in multiple sclerosis. EBioMedicine (2022) 76:103798. doi: 10.1016/j.ebiom.2021.103798
119. Miyauchi E, Kim SW, Suda W, Kawasumi M, Onawa S, Taguchi-Atarashi N, et al. Gut microorganisms act together to exacerbate inflammation in spinal cords. Nature (2020) 585(7823):102–6. doi: 10.1038/s41586-020-2634-9
120. Cignarella F, Cantoni C, Ghezzi L, Salter A, Dorsett Y, Chen L, et al. Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota. Cell Metab (2018) 27(6):1222–1235 e6. doi: 10.1016/j.cmet.2018.05.006
121. Kadowaki A, Saga R, Lin Y, Sato W, Yamamura T. Gut microbiota-dependent CCR9+CD4+ T cells are altered in secondary progressive multiple sclerosis. Brain (2019) 142(4):916–31. doi: 10.1093/brain/awz012
122. Kadowaki A, Quintana FJ. The gut-CNS axis in multiple sclerosis. Trends Neurosci (2020) 43(8):622–34. doi: 10.1016/j.tins.2020.06.002
123. Dohnalova L, Lundgren P, Carty JRE, Goldstein N, Wenski SL, Nanudorn P, et al. A microbiome-dependent gut-brain pathway regulates motivation for exercise. Nature (2022) 612(7941):739–47. doi: 10.1038/s41586-022-05525-z
124. Liu Y, Wang Y, Ni Y, Cheung CKY, Lam KSL, Wang Y, et al. Gut microbiome fermentation determines the efficacy of exercise for diabetes prevention. Cell Metab (2020) 31(1):77–91 e5. doi: 10.1016/j.cmet.2019.11.001
125. O'Sullivan O, Cronin O, Clarke SF, Murphy EF, Molloy MG, Shanahan F, et al. Exercise and the microbiota. Gut Microbes (2015) 6(2):131–6. doi: 10.1080/19490976.2015.1011875
126. Barone M, Mendozzi L, D'Amico F, Saresella M, Rampelli S, Piancone F, et al. Influence of a high-impact multidimensional rehabilitation program on the gut microbiota of patients with multiple sclerosis. Int J Mol Sci (2021) 22(13):7173. doi: 10.3390/ijms22137173
127. Mokhtarzade M, Molanouri Shamsi M, Abolhasani M, Bakhshi B, Sahraian MA, Quinn LS, et al. Home-based exercise training influences gut bacterial levels in multiple sclerosis. Complement Ther Clin Pract (2021) 45:101463. doi: 10.1016/j.ctcp.2021.101463
128. Comabella M, Montalban X, Munz C, Lunemann JD. Targeting dendritic cells to treat multiple sclerosis. Nat Rev Neurol (2010) 6(9):499–507. doi: 10.1038/nrneurol.2010.112
129. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature (1998) 392(6673):245–52. doi: 10.1038/32588
130. Poppensieker K, Otte DM, Schurmann B, Limmer A, Dresing P, Drews E, et al. CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells. Proc Natl Acad Sci U S A (2012) 109(10):3897–902. doi: 10.1073/pnas.1114153109
131. Ruland C, Renken H, Kuzmanov I, Fattahi Mehr A, Schwarte K, Cerina M, et al. Chemokine CCL17 is expressed by dendritic cells in the CNS during experimental autoimmune encephalomyelitis and promotes pathogenesis of disease. Brain Behav Immun (2017) 66:382–93. doi: 10.1016/j.bbi.2017.06.010
132. Ilarregui JM, Croci DO, Bianco GA, Toscano MA, Salatino M, Vermeulen ME, et al. Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat Immunol (2009) 10(9):981–91. doi: 10.1038/ni.1772
133. Huang YM, Kouwenhoven M, Jin YP, Press R, Huang WX, Link H. Dendritic cells derived from patients with multiple sclerosis show high CD1a and low CD86 expression. Mult Scler (2001) 7(2):95–9. doi: 10.1177/135245850100700204
134. Li C, Bi Y, Li Y, Yang H, Yu Q, Wang J, et al. Dendritic cell MST1 inhibits Th17 differentiation. Nat Commun (2017) 8:14275. doi: 10.1038/ncomms14275
135. Zhou L, Yao L, Zhang Q, Xie W, Wang X, Zhang H, et al. REGgamma controls Th17 cell differentiation and autoimmune inflammation by regulating dendritic cells. Cell Mol Immunol (2020) 17(11):1136–47. doi: 10.1038/s41423-019-0287-0
136. Kim TW, Kim Y, Jung W, Kim DE, Keum H, Son Y, et al. Bilirubin nanomedicine ameliorates the progression of experimental autoimmune encephalomyelitis by modulating dendritic cells. J Control Release (2021) 331:74–84. doi: 10.1016/j.jconrel.2021.01.019
137. Shen PX, Li X, Deng SY, Zhao L, Zhang YY, Deng X, et al. Urolithin A ameliorates experimental autoimmune encephalomyelitis by targeting aryl hydrocarbon receptor. EBioMedicine (2021) 64:103227. doi: 10.1016/j.ebiom.2021.103227
138. Wang J, Wang J, Hong W, Zhang L, Song L, Shi Q, et al. Optineurin modulates the maturation of dendritic cells to regulate autoimmunity through JAK2-STAT3 signaling. Nat Commun (2021) 12(1):6198. doi: 10.1038/s41467-021-26477-4
139. von Glehn F, Pochet N, Thapa B, Raheja R, Mazzola MA, Jangi S, et al. Defective induction of IL-27-mediated immunoregulation by myeloid DCs in multiple sclerosis. Int J Mol Sci (2023) 24(9):8000. doi: 10.3390/ijms24098000
140. Stasiolek M, Bayas A, Kruse N, Wieczarkowiecz A, Toyka KV, Gold R, et al. Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis. Brain (2006) 129(Pt 5):1293–305. doi: 10.1093/brain/awl043
141. Bosnjak B, Do KTH, Forster R, Hammerschmidt SI. Imaging dendritic cell functions. Immunol Rev (2022) 306(1):137–63. doi: 10.1111/imr.13050
142. Giles DA, Duncker PC, Wilkinson NM, Washnock-Schmid JM, Segal BM. CNS-resident classical DCs play a critical role in CNS autoimmune disease. J Clin Invest (2018) 128(12):5322–34. doi: 10.1172/JCI123708
143. Reizis B. Plasmacytoid dendritic cells: development, regulation, and function. Immunity (2019) 50(1):37–50. doi: 10.1016/j.immuni.2018.12.027
144. Thewissen K, Nuyts AH, Deckx N, Van Wijmeersch B, Nagels G, D'Hooghe M, et al. Circulating dendritic cells of multiple sclerosis patients are proinflammatory and their frequency is correlated with MS-associated genetic risk factors. Mult Scler (2014) 20(5):548–57. doi: 10.1177/1352458513505352
145. Schwab N, Zozulya AL, Kieseier BC, Toyka KV, Wiendl H. An imbalance of two functionally and phenotypically different subsets of plasmacytoid dendritic cells characterizes the dysfunctional immune regulation in multiple sclerosis. J Immunol (2010) 184(9):5368–74. doi: 10.4049/jimmunol.0903662
146. Chiang LM, Chen YJ, Chiang J, Lai LY, Chen YY, Liao HF. Modulation of dendritic cells by endurance training. Int J Sports Med (2007) 28(9):798–803. doi: 10.1055/s-2007-964914
147. Mackenzie B, Andrade-Sousa AS, Oliveira-Junior MC, Assumpcao-Neto E, Brandao-Rangel MA, Silva-Renno A, et al. Dendritic cells are involved in the effects of exercise in a model of asthma. Med Sci Sports Exerc (2016) 48(8):1459–67. doi: 10.1249/MSS.0000000000000927
148. Fernandes P, de Mendonca Oliveira L, Bruggemann TR, Sato MN, Olivo CR, Arantes-Costa FM. Physical exercise induces immunoregulation of TREG, M2, and pDCs in a lung allergic inflammation model. Front Immunol (2019) 10:854. doi: 10.3389/fimmu.2019.00854
149. Brown FF, Campbell JP, Wadley AJ, Fisher JP, Aldred S, Turner JE. Acute aerobic exercise induces a preferential mobilisation of plasmacytoid dendritic cells into the peripheral blood in man. Physiol Behav (2018) 194:191–8. doi: 10.1016/j.physbeh.2018.05.012
150. de Oliveira S, Rosowski EE, Huttenlocher A. Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol (2016) 16(6):378–91. doi: 10.1038/nri.2016.49
151. Naegele M, Tillack K, Reinhardt S, Schippling S, Martin R, Sospedra M. Neutrophils in multiple sclerosis are characterized by a primed phenotype. J Neuroimmunol (2012) 242(1-2):60–71. doi: 10.1016/j.jneuroim.2011.11.009
152. Hertwig L, Pache F, Romero-Suarez S, Sturner KH, Borisow N, Behrens J, et al. Distinct functionality of neutrophils in multiple sclerosis and neuromyelitis optica. Mult Scler (2016) 22(2):160–73. doi: 10.1177/1352458515586084
153. Haschka D, Tymoszuk P, Bsteh G, Petzer V, Berek K, Theurl I, et al. Expansion of neutrophils and classical and nonclassical monocytes as a hallmark in relapsing-remitting multiple sclerosis. Front Immunol (2020) 11:594. doi: 10.3389/fimmu.2020.00594
154. McGinley AM, Sutton CE, Edwards SC, Leane CM, DeCourcey J, Teijeiro A, et al. Interleukin-17A serves a priming role in autoimmunity by recruiting IL-1beta-producing myeloid cells that promote pathogenic T cells. Immunity (2020) 52(2):342–356 e6. doi: 10.1016/j.immuni.2020.01.002
155. Levesque SA, Pare A, Mailhot B, Bellver-Landete V, Kebir H, Lecuyer MA, et al. Myeloid cell transmigration across the CNS vasculature triggers IL-1beta-driven neuroinflammation during autoimmune encephalomyelitis in mice. J Exp Med (2016) 213(6):929–49. doi: 10.1084/jem.20151437
156. Pulli B, Bure L, Wojtkiewicz GR, Iwamoto Y, Ali M, Li D, et al. Multiple sclerosis: myeloperoxidase immunoradiology improves detection of acute and chronic disease in experimental model. Radiology (2015) 275(2):480–9. doi: 10.1148/radiol.14141495
157. Harada Y, Zhang J, Imari K, Yamasaki R, Ni J, Wu Z, et al. Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis. Pain (2019) 160(9):2050–62. doi: 10.1097/j.pain.0000000000001596
158. Skinner DD, Syage AR, Olivarria GM, Stone C, Hoglin B, Lane TE. Sustained infiltration of neutrophils into the CNS results in increased demyelination in a viral-induced model of multiple sclerosis. Front Immunol (2022) 13:931388. doi: 10.3389/fimmu.2022.931388
159. Khaw YM, Cunningham C, Tierney A, Sivaguru M, Inoue M. Neutrophil-selective deletion of Cxcr2 protects against CNS neurodegeneration in a mouse model of multiple sclerosis. J Neuroinflammation (2020) 17(1):49. doi: 10.1186/s12974-020-1730-y
160. Yan Z, Yang W, Parkitny L, Gibson SA, Lee KS, Collins F, et al. Deficiency of Socs3 leads to brain-targeted EAE via enhanced neutrophil activation and ROS production. JCI Insight (2019) 5(9):e126520. doi: 10.1172/jci.insight.126520
161. Wlodarczyk A, Lobner M, Cedile O, Owens T. Comparison of microglia and infiltrating CD11c(+) cells as antigen presenting cells for T cell proliferation and cytokine response. J Neuroinflammation (2014) 11:57. doi: 10.1186/1742-2094-11-57
162. Shi K, Li H, Chang T, He W, Kong Y, Qi C, et al. Bone marrow hematopoiesis drives multiple sclerosis progression. Cell (2022) 185(13):2234–2247 e17. doi: 10.1016/j.cell.2022.05.020
163. Rumble JM, Huber AK, Krishnamoorthy G, Srinivasan A, Giles DA, Zhang X, et al. Neutrophil-related factors as biomarkers in EAE and MS. J Exp Med (2015) 212(1):23–35. doi: 10.1084/jem.20141015
164. Casserly CS, Nantes JC, Whittaker Hawkins RF, Vallieres L. Neutrophil perversion in demyelinating autoimmune diseases: Mechanisms to medicine. Autoimmun Rev (2017) 16(3):294–307. doi: 10.1016/j.autrev.2017.01.013
165. Liu L, Belkadi A, Darnall L, Hu T, Drescher C, Cotleur AC, et al. CXCR2-positive neutrophils are essential for cuprizone-induced demyelination: relevance to multiple sclerosis. Nat Neurosci (2010) 13(3):319–26. doi: 10.1038/nn.2491
166. Mezquita L, Auclin E, Ferrara R, Charrier M, Remon J, Planchard D, et al. Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer. JAMA Oncol (2018) 4(3):351–7. doi: 10.1001/jamaoncol.2017.4771
167. Wang RH, Wen WX, Jiang ZP, Du ZP, Ma ZH, Lu AL, et al. The clinical value of neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), platelet-to-lymphocyte ratio (PLR) and systemic inflammation response index (SIRI) for predicting the occurrence and severity of pneumonia in patients with intracerebral hemorrhage. Front Immunol (2023) 14:1115031. doi: 10.3389/fimmu.2023.1115031
168. D'Amico E, Zanghi A, Romano A, Sciandra M, Palumbo GAM, Patti F. The neutrophil-to-lymphocyte ratio is related to disease activity in relapsing remitting multiple sclerosis. Cells (2019) 8(10):1114. doi: 10.3390/cells8101114
169. Fahmi RM, Ramadan BM, Salah H, Elsaid AF, Shehta N. Neutrophil-lymphocyte ratio as a marker for disability and activity in multiple sclerosis. Mult Scler Relat Disord (2021) 51:102921. doi: 10.1016/j.msard.2021.102921
170. Radom-Aizik S, Zaldivar F Jr., Leu SY, Galassetti P, Cooper DM. Effects of 30 min of aerobic exercise on gene expression in human neutrophils. J Appl Physiol (1985) (2008) 104(1):236–43. doi: 10.1152/japplphysiol.00872.2007
171. Radom-Aizik S, Zaldivar F Jr., Oliver S, Galassetti P, Cooper DM. Evidence for microRNA involvement in exercise-associated neutrophil gene expression changes. J Appl Physiol (1985) (2010) 109(1):252–61. doi: 10.1152/japplphysiol.01291.2009
172. Ferrer MD, Tauler P, Sureda A, Tur JA, Pons A. Antioxidant regulatory mechanisms in neutrophils and lymphocytes after intense exercise. J Sports Sci (2009) 27(1):49–58. doi: 10.1080/02640410802409683
173. Sureda A, Ferrer MD, Tauler P, Maestre I, Aguilo A, Cordova A, et al. Intense physical activity enhances neutrophil antioxidant enzyme gene expression. Immunocytochemistry evidence for catalase secretion. Free Radic Res (2007) 41(8):874–83. doi: 10.1080/10715760701416459
174. Braz GR, Ferreira DS, Pedroza AA, da Silva AI, Sousa SM, Pithon-Curi TC, et al. Effect of moderate exercise on peritoneal neutrophils from juvenile rats. Appl Physiol Nutr Metab (2015) 40(9):959–62. doi: 10.1139/apnm-2015-0056
175. Murphy EA, Davis JM, Brown AS, Carmichael MD, Ghaffar A, Mayer EP. Oat beta-glucan effects on neutrophil respiratory burst activity following exercise. Med Sci Sports Exerc (2007) 39(4):639–44. doi: 10.1249/mss.0b013e3180306309
176. Su SH, Jen CJ, Chen HI. NO signaling in exercise training-induced anti-apoptotic effects in human neutrophils. Biochem Biophys Res Commun (2011) 405(1):58–63. doi: 10.1016/j.bbrc.2010.12.123
177. Mooren FC, Volker K, Klocke R, Nikol S, Waltenberger J, Kruger K. Exercise delays neutrophil apoptosis by a G-CSF-dependent mechanism. J Appl Physiol (1985) (2012) 113(7):1082–90. doi: 10.1152/japplphysiol.00797.2012
178. Leicht CA, Goosey-Tolfrey VL, Bishop NC. Comparable neutrophil responses for arm and intensity-matched leg exercise. Med Sci Sports Exerc (2017) 49(8):1716–23. doi: 10.1249/MSS.0000000000001258
179. Bartlett DB, Fox O, McNulty CL, Greenwood HL, Murphy L, Sapey E, et al. Habitual physical activity is associated with the maintenance of neutrophil migratory dynamics in healthy older adults. Brain Behav Immun (2016) 56:12–20. doi: 10.1016/j.bbi.2016.02.024
180. Bote ME, Garcia JJ, HinChado MD, Ortega E. An exploratory study of the effect of regular aquatic exercise on the function of neutrophils from women with fibromyalgia: role of IL-8 and noradrenaline. Brain Behav Immun (2014) 39:107–12. doi: 10.1016/j.bbi.2013.11.009
181. Ondracek AS, Aszlan A, Schmid M, Lenz M, Mangold A, Artner T, et al. Physical exercise promotes DNase activity enhancing the capacity to degrade neutrophil extracellular traps. Biomedicines (2022) 10(11):2849. doi: 10.3390/biomedicines10112849
182. Joisten N, Proschinger S, Rademacher A, Schenk A, Bloch W, Warnke C, et al. High-intensity interval training reduces neutrophil-to-lymphocyte ratio in persons with multiple sclerosis during inpatient rehabilitation. Mult Scler (2021) 27(7):1136–9. doi: 10.1177/1352458520951382
183. Distefano-Gagne F, Bitarafan S, Lacroix S, Gosselin D. Roles and regulation of microglia activity in multiple sclerosis: insights from animal models. Nat Rev Neurosci (2023) 24(7):397–415. doi: 10.1038/s41583-023-00709-6
184. Prinz M, Masuda T, Wheeler MA, Quintana FJ. Microglia and central nervous system-associated macrophages-from origin to disease modulation. Annu Rev Immunol (2021) 39:251–77. doi: 10.1146/annurev-immunol-093019-110159
185. Jackle K, Zeis T, Schaeren-Wiemers N, Junker A, van der Meer F, Kramann N, et al. Molecular signature of slowly expanding lesions in progressive multiple sclerosis. Brain (2020) 143(7):2073–88. doi: 10.1093/brain/awaa158
186. Funes SC, Rios M, Escobar-Vera J, Kalergis AM. Implications of macrophage polarization in autoimmunity. Immunology (2018) 154(2):186–95. doi: 10.1111/imm.12910
187. Zrzavy T, Hametner S, Wimmer I, Butovsky O, Weiner HL, Lassmann H. Loss of 'homeostatic' microglia and patterns of their activation in active multiple sclerosis. Brain (2017) 140(7):1900–13. doi: 10.1093/brain/awx113
188. Marzan DE, Brugger-Verdon V, West BL, Liddelow S, Samanta J, Salzer JL. Activated microglia drive demyelination via CSF1R signaling. Glia (2021) 69(6):1583–604. doi: 10.1002/glia.23980
189. Kent SA, Miron VE. Microglia regulation of central nervous system myelin health and regeneration. Nat Rev Immunol (2023). doi: 10.1038/s41577-023-00907-4
190. Rawji KS, Young AMH, Ghosh T, Michaels NJ, Mirzaei R, Kappen J, et al. Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system. Acta Neuropathol (2020) 139(5):893–909. doi: 10.1007/s00401-020-02129-7
191. Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci (2013) 16(9):1211–8. doi: 10.1038/nn.3469
192. Cignarella F, Filipello F, Bollman B, Cantoni C, Locca A, Mikesell R, et al. TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis. Acta Neuropathol (2020) 140(4):513–34. doi: 10.1007/s00401-020-02193-z
193. Wang Y, Kyauk RV, Shen YA, Xie L, Reichelt M, Lin H, et al. TREM2-dependent microglial function is essential for remyelination and subsequent neuroprotection. Glia (2023) 71(5):1247–58. doi: 10.1002/glia.24335
194. Sun W, Wang Q, Zhang R, Zhang N. Ketogenic diet attenuates neuroinflammation and induces conversion of M1 microglia to M2 in an EAE model of multiple sclerosis by regulating the NF-kappaB/NLRP3 pathway and inhibiting HDAC3 and P2X7R activation. Food Funct (2023) 14(15):7247–69. doi: 10.1039/d3fo00122a
195. Naeem AG, El-Naga RN, Michel HE. Nebivolol elicits a neuroprotective effect in the cuprizone model of multiple sclerosis in mice: emphasis on M1/M2 polarization and inhibition of NLRP3 inflammasome activation. Inflammopharmacology (2022) 30(6):2197–209. doi: 10.1007/s10787-022-01045-4
196. Che J, Li D, Hong W, Wang L, Guo Y, Wu M, et al. Discovery of new macrophage M2 polarization modulators as multiple sclerosis treatment agents that enable the inflammation microenvironment remodeling. Eur J Med Chem (2022) 243:114732. doi: 10.1016/j.ejmech.2022.114732
197. Ortega E, Forner MA, Barriga C. Exercise-induced stimulation of murine macrophage chemotaxis: role of corticosterone and prolactin as mediators. J Physiol (1997) 498(Pt 3):729–34. doi: 10.1113/jphysiol.1997.sp021897
198. Ceddia MA, Voss EW Jr., Woods JA. Intracellular mechanisms responsible for exercise-induced suppression of macrophage antigen presentation. J Appl Physiol (1985) (2000) 88(2):804–10. doi: 10.1152/jappl.2000.88.2.804
199. Forner MA, Barriga C, Ortega E. Exercise-induced stimulation of murine macrophage phagocytosis may be mediated by thyroxine. J Appl Physiol (1985) (1996) 80(3):899–903. doi: 10.1152/jappl.1996.80.3.899
200. Feng L, Li G, An J, Liu C, Zhu X, Xu Y, et al. Exercise training protects against heart failure via expansion of myeloid-derived suppressor cells through regulating IL-10/STAT3/S100A9 pathway. Circ Heart Fail (2022) 15(3):e008550. doi: 10.1161/CIRCHEARTFAILURE.121.008550
201. Woods JA, Davis JM, Mayer EP, Ghaffar A, Pate RR. Effects of exercise on macrophage activation for antitumor cytotoxicity. J Appl Physiol (1985) (1994) 76(5):2177–85. doi: 10.1152/jappl.1994.76.5.2177
202. Brown AS, Davis JM, Murphy EA, Carmichael MD, Carson JA, Ghaffar A, et al. Gender differences in macrophage antiviral function following exercise stress. Med Sci Sports Exerc (2006) 38(5):859–63. doi: 10.1249/01.mss.0000218125.21509.cc
203. Murugathasan M, Jafari A, Amandeep A, Hassan SA, Chihata M, Abdul-Sater AA. Moderate exercise induces trained immunity in macrophages. Am J Physiol Cell Physiol (2023) 325(2):C429–42. doi: 10.1152/ajpcell.00130.2023
204. Sung YH, Kim SC, Hong HP, Park CY, Shin MS, Kim CJ, et al. Treadmill exercise ameliorates dopaminergic neuronal loss through suppressing microglial activation in Parkinson's disease mice. Life Sci (2012) 91(25-26):1309–16. doi: 10.1016/j.lfs.2012.10.003
205. Gerecke KM, Kolobova A, Allen S, Fawer JL. Exercise protects against chronic restraint stress-induced oxidative stress in the cortex and hippocampus. Brain Res (2013) 1509:66–78. doi: 10.1016/j.brainres.2013.02.027
206. Nakanishi K, Sakakima H, Norimatsu K, Otsuka S, Takada S, Tani A, et al. Effect of low-intensity motor balance and coordination exercise on cognitive functions, hippocampal Abeta deposition, neuronal loss, neuroinflammation, and oxidative stress in a mouse model of Alzheimer's disease. Exp Neurol (2021) 337:113590. doi: 10.1016/j.expneurol.2020.113590
207. Zhang SS, Zhu L, Peng Y, Zhang L, Chao FL, Jiang L, et al. Long-term running exercise improves cognitive function and promotes microglial glucose metabolism and morphological plasticity in the hippocampus of APP/PS1 mice. J Neuroinflammation (2022) 19(1):34. doi: 10.1186/s12974-022-02401-5
208. Zhang X, He Q, Huang T, Zhao N, Liang F, Xu B, et al. Treadmill exercise decreases abeta deposition and counteracts cognitive decline in APP/PS1 mice, possibly via hippocampal microglia modifications. Front Aging Neurosci (2019) 11:78. doi: 10.3389/fnagi.2019.00078
209. Wang W, Lv Z, Gao J, Liu M, Wang Y, Tang C, et al. Treadmill exercise alleviates neuronal damage by suppressing NLRP3 inflammasome and microglial activation in the MPTP mouse model of Parkinson's disease. Brain Res Bull (2021) 174:349–58. doi: 10.1016/j.brainresbull.2021.06.024
210. Liu MX, Luo L, Fu JH, He JY, Chen MY, He ZJ, et al. Exercise-induced neuroprotection against cerebral ischemia/reperfusion injury is mediated via alleviating inflammasome-induced pyroptosis. Exp Neurol (2022) 349:113952. doi: 10.1016/j.expneurol.2021.113952
211. Bernardes D, de Oliveira ALR. Regular exercise modifies histopathological outcomes of pharmacological treatment in experimental autoimmune encephalomyelitis. Front Neurol (2018) 9:950. doi: 10.3389/fneur.2018.00950
212. Rizzo FR, Guadalupi L, Sanna K, Vanni V, Fresegna D, De Vito F, et al. Exercise protects from hippocampal inflammation and neurodegeneration in experimental autoimmune encephalomyelitis. Brain Behav Immun (2021) 98:13–27. doi: 10.1016/j.bbi.2021.08.212
213. Zaychik Y, Fainstein N, Touloumi O, Goldberg Y, Hamdi L, Segal S, et al. High-intensity exercise training protects the brain against autoimmune neuroinflammation: regulation of microglial redox and pro-inflammatory functions. Front Cell Neurosci (2021) 15:640724. doi: 10.3389/fncel.2021.640724
214. Jensen SK, Michaels NJ, Ilyntskyy S, Keough MB, Kovalchuk O, Yong VW. Multimodal enhancement of remyelination by exercise with a pivotal role for oligodendroglial PGC1alpha. Cell Rep (2018) 24(12):3167–79. doi: 10.1016/j.celrep.2018.08.060
215. Golzari Z, Shabkhiz F, Soudi S, Kordi MR, Hashemi SM. Combined exercise training reduces IFN-gamma and IL-17 levels in the plasma and the supernatant of peripheral blood mononuclear cells in women with multiple sclerosis. Int Immunopharmacol (2010) 10(11):1415–9. doi: 10.1016/j.intimp.2010.08.008
216. Ercan Z, Bilek F, Demir CF. The effect of aerobic exercise on Neurofilament light chain and glial Fibrillary acidic protein level in patients with relapsing remitting type multiple sclerosis. Mult Scler Relat Disord (2021) 55:103219. doi: 10.1016/j.msard.2021.103219
217. Gravesteijn AS, Beckerman H, Willemse EA, Hulst HE, de Jong BA, Teunissen CE, et al. Brain-derived neurotrophic factor, neurofilament light and glial fibrillary acidic protein do not change in response to aerobic training in people with MS-related fatigue - a secondary analysis of a randomized controlled trial. Mult Scler Relat Disord (2023) 70:104489. doi: 10.1016/j.msard.2022.104489
218. Zhang L, Liu Y, Wang X, Wang D, Wu H, Chen H, et al. Treadmill exercise improve recognition memory by TREM2 pathway to inhibit hippocampal microglial activation and neuroinflammation in Alzheimer's disease model. Physiol Behav (2022) 251:113820. doi: 10.1016/j.physbeh.2022.113820
219. Xu J, Zhang L, Li M, He X, Luo J, Wu R, et al. TREM2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repair. J Neuroinflammation (2023) 20(1):50. doi: 10.1186/s12974-023-02741-w
220. Lezmy J, Arancibia-Carcamo IL, Quintela-Lopez T, Sherman DL, Brophy PJ, Attwell D. Astrocyte Ca(2+)-evoked ATP release regulates myelinated axon excitability and conduction speed. Science (2021) 374(6565):eabh2858. doi: 10.1126/science.abh2858
221. Lee JH, Kim JY, Noh S, Lee H, Lee SY, Mun JY, et al. Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis. Nature (2021) 590(7847):612–7. doi: 10.1038/s41586-020-03060-3
222. Mishra A, Reynolds JP, Chen Y, Gourine AV, Rusakov DA, Attwell D. Publisher Correction: Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat Neurosci (2020) 23(9):1176. doi: 10.1038/s41593-020-0680-0
223. Meyer T, Shimon D, Youssef S, Yankovitz G, Tessler A, Chernobylsky T, et al. NAD(+) metabolism drives astrocyte proinflammatory reprogramming in central nervous system autoimmunity. Proc Natl Acad Sci U S A (2022) 119(35):e2211310119. doi: 10.1073/pnas.2211310119
224. Lu SZ, Wu Y, Guo YS, Liang PZ, Yin S, Yin YQ, et al. Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis. J Exp Med (2022) 219(9):e20210998. doi: 10.1084/jem.20210998
225. Kalinin S, Meares GP, Lin SX, Pietruczyk EA, Saher G, Spieth L, et al. Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis. Glia (2020) 68(3):600–16. doi: 10.1002/glia.23742
226. Wheeler MA, Clark IC, Tjon EC, Li Z, Zandee SEJ, Couturier CP, et al. MAFG-driven astrocytes promote CNS inflammation. Nature (2020) 578(7796):593–9. doi: 10.1038/s41586-020-1999-0
227. Escartin C, Galea E, Lakatos A, O'Callaghan JP, Petzold GC, Serrano-Pozo A, et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci (2021) 24(3):312–25. doi: 10.1038/s41593-020-00783-4
228. Molina-Gonzalez I, Holloway RK, Jiwaji Z, Dando O, Kent SA, Emelianova K, et al. Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration. Nat Commun (2023) 14(1):3372. doi: 10.1038/s41467-023-39046-8
229. Kuipers HF, Yoon J, van Horssen J, Han MH, Bollyky PL, Palmer TD, et al. Phosphorylation of alphaB-crystallin supports reactive astrogliosis in demyelination. Proc Natl Acad Sci U S A (2017) 114(9):E1745–54. doi: 10.1073/pnas.1621314114
230. Colombo E, Triolo D, Bassani C, Bedogni F, Di Dario M, Dina G, et al. Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes. Proc Natl Acad Sci U.S.A (2021) 118(27):e2025804118. doi: 10.1073/pnas.2025804118
231. Zare Z, Tehrani M, Zarbakhsh S, Mohammadi M. Protective effects of treadmill exercise on apoptotic neuronal damage and astrocyte activation in ovariectomized and/or diabetic rat prefrontal cortex: molecular and histological aspects. Int J Neurosci (2022) 23:1–9. doi: 10.1080/00207454.2022.2148529
232. Feng S, Wu C, Zou P, Deng Q, Chen Z, Li M, et al. High-intensity interval training ameliorates Alzheimer's disease-like pathology by regulating astrocyte phenotype-associated AQP4 polarization. Theranostics (2023) 13(10):3434–50. doi: 10.7150/thno.81951
233. Lai Z, Shan W, Li J, Min J, Zeng X, Zuo Z. Appropriate exercise level attenuates gut dysbiosis and valeric acid increase to improve neuroplasticity and cognitive function after surgery in mice. Mol Psychiatry (2021) 26(12):7167–87. doi: 10.1038/s41380-021-01291-y
234. Kelty TJ, Mao X, Kerr NR, Childs TE, Ruegsegger GN, Booth FW. Resistance-exercise training attenuates LPS-induced astrocyte remodeling and neuroinflammatory cytokine expression in female Wistar rats. J Appl Physiol (1985) (2022) 132(2):317–26. doi: 10.1152/japplphysiol.00571.2021
235. Belaya I, Ivanova M, Sorvari A, Ilicic M, Loppi S, Koivisto H, et al. Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer's disease. J Neuroinflammation (2020) 17(1):271. doi: 10.1186/s12974-020-01935-w
236. Fahimi A, Baktir MA, Moghadam S, Mojabi FS, Sumanth K, McNerney MW, et al. Physical exercise induces structural alterations in the hippocampal astrocytes: exploring the role of BDNF-TrkB signaling. Brain Struct Funct (2017) 222(4):1797–808. doi: 10.1007/s00429-016-1308-8
237. Ying N, Luo H, Li B, Gong K, Shu Q, Liang F, et al. Exercise alleviates behavioral disorders but shapes brain metabolism of APP/PS1 mice in a region- and exercise-specific manner. J Proteome Res (2023) 22(6):1649–59. doi: 10.1021/acs.jproteome.2c00691
238. Barad Z, Augusto J, Kelly AM. Exercise-induced modulation of neuroinflammation in ageing. J Physiol (2023) 601(11):2069–83. doi: 10.1113/JP282894
239. Azzolini F, Gilio L, Pavone L, Iezzi E, Dolcetti E, Bruno A, et al. Neuroinflammation is associated with GFAP and sTREM2 levels in multiple sclerosis. Biomolecules (2022) 12(2):222. doi: 10.3390/biom12020222
240. Afzal R, Dowling JK, McCoy CE. Impact of exercise on immunometabolism in multiple sclerosis. J Clin Med (2020) 9(9):3038. doi: 10.3390/jcm9093038
241. Silveira LS, Batatinha HAP, Castoldi A, Camara NOS, Festuccia WT, Souza CO, et al. Exercise rescues the immune response fine-tuned impaired by peroxisome proliferator-activated receptors gamma deletion in macrophages. J Cell Physiol (2019) 234(4):5241–51. doi: 10.1002/jcp.27333
Keywords: multiple sclerosis, exercise, immune cell, adaptive immunity, innate immunity
Citation: Zong B, Yu F, Zhang X, Zhao W, Li S and Li L (2023) Mechanisms underlying the beneficial effects of physical exercise on multiple sclerosis: focus on immune cells. Front. Immunol. 14:1260663. doi: 10.3389/fimmu.2023.1260663
Received: 18 July 2023; Accepted: 13 September 2023;
Published: 29 September 2023.
Edited by:
Rajnikant Mishra, Banaras Hindu University, IndiaReviewed by:
Jinming Han, Capital Medical University, ChinaSachin Tiwari, Indian Institute of Technology Roorkee, India
Copyright © 2023 Zong, Yu, Zhang, Zhao, Li and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Lin Li, lilin.xtt@163.com