Albert Frank Magnusen1†
Manoj Kumar Pandey- 1Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
- 2Department of Paediatrics of University of Cincinnati College of Medicine, Cincinnati, OH, United States
Parkinson's disease (PD) is a movement disorder attributed to the loss of dopaminergic (DA) neurons mainly in the substantia nigra pars compacta. Motor symptoms include resting tremor, rigidity, and bradykinesias, while non-motor symptoms include autonomic dysfunction, anxiety, and sleeping problems. Genetic mutations in a number of genes (e.g., LRRK2, GBA, SNCA, PARK2, PARK6, and PARK7) and the resultant abnormal activation of microglial cells are assumed to be the main reasons for the loss of DA neurons in PD with genetic causes. Additionally, immune cell infiltration and their participation in major histocompatibility complex I (MHCI) and/or MHCII-mediated processing and presentation of cytosolic or mitochondrial antigens activate the microglial cells and cause the massive generation of pro-inflammatory cytokines and chemokines, which are all critical for the propagation of brain inflammation and the neurodegeneration in PD with genetic and idiopathic causes. Despite knowing the involvement of several of such immune devices that trigger neuroinflammation and neurodegeneration in PD, the exact disease mechanism or the innovative biomarker that could detect disease severity in PD linked to LRRK2, GBA, SNCA, PARK2, PARK6, and PARK7 defects is largely unknown. The current review has explored data from genetics, immunology, and in vivo and ex vivo functional studies that demonstrate that certain genetic defects might contribute to microglial cell activation and massive generation of a number of pro-inflammatory cytokines and chemokines, which ultimately drive the brain inflammation and lead to neurodegeneration in PD. Understanding the detailed involvement of a variety of immune mediators, their source, and the target could provide a better understanding of the disease process. This information might be helpful in clinical diagnosis, monitoring of disease progression, and early identification of affected individuals.
Introduction
Parkinson's disease (PD) is a neurodegenerative brain disorder that mainly happens due to progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNPC) and its impact on impairment of motor function that includes static tremor, bradykinesia, muscle stiffness, postural instability, balance difficulty, and walking problem (1, 2). Pro-inflammatory cytokines and chemokines have been linked to disease manifestations of Alzheimer's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis, prion disease, systemic lupus erythematosus, depression, migraine, and schizophrenia as reviewed in refs. (3–12). Microglial cells (MGCs) are residential macrophages (Mϕs) of the central nervous system (CNS), which are exquisitely sensitive to the pathophysiological insults and the resultant alteration in their morphology and phenotype to activated state (13). Such MGCs cause massive generation of pro-inflammatory cytokines, chemokines, reactive oxygen species (ROS), and nitric oxide (NO), which all contribute to the clearance of infectious agents (14). However, prolonged or excessive activation of MGCs results in pathological forms of inflammation that contribute to the progression of neurodegenerative and neoplastic diseases (15–17). Activated MGCs express major histocompatibility complex II (MHC class II), which is required for activation of naive CD4+ T cells and the production of numerous pro-inflammatory cytokines and chemokines that modulate the differentiation of effector T cells (18).
Effector T cells, i.e., T helper 1 (Th1), Th2, Th17, T regulatory (Treg), and T follicular helper (Tfh) cells as well as their signature cytokines, i.e., interferon gamma (IFNγ; TH1), interleukin 4 (IL-4; TH2) (19, 20), IL-17 (TH17) (21, 22), transforming growth factor beta (TGFβ; Treg), and IL-6 (Tfh), drive tissue inflammation in several visceral and brain diseases (23–28). The T helper cell subsets can produce IL-10, a cytokine with broad immunoregulatory properties (29). Th1 cells produce IFNγ, IL-2, and tumor necrosis factor alpha (TNFα) to clear intracellular pathogens and evoke cell-mediated immunity, whereas Th2 cells produce IL-4, IL-5, and IL-13 to clear extracellular organisms and evoke strong allergic responses (19, 30–33). In contrast to Th1 and Th2 cell differentiation, which depend on their respective effector cytokines (IFNγ and IL-4), Th17 cell differentiation does not require IL-17 but has a critical need for TGFβ and IL-6 (34–36). Treg cells produce IL-10 and TGFβ to cause immune tolerance and inhibit IFNγ synthesis (37) as well as block T helper cell differentiation of naive T cells into effector T cells (38).
The MGCs' interaction to effector T cells and the resulting production of pro-inflammatory cytokines, chemokines, and the neurodegeneration have been observed in Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis (MS), and prion diseases (17, 39, 40). The SNPC of PD patients have shown CD4+ T cells, CD8+ T cells, human leukocyte antigen DR isotype (HLA-DR) expressing inflammatory subset of MGCs, and increased incidence of pro-inflammatory cytokines, i.e., IFNγ, TNF, IL-1β expressing glial cells (41–43). Additionally, the striatal dopaminergic (DA) regions and cerebrospinal fluid (CSF) of PD patients have shown elevated levels of IL-1β, IL-2, IL-6, TNF, and TGFβ1 (44, 45). Peripheral blood analyses of PD patients have shown marked increases of innate and adaptive immune cells that include monocytes (MOs), IFNγ, IL-4, and IL-17 producing memory and effector T cells as well as their association to severity of the disease (43, 46–51). Elevated serum levels of TNF (52, 53), IL-1β (52, 54, 55), and IL-6 (52–54) have been observed in PD patients as reviewed in Qin et al. (56). PD patients have also shown increased serum level of cytokine receptors such as TNF receptors (e.g., TNFRs) and their link to late disease onset (57, 58). MO differentiation into the tissue-specific MGCs, Mϕs, and dendritic cells (DCs) as well as the trafficking of CD4+ and CD8+ T cells to sites of inflammation requires growth factors, i.e., granulocyte colony-stimulating factor (GCSF), granulocyte Mϕ colony-stimulating factor (GMCSF), and the Mϕ colony-stimulating factor (MCSF), as well as the number of C-C motif ligand (CCL) and the C-X-C motif ligand (CXCL) chemokines (59–69). However, the exact mechanism by which such immune inflammation occurs in PD is unknown. It is speculated that abnormal brain or circulatory level of several proteins and enzymes has been associated with the development of neuroinflammation in PD. Indeed, several of such proteins have been associated with activation of residential MGCs and the infiltrated lymphocytes and their combined impact on the generation of pro-inflammatory cytokines (e.g., IFNβ, IFNγ, TNFα, IL-1β, IL-6, IL-18, and TGFβ1), which lead to the loss of DA neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 2,4,5-trihydroxyphenethylamine or 6-hydroxydopamin (6-OHDA)-induced mouse models of idiopathic PD (Table 1A). Additionally, human patients with idiopathic PD have also suggested elevated brain or circulatory level of proteins or enzymes linked to MGC activation, pro-inflammatory cytokine and chemokine (e.g., IFNβ, IFNγ, TNFα, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, CCL2, CXCL1) production, loss of DA neurons, and the development of motor symptoms (Table 1B). The current review is an update on the involvement of a variety of innate and adaptive immune mediators as well as their source and targets involved in the propagation of disease manifestations in mouse and human PD associated with LRRK2, GBA, SNCA, PARK2, PARK6, and PARK7 defects. These results will likely provide much needed insights into the disease mechanism and will be useful for the identification of potential biomarkers at the level of distinguished cytokines and chemokines in different forms of PD.
Table 1A. Cytokines and their source in the mouse model of idiopathic PD.
Table 1B. Cytokines and their source in idiopathic human PD.
LRRK2 Gene Defects and Pro-inflammatory Immune Mediators in PD
The leucine-rich-repeat kinase 2 (LRRK2) gene encodes a large, multidomain LRRK2 protein comprised of a GTPase and a kinase domain (85). Although the precise physiological function of LRRK2 remains largely unknown, recent studies have indicated that LRRK2 is involved in cellular functions such as neurite outgrowth, cytoskeletal maintenance, vesicle trafficking, autophagic protein degradation, and the regulation of signaling pathways, including the Wingless-INT (WNT), Fas-Fas ligand (FasL or CD95L or CD178)-associated protein with death domain (FADD), mitogen-activated protein kinase (MAPK), and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) (86–88).
The resting neuronal cells, i.e., neurons (NCs), MGCs, and astrocytes (ACs), expressed a low level of LRRK2 (89, 90). However, several of the pro-inflammatory mediators (e.g., IFNβ, IFNγ, TNFα, IL-6, and LPS) cause upregulation of LRRK2 in immune cells, i.e., monocytes (MOs), Mϕs, and T and B cells, and in neuronal cells, i.e., MGCs and NCs (88, 91–95). LRRK2 is critical for the propagation of Crohn's disease (96, 97), leprosy (98), and neuronal toxicity (99–102).
Indeed, LRRK2 gene mutations have been linked to increased LRRK2 kinase substrate phosphorylation and the formation of intracellular alpha-synuclein (α-syn)-positive inclusions in Lewy bodies (LBs) and preferential loss of DA neurons and the development of motor symptoms, including tremor, rigidity, postural instability, and bradykinesia in late-onset familial and idiopathic PD (100, 103–119). The brain regions, blood, and cells of LRRK2-associated mouse models of PD have shown abnormal expression of LRRK2 kinase and their association with elevated brain and circulatory level of pro-inflammatory cytokines (e.g., IFNγ, TNFα, IL-1α, IL-1β, IL-6, IL-8, IL-10, and IL-12), chemokines (e.g., CCL2, CCL3, CCL4, CCL5, CXCL1, and CXCL10), and growth factors (e.g., GCSF and MCSF), as well as their link to the loss of NCs and the development of cognitive defects (Table 2A). The blood cells, sera, and CSF of LRRK2-associated human patients with PD have also shown abnormal expression of LRRK2 kinase and their link to elevated levels of pro-inflammatory cytokines and growth factors (e.g., IFNγ, TNFα, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, GCSF, PDGF, and VEGF), loss of NCs, and the development of cognitive defects in PD (Table 2B). These data suggest that LRKK2 defects and the resultant higher expression of LRRK2 kinases cause cellular activation and the higher generation of pro-inflammatory cytokines and chemokines (Tables 2A,B) that lead to DA neuron damage in LRRK2-associated PD (Figure 1A).
Figure 1. The genetic mutation-induced inflammatory immune reactions develop neurodegeneration in Parkinson's disease. The LRRK2 defects cause over activation of LRRK2 kinases. This defect triggers the formation of aggregated alpha-synuclein (Agg α-syn) and increased generation of pro-inflammatory cytokines and chemokines that lead to the loss of dopaminergic (DA) neurons in LRRK2-associated PD (A). The GBA mutations and the resultant deficiency of glucocerebrosidase (GCase) trigger the formation of glycosphingolipids and Agg α-syn, which trigger increased generation of pro-inflammatory cytokines and chemokines and lead to the loss of DA neurons in GBA-associated PD (B). The SNCA defects and the resultant overproduction of normal/Agg α-syn activate the brain production of inflammatory cytokines and chemokines that cause death of DA neurons in SNCA-associated PD (C). The PARK2, PARK6, and PARK7 defects and the subsequent deficiency of PARKIN, PINK, and DJ-1 proteins cause mitochondrial damage and the formation of Agg α-syn. These abnormalities trigger cellular activation and massive generation of ROS, pro-inflammatory cytokines, and chemokines that lead to the loss of DA neurons in PARK2-, PARK6-, and PARK7-associated PD (D–F).
Table 2A. Cytokines and their source in the LRRK2 mouse model of PD.
Table 2B. Cytokines and their source in the LRRK2-associated human PD.
GBA1 Gene Defects and Pro-inflammatory Immune Mediators in PD
The GBA1 gene encodes the lysosomal enzyme, acid β-glucosidase (glucocerebrosidase, GCase). This later enzyme cleaves the β-D-glucosidic bond from the glycosphingolipid substrates (glucosylceramide; GC), yielding β-D-glucose and ceramide, and its deacylated product, glucosylsphingosine (GS), resulting in the formation of β-D-glucose and sphingosine (125, 126). The three types of Gaucher disease (GD), i.e., types 1, 2, and 3, have been characterized by recessive mutations in the GBA1 gene. Pathogenic mutations in GBA1 and the resultant GCase deficiency cause excess tissue accumulation of GC and chronic tissue inflammation in type 1 GD (59, 125, 127–133). We have identified immune complexes of GC-specific immunoglobulin G (IgG) antibodies in experimental and clinical Gaucher disease, which induce massive generation of complement C5a (C5a) and the activation of C5a receptor (e.g., C5aR1). Such C5a–C5aR1 activation is what tips the balance between GC formation and its degradation through the control of an enzyme termed as glucosylceramide synthase (GCS) that produces the GC and fuels inflammation in visceral tissues (e.g., blood, bone marrow, lung, liver, spleen, and lymph node) in type 1 experimental and clinical GD (131).
Excess brain accumulation of GC has been linked to the formation of abnormal species of α-syn, microglial cell activation, generation of pro-inflammatory cytokines (e.g., TNFα, IL-1β, and IL-6), and the loss of neurons in patients with GD types 2 and 3 (134–139). Heterozygous mutations in the GBA1 gene are implicated in dementia with LBs (DLB) in idiopathic PD (140, 141). Similarly, the heterozygous GBA1 mutations have emerged as the major genetic risk for developing PD (133, 138, 142–159).
Brains of the GBA1 mouse model of PD have shown partial GCase deficiency and its impact on increased production of TNFα, IL-1β, TGFβ1, CCL2, CCL3, CCL5, VCAM-1, ICAM-1, and MCSF as well as their link to the neuronal cell death (Table 3A). Plasma, sera, CSF, and blood-derived MOs of PD patients with GBA mutations have shown partial GCase deficiency and its impact on the higher production of pro-inflammatory cytokines (e.g., IFNγ, TNFα, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-13, CCL2, CCL3, CCL18, and SF), midbrain damage, and cognitive defects (Table 3B). These studies suggest that GBA defects and the resultant GCase deficiency cause excess tissue storage of glycosphingolipids and/or the formation of abnormal species of α-syn. These abnormal proteins and/or lipids trigger residential and infiltrated immune cell (e.g., MOs and MGCs) activation and massive brain generation of pro-inflammatory cytokines and chemokines (Tables 3A,B), which are all critical for the development of brain inflammation and neurodegeneration in GBA-associated PD (Figure 1B).
Table 3A. Cytokines and their source in the mouse model of GBA1 PD.
Table 3B. Cytokines and their source in the GBA-associated human PD.
SNCA gENE Defects and Pro-inflammatory Immune Mediators in PD
SNCA encodes the α-syn, which is an 18-kDa protein composed of 140 amino acids and expressed in presynaptic terminals of the neocortex, hippocampus, substantia nigra (SN), NCs, ACs, and oligodendrocytes as well as CSF, serum, plasma, and hematopoietic cells (166–173). The brain α-syn interacts with proteins and lipids and controls the synaptic vesicle recycling and neurotransmitter release (174–177). However, the SNCA defect and the resultant excess generation and/or formation of normal endogenous or aggregated Agg α-syn in cytoplasmic inclusions of NCs termed as LBs and Lewy neurites (LNs) lead to neuronal toxicity and neurodegeneration in early- and late-onset PD (166, 178–185). Strikingly, LBs and LNs of the idiopathic forms of PD have also shown excess of α-syn and the Agg α-syn without any SNCA mutation (183, 186–188). In contrast, overexpression of wild-type SNCA and the resultant higher production of WT α-syn show their link to neurotoxicity in Drosophila melanogaster (189) and rodent models (190). Normal and Agg α-syn have shown TLR2- or TLR4-mediated MGC activation and neuronal loss in PD and mouse models (70, 191–198). PD genome-wide association studies (GWAS) identified the risk variants in certain loci associated to disease risk such as HLA-DR locus, which encodes for the major histocompatibility complex I (MHC class II) known for triggering the antigen presentation to CD4+ T cells (199–202). Two classical pathways of antigen presentation have been described for the presentation of endogenous antigens on MHC I molecules and the presentation of exogenous antigens, such as intracellular pathogens, on MHC class II molecules [reviewed by Blum et al. (203)]. The MHCII pathway is performed by specialized antigen-presenting cells, i.e., Mϕs, DCs, and DA neurons, which present peptides on MHCII molecules, ensuring its efficient recognition by CD4+ T cells (204). In addition to the increased brain infiltration of effector T-cell subsets in PD patients (42, 43), MHCII-mediated presentation of α-syn to CD4+ T cells has been linked to neuroinflammation in a mouse model and human PD (205–207). α-Syn peptide-stimulated T cells have shown development of activated subsets of helper and cytotoxic T cells and increased production of IFNγ, IL-2, and IL-5 (205). In addition, one of the peptide regions strongly binds to MHC encoded by HLA (DRB1*15:01, DRB5*01:01) linked to PD by GWAS (201, 208–210).
The sera, MGCs, and brain regions of the SNCA mouse model of PD have shown overexpression of different species of α-syn and pro-inflammatory cytokines (e.g., IFNγ, TNFα, IL-1α, IL-1β, IL-6, IL-10, TGFβ, CCL2, CCL3, CCL5, CXCL10, and ICAM-1) as well as their link to neuronal cell death and cognitive defects (Table 4A). The blood-derived immune cells, sera, and brain regions of PD patients with SNCA defect have also shown overexpression of α-syn and their association with cellular activation and increased generation of pro-inflammatory mediators (e.g., IFNγ, TNFα, IL-1β, IL-4, IL-5, IL-6, IL-18, and CCL2) as well as their link to neuronal cell damage (Table 4B). Hence, SNCA defects and the resultant increased making of normal and/or Agg α-syn promote the activation of peripheral immune cells and the brain MGCs. Such cells cause massive generation of NO, ROS, and pro-inflammatory cytokines and chemokines (Tables 4A,B), which are all critical for promoting brain inflammation and neurodegeneration in SNCA-associated PD (Figure 1C).
Table 4A. Cytokines and their source in the mouse model of SNCA PD.
Table 4B. Cytokines and their source in the SNCA-associated human PD.
PARK2 Gene Defects and Pro-inflammatory Immune Mediators in PD
The PARK2 gene encodes cytosolic ubiquitin E3 ligase termed as parkin protein, which is critical for the targeting, breakdown, and recycling of damaged proteins as well as the regulation of mitophagy and survival of DA neurons (224). PARK2 mutations cause a loss of parkin function that leads to the excess accumulation of dysfunctional mitochondria and the resultant massive generation of oxidative stress and death of DA neurons in autosomal recessive and idiopathic PD (225–235). CD4+ and CD8+ cell infiltration, MGC activation, increased generation of pro-inflammatory cytokines, and the loss of DA neurons have been observed in mouse model and human PD (43, 236).
Parkin plays a protective role during bacterial and viral infection and chemically induced oxidative and ER stress by altering the mitochondrial ROS and pro-inflammatory cytokine-mediated downstream signaling cascades (237–247). Biochemical and genetic studies reveal that parkin also acts in tandem with phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), which is accountable for controlling the mitochondrial quality (248). Indeed, mutations in the genes that encode PINK1 and Parkin showed massive mitochondrial damage and the development of familial PD (229). It has been shown that autophagy, the recycling of self-components through lysosomal degradation, is involved in the presentation of endogenous antigens on both MHC class I and class II molecules (249, 250), highlighting that vacuolar content can also be presented on MHC class I/II molecules. The mitochondrial MHCI-mediated antigen processing and presentation to CD8+ T cells have been valued for induction of neuroinflammation in mouse models and human PD (42, 43, 205, 251, 252). To understand the exact role of parkin and PINK1 in the development of brain inflammation in PD, Matheoud et al. (252) have discovered a pathway for mitochondrial antigen presentation, in which mitochondria-derived vesicles targeted endolysosomes for processing and presentation by MHC class I molecules. Using both in vitro and in vivo experiments, this study has demonstrated that parkin and PINK1 inhibit mitochondria-derived vesicle formation and mitochondrial antigen presentation, and therefore, in the absence of PINK1 or parkin, mitochondrial antigen presentation triggers DC and CD8+ T-cell activation and increased generation of pro-inflammatory cytokines. These data suggest that PINK1 and/or parkin has a key role in the activation of innate and adaptive immune cells by repressing the presentation of mitochondrial antigens, which suggests the involvement of autoimmune reactions in PD (252). PARK2 mutations and their link to α-syn inclusions and LB formation have also been observed in exceptional cases of PARK2-associated PD (253–255). The exact mechanism by which PARK2 defects propagate brain inflammation and neurodegeneration in PD is poorly defined.
The MGCs, Mϕs, and sera of the PARK2 mouse model displayed decreased expression of parkin and its link to the increased generation of pro-inflammatory cytokines and chemokines (e.g., IFNβ1, TNFα, IL-1β, IL-12, IL-13, IL-17, CCL2, and CXCL1), loss of DA neurons, and cognitive defects in PD (Table 5A). The sera, MGCs, Mϕs, and midbrain regions of PARK2-associated human PD also displayed decreased expression of parkin and its link to increased generation of pro-inflammatory cytokines (e.g., IFNβ1, TNFα, IL-1β, IL-6, IL-12, IL-13, CCL2, CCL4, and CXCL1), loss of DA neurons, and cognitive defects in PD (Table 5B). These findings suggest that PARK2 and the resultant deficiency of parkin are associated with mitochondrial damage and/or the formation of Agg α-syn. These defects cause cellular activation and massive generation of pro-inflammatory cytokines and chemokines (Tables 5A,B), which lead to the loss of DA neurons in PARK2-associated PD (Figure 1D).
Table 5A. Cytokines and their source in the mouse model of PARK2 PD.
Table 5B. Cytokines and their source in the PARK2-associated human PD.
PARK6 Gene Defects and Pro-inflammatory Immune Mediators in PD
The PARK6 gene encodes PINK1, which is a universally expressed serine/threonine kinase with a mitochondrial targeting sequence that directs the import of PINK1 as well as the activation and recruitment of parkin into the mitochondria for clearance of damaged mitochondria (260–267). PINK1-deficient cells, including NCs, are more susceptible to various insults (268, 269). PINK1 and parkin control the degradation of dysfunctional mitochondria (270, 271). PARK6 defects and the resultant deficiency of PINK1 lead to mitochondrial dysfunctions and the development of autosomal recessive and early-onset PD (261, 272–274). Pink1-deficient Drosophila displayed mitochondrial damage associated with apoptotic muscle degeneration and DA neuron loss, whereas Parkin overexpression protected such PINK1-induced defects (248, 275, 276). Several studies have shown that PINK1, like parkin, modulates NF-κB activity and brain generation of pro-inflammatory cytokines (277). PINK1-deficient T cells have reduced protein kinase B (PKB or Akt) activity, which is critical for inducible regulatory T cells (iTreg) development (278). PINK1-deficient iTreg cells showed reduced capacity to suppress lymphocyte proliferation (278). Importantly, the autologous transfer of Treg cells to MPTP-treated mice attenuated MGC activation and provides neuroprotection (279).
Strikingly, Treg cells from PD patients also have impaired suppressor function (47). T-cell subset infiltration and their interaction with MGCs and DA neurons are critical for the development of neuroinflammation and neurodegeneration in MPTP-induced mouse model and human patients with PD (43, 47, 48, 280, 281). Gram-negative bacteria-induced intestinal infection in Pink1−/− mice showed mitochondrial antigen presentation to CD8+ T cells in the periphery and in the brain and their link to loss of DA axonal varicosities in the striatum and the motor impairment. These data suggest the relevance of the gut–brain axis that could develop brain inflammation and neurodegeneration in PD (282, 283).
The blood, brain regions, and cells of the mouse model of PARK6-associated PD have shown PINK1 deficiency and its impact on increased blood or brain generation of pro-inflammatory cytokines and chemokines (e.g., IFNγ, IFNβ1, TNFα, IL-1β, IL-2, IL-6, IL-10, IL-12, IL-13, IL-17, TGFβ, CCL2, CCL4, and CXCL1), loss of neuronal cells, and the development of cognitive defects in PD (Table 6A). Additionally, PARK6-associated PD patients have also shown PINK1 deficiency and its impact on increased generation of pro-inflammatory cytokines and chemokines (e.g., IFNβ1, IL-6, IL-12, IL-13, CCL2, CCL4, and CXCL1), loss of NCs, and the development of cognitive defects (Table 6B). These findings suggest that PARK6 and the resultant PINK1 defects trigger residential and infiltrated immune cell activation and increased production of pro-inflammatory cytokines and chemokines (Tables 6A,B), which ultimately lead to the loss of DA neurons in PARK6-associated PD (Figure 1E).
Table 6A. Cytokines and their source in the mouse model of PARK6 PD.
Table 6B. Cytokines and their source in the PARK6-associated human PD.
PARK7 gENE Defects and Pro-inflammatory Immune Mediators in PD
PARK7 encodes a protein deglycase DJ-1, which belongs to the peptidase C56 family of proteins and ubiquitously expressed under physiological conditions (286). Like PINK1 and parkin, DJ-1 is required for controlling mitochondrial damage and production of oxidative stress (287–289). Several chemicals and physiological factors trigger the upregulation of DJ-1, which protects the oxidative and endoplasmic reticulum stress-induced damage of endothelial cells, Mϕs, fibroblast, NCs, and islet β cells (290–296), and therefore, DJ-1 deficiency has been associated with the development of several diseases (e.g., stroke, male infertility, cancers, diabetes, and neurodegenerative illnesses) (290, 297, 298). Escherichia coli- or Pseudomonas aeruginosa-mediated excess activation of MAPK signaling and the resultant induction of brain inflammation have been observed in DJ-1-deficient Caenorhabditis elegans (299). Mutations in PARK7 and the resultant deficiency or the oxidized form of DJ-1 protein cause autosomal recessive early-onset and idiopathic PD as reviewed in ref. (300).
Brain regions and their cells of the mouse model of PARK7-associated PD have shown DJ-1 deficiency and its effect on increased production of IFNγ, IL-1β, IL-1Ra, IL-6, IL-16, IL-17, CXCL11, and NGF as well as on the damage of ACs and DA neurons (Table 7A). Furthermore, abnormal cellular and brain region expression of DJ-1 has been associated with the formation of α-syn and Tau containing LBs, mitochondrial damage, increased production of ROS, and their link to the loss of NCs in PD patients with PARK7 mutation (Table 7B). These data suggest that PARK7 and the resultant DJ-1 deficiency induced mitochondrial damage and/or the formation of Agg α-syn and Tau comprising LB. These abnormal proteins cause massive generation of pro-inflammatory cytokines and chemokines (Tables 7A,B), which ultimately lead to the death of DA neurons in PARK7-associated PD (Figure 1F).
Table 7A. Cytokines and their source in the mouse model of PARK7 PD.
Table 7B. Cytokines and their source in the PARK7-associated human PD.
Conclusion
The molecular mechanisms by which LRRK2, GBA, SNCA, PARK2, PARK6, and PARK7 defects trigger neuroinflammation and neurodegeneration in PD are poorly defined and need more studies. However, the abnormal function of LRRK2, GBA, SNCA, PARK2, PARK6, and PARK7 genes has been linked to alteration in innate and adaptive immune responses in cancer, stroke, diabetes, male infertility, Crohn's disease, and infectious diseases (59, 96–98, 125, 127–133, 237–245, 290, 297, 298, 306–309). Findings from mouse models, cell system, and human specimens have shown that the abnormal expressions of LRRK2, GBA, SNCA, PARK2, PARK6, and PARK7 genes and their corresponding proteins or enzymes (e.g., LRRK2, GCase, α-syn, parkin, PINK1, and DJ-1) are linked to the activation of MGCs, ACs, and NCs and the massive production of growth factors (e.g., GCSF, GMCSF, MCSF) and CCL and CXCL chemokines (i.e., CCL2/MCP1, CCL3/MIP1α, CCL4/MIP1β, CCL5/RANTES, CXCL1, and CXCL10), which are all accountable for the development and trafficking of immunological cells from the peripheral blood and bone marrow to the sites of inflammation for the generation of pro-inflammatory cytokines that lead to tissue destruction (61–69). The CCL2/MCP1, CCL3/MIP1α, CCL4/MIP1β, CCL5/RANTES, CXCL1, and CXCL10 chemokines are specific chemoattractants for tissue recruitment of several inflammatory subsets of MOs, Mφs, DCs, and CD4+ and CD8+ T cells (59, 60). Certain inflammatory conditions cause accelerated migration of immunological cell precursors out of the bone marrow and into the circulation (310–312). A similar condition is thought to occur in PD due to genetic defects in LRRK2, GBA, SNCA, PARK2, PARK6, and PARK7 genes and the resultant alteration in the expression of their corresponding proteins or enzymes, i.e., LRRK2, GCase, α-Syn, parkin, PINK1, and DJ-1, which leads to the establishment of a network of several of the innate and adaptive immune cells, i.e., MOs and memory and effector T cells (43, 46–51). Hence, it is possible that immune cell integration and the resultant generation of pro-inflammatory cytokines at the periphery alter the blood–brain barrier integrity. This situation permits the recruitment of immune cells, to the specific region of the brain where infiltrated (e.g., MOs, DCs, CD4+ T cells, and CD8+ T cells) and residential immune cells (e.g., MGCs) meet and amplify their activation, and the resultant massive generation of pro-inflammatory cytokines (e.g., IFNγ, TNFα, IL-1β, IL-6, IL-8, IL-12, and IL-17), which are all lethal to DA neurons, and this condition develops neurodegeneration in PD.
Author Contributions
AFM and SLH prepared and designed the tables. RR designed the figures and assisted in the writing and critical review of the text. MKP conceptualized, designed, wrote, reviewed, edited, and approved the submitted version of the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by Division of Human Genetics, Cincinnati Children's Hospital Medical Center; Cincinnati, OH, USA (31-40327-584000-143032 to MKP), and Michael J. Fox Foundation; New York, NY, USA; (31-90000-584000-305961 to MKP). This study was supported in part by Cincinnati Children's Research Innovation/Pilot Research Award (31-41642-584000-143032 to MKP), and University of Cincinnati Center for Clinical and Translational Science Just-in-Time Core Research Award (31-41268-584000 to MKP).
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.
The handling editor declared a past co-authorship with the author MKP.
Acknowledgments
We would like to acknowledge BioRender tools for developing the figures and Mr. Charles D. Loftice for office and laboratory support.
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Keywords: neuroimmunology, immunogenetics, innate and adaptive immunity, glycosphingolipid, aggregated proteins, brain disease, neuroinflammation, mitochondrial disease
Citation: Magnusen AF, Hatton SL, Rani R and Pandey MK (2021) Genetic Defects and Pro-inflammatory Cytokines in Parkinson's Disease. Front. Neurol. 12:636139. doi: 10.3389/fneur.2021.636139
Received: 30 November 2020; Accepted: 06 May 2021;
Published: 22 June 2021.
Edited by:
Marcelo A. Kauffman, University of Buenos Aires, ArgentinaReviewed by:
Luca Magistrelli, University of Eastern Piedmont, ItalyQiying Sun, Xiangya Hospital, Central South University, China
Copyright © 2021 Magnusen, Hatton, Rani and Pandey. 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: Manoj Kumar Pandey, manoj.pandey@cchmc.org
†These authors have contributed equally to this work