Pengyue Zhang
Yulong Bai
Feng Zhang
Xiangjian Zhang
Yunping Deng
Yuchuan Ding- 1Institute of Acupuncture, Tuina and Rehabilitation, The Second Clinical Medical School, Yunnan University of Traditional Chinese Medicine, Kunming, China
- 2Department of Rehabilitation Medicine, Huashan Hospital Affiliated to Fudan University, Shanghai, China
- 3Department of Rehabilitation Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- 4Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, China
- 5Department of Anatomy and Neurobiology, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States
- 6Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States
Editorial on the Research Topic
Therapeutic relevance and mechanisms of neuro-immune communication in brain injury
For many years, the central nervous system (CNS) was thought to be immune-privileged due to the presence of the blood-brain barrier (BBB) and the absence of lymphatic vasculature. However, recent studies have uncovered the intricate interactions between the CNS and the immune system. In particular, microglia–resident immune cells in the brain–share developmental origins and functions with monocytes in the immune system, playing crucial roles in monitoring and modulating neuronal activity (Vidal-Itriago et al., 2022).
Recent studies have revealed that the dura and meningeal compartments may serve as critical channels for communication between the CNS and the immune system. Numerous immune cells reside in the dura and meninges, and the cerebrospinal fluid (CSF) produced by the choroid plexus in the brain can enter the cervical lymph nodes and cranial bone marrow via the dura lymphatic system (Aspelund et al., 2015; Vera Quesada et al., 2023). This evidence suggests that the brain can regulate the immune system through molecules in the CSF (Kisler and Zlokovic, 2022; Mazzitelli et al., 2022; Pulous et al., 2022). Additionally, inflammatory factors released at injury sites can stimulate and regulate peripheral nerves through specific cytokines, such as pathogen-associated molecular patterns, TNF, and IL-1ß (Bourhy et al., 2022). Using optogenetics and chemogenetics, Poller and colleagues demonstrated that brain motor circuits can regulate neutrophil mobilization, distribution, and function during stress through skeletal-muscle-derived chemokines (Poller et al., 2022). At the same time, stress can mobilize bone marrow-derived monocytes to the brain via the hypothalamic-pituitary-adrenal (HPA) axis, exacerbating neuroinflammation and worsening anxiety-like behaviors (Niraula et al., 2018). These findings indicate that although the brain is immune-privileged, it still regulates and communicates with the immune system. Conversely, the immune system also affects brain function. Dysregulation of the immune system is a critical cause and shared characteristic of neurological disorders, such as cerebral ischemia, intracerebral hemorrhage, brain trauma, and neurodegenerative diseases. In brain injury, microglia are activated and participate in neuroinflammatory responses, BBB permeability, the removal of dead cells and debris, and subsequent neurogenesis, synaptogenesis, and myelination through the release of soluble factors and phagocytic capacity (Paolicelli et al., 2022). Meanwhile, BBB destruction promotes mononuclear cell infiltration from the peripheral blood, facilitating crosstalk between the CNS and the immune system (Buckley and McGavern, 2022). As such, neuroimmune communication is not only an essential pathophysiological mechanism but also a potential therapeutic target for brain injury.
Although the neuroinflammatory response to brain injury has both favorable and unfavorable aspects, existing research suggests that nearly all current brain injury treatments can achieve neuroprotection by inhibiting the neuroinflammatory response.
Neuroprotection against synthetic drugs and natural extracts
Neuroinflammation can exacerbate both acute and secondary injury and lead to adverse long-term outcomes in brain injury. Based on the inflammatory signaling pathway, neuroscientists have found many drugs for the treatment of brain injury in animal studies, such as salvinorin A (a highly selective kappa opioid receptor agonist) (Misilimu et al., 2022), morphine (Rahimi et al., 2021), ACT001 (a sesquiterpene lactone derivative) (Cai et al., 2022), febuxostat (Wang et al., 2022), ethyl pyruvate (Shi et al., 2015), and amantadine (Leclerc et al., 2021). Traditional Chinese medicine formulas and natural extracts have been confirmed to be neuroprotective by regulating the neuroinflammatory response. These include Hu'po Anshen decoction (Shen et al., 2022), cordycepin (Wei et al., 2021), sinomenine (Hong et al., 2022), Rhodiola crenulate (Xie et al., 2022), parthenolide (Ding et al., 2022), and breviscapine (Pengyue et al., 2017). On this topic, Sun et al. found that casein kinase 2 can regulate NR2B phosphorylation, reduce neuroinflammation, and attenuate brain injury induced by intracerebral hemorrhage, and Cui et al. summarized the platelet-Tregs interaction in neuroinflammation after stroke: their works provide some new potential therapeutic targets for the regulation of neuroinflammation and treatment of brain injury. In addition, Wang et al. found that fo cused ultrasounds can improve the delivery of natural extracts into the brain. These studies will promote the development and application of drugs for the treatment of brain injury. Nevertheless, there is still a need for advancement and research in the clinical application of these synthetic drugs (Kakehi and Tompkins, 2021). Although Chinese traditional medicine has been widely used for the treatment of brain injury, it has been administered as an adjunctive treatment only, and its clinical effectiveness needs to be further verified.
Neuroprotection through rehabilitation
To date, rehabilitation is a widely used and effective treatment for brain injury in the clinic. Rehabilitation programs include stimulation with electricity, magnetism, light, and heat on the CNS and peripheral nervous system (PNS), along with physical therapy, virtual reality, motion imagination, and so on. Although the neuroprotective mechanism of rehabilitation involves multiple targets and multiple factors, inflammatory regulation is its pivotal process. Transcranial-direct-current-stimulation (TDCS) can decrease microglial activation and reduce the release of pro-inflammatory cytokines in experimental stroke models (Zhang et al., 2020; Kaviannejad et al., 2022a,b; Walter et al., 2022). Peripheral nerve electrical stimulation not only promotes nerve regeneration and ameliorates dysfunction but also regulates the neuroinflammatory response in the CNS and PNS (Chu et al., 2022). Exercise immediately after a stroke inhibits the activation of astrocytes and microglia cells and decreases the release of proinflammatory cytokines (Zhang et al., 2017). On this topic, Luo et al. observed that repetitive transcranial magnetic stimulation (TMS) inhibits inflammatory signaling pathways and promotes anti-inflammatory polarization of microglia in ischemic rats.
Neuroprotection through rehabilitation treatments using traditional Chinese medicine
Traditional Chinese medicine has been widely used in rehabilitation for the prevention and treatment of nervous system disorders. Examples include acupuncture and electric acupuncture, moxibustion, Tai Chi, Baduanjin, Yi Jin Jing, and five-fowl play (Zhang et al., 2017). The neuroprotective mechanisms of acupuncture for brain injury have been relatively well studied. In the traumatic brain injury model, researchers found that acupuncture inhibits M1 polarization of microglia by regulating RhoA/ROCK2 and TLR4/TRIF/MyD88 signaling pathways, thereby mitigating neuroinflammation in the acute, subacute, and chronic phases after TBI (Cavalli et al., 2018; Zhu et al., 2020; Cao et al., 2022). In stroke, electric acupuncture increases miR-223 and α7nAChR protein levels, inhibits NLRP3 inflammasome activation, and alleviates neuroinflammation (Jiang et al., 2019; Sha et al., 2019; Xin et al., 2022).
Neuroprotection through stem cell-based therapy
Brain injury leads to the loss of neural cells. Stem cells (such as neural stem cells and mesenchymal stem cells), which can proliferate, migrate, and differentiate into neural cells, can take part in nerve repair and neural plasticity by replacing the injured neural cells (Liu et al., 2022). Also, transplanted stem cells can suppress the neuroinflammatory response by sequestering the inflammatory/immune cells at the injury site and releasing anti-inflammatory factors (Mashkouri et al., 2016; Borlongan and Rosi, 2022). In addition, recent evidence indicates that the stem cells modulate microglia M1/M2 phenotypes and suppress NLRP3 inflammasome-mediated inflammation by secreting an exosome rich in multiple miRNAs (Liu et al., 2021). It is worth noting that stem cell-derived exosomes can be genetically reconstructed and deliver functional bioactive molecules (Liu et al., 2021). Thus, stem cell-derived exosomes will promote the clinical application of stem cell-based therapy in the treatment of brain injury because they can cross the blood-brain barrier more easily, cannot block blood vessels, do not induce malignant transformation, and can be genetically reconstructed.
Overall, neuroimmune communication is correlated with the physiological functions of various tissues and organs and the internal environmental balance. Dysregulation of neuroimmune communication homeostasis is both the underlying pathological mechanism and the potential therapeutic target in brain injury. A thorough clarification of the cellular and molecular mechanisms of neuroimmune communication in brain injury is an essential and necessary endeavor in the search for new therapeutic targets for this type of disorder.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Funding
This study was supported by the National Natural Science Foundation of China (81960731 and 81660384), the Joint Special Project of Traditional Chinese Medicine in Science and Technology Department of Yunnan Province [2019FF002(-008), 202001AZ070001-002, and 030], the Yunnan Province Biological Medicine Major Special Project (202102AA100016), the Yunnan Province University Innovation Team Projects (2019YGC04), and the Basic Research in Science and Technology Program of Yunnan Province (202101BA070001-116).
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
Aspelund, A., Antila, S., Proulx, S. T., Karlsen, T. V., Karaman, S., Detmar, M., et al. (2015). A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999. doi: 10.1084/jem.20142290
Borlongan, M. C., and Rosi, S. (2022). Stem cell therapy for sequestration of traumatic brain injury-induced inflammation. Int. J. Mol. Sci. 23, 18, 10286. doi: 10.3390/ijms231810286
Bourhy, L., Mazeraud, A., Bozza, F. A., Turc, G., Lledo, P. M., and Sharshar, T. (2022). Neuro-inflammatory response and brain-peripheral crosstalk in sepsis and stroke. Front. Immunol. 13, 834649. doi: 10.3389/fimmu.2022.834649
Buckley, M. W., and McGavern, D. B. (2022). Immune dynamics in the CNS and its barriers during homeostasis and disease. Immunol. Rev. 306, 58–75. doi: 10.1111/imr.13066
Cai, L., Gong, Q., Qi, L., Xu, T., Suo, Q., Li, X., et al. (2022). ACT001 attenuates microglia-mediated neuroinflammation after traumatic brain injury via inhibiting AKT/NFkappaB/NLRP3 pathway. Cell Commun. Signal. 20, 56. doi: 10.1186/s12964-022-00862-y
Cao, L. X., Lin, S. J., Zhao, S. S., Wang, S. Q., Zeng, H., Chen, W. A., et al. (2022). Effects of acupuncture on microglial polarization and the TLR4/TRIF/MyD88 pathway in a rat model of traumatic brain injury. Acupunct. Med. 9645284221108214. doi: 10.1177/09645284221108214
Cavalli, L., Briscese, L., Cavalli, T., Andre, P., and Carboncini, M. C. (2018). Role of Acupuncture in the Management of Severe Acquired Brain Injuries (sABIs). Evid. Based Complement. Alternat. Med. 2018, 8107508. doi: 10.1155/2018/8107508
Chu, X. L., Song, X. Z., Li, Q., Li, Y. R., He, F., Gu, X. S., et al. (2022). Basic mechanisms of peripheral nerve injury and treatment via electrical stimulation. Neural Regen Res. 17, 2185–2193. doi: 10.4103/1673-5374.335823
Ding, W., Cai, C., Zhu, X., Wang, J., and Jiang, Q. (2022). Parthenolide ameliorates neurological deficits and neuroinflammation in mice with traumatic brain injury by suppressing STAT3/NF-kappaB and inflammasome activation. Int. Immunopharmacol. 108, 108913. doi: 10.1016/j.intimp.2022.108913
Hong, H., Lu, X., Lu, Q., Huang, C., and Cui, Z. (2022). Potential therapeutic effects and pharmacological evidence of sinomenine in central nervous system disorders. Front. Pharmacol. 13, 1015035. doi: 10.3389/fphar.2022.1015035
Jiang, T., Wu, M., Zhang, Z., Yan, C., Ma, Z., He, S., et al. (2019). Electroacupuncture attenuated cerebral ischemic injury and neuroinflammation through alpha7nAChR-mediated inhibition of NLRP3 inflammasome in stroke rats. Mol. Med. 25, 22. doi: 10.1186/s10020-019-0091-4
Kakehi, S., and Tompkins, D. M. (2021). A review of pharmacologic neurostimulant use during rehabilitation and recovery after brain injury. Ann. Pharmacother. 55, 1254–1266. doi: 10.1177/1060028020983607
Kaviannejad, R., Karimian, S. M., Riahi, E., and Ashabi, G. (2022a). A single immediate use of the cathodal transcranial direct current stimulation induces neuroprotection of hippocampal region against global cerebral ischemia. J. Stroke Cerebrovasc. Dis. 31, 106241. doi: 10.1016/j.jstrokecerebrovasdis.2021.106241
Kaviannejad, R., Karimian, S. M., Riahi, E., and Ashabi, G. (2022b). Using dual polarities of transcranial direct current stimulation in global cerebral ischemia and its following reperfusion period attenuates neuronal injury. Metab. Brain Dis. 37, 1503–1516. doi: 10.1007/s11011-022-00985-8
Kisler, K., and Zlokovic, B. V. (2022). How the brain regulates its own immune system. Nat. Neurosci. 25, 532–534. doi: 10.1038/s41593-022-01066-w
Leclerc, A. M., Riker, R. R., Brown, C. S., May, T., Nocella, K., Cote, J., et al. (2021). Amantadine and modafinil as neurostimulants following acute stroke: a retrospective study of intensive care unit patients. Neurocrit. Care. 34, 102–111. doi: 10.1007/s12028-020-00986-4
Liu, H., Wei, T., Huang, Q., Liu, W., Yang, Y., Jin, Y., et al. (2022). The roles, mechanism, and mobilization strategy of endogenous neural stem cells in brain injury. Front. Aging Neurosci. 14, 924262. doi: 10.3389/fnagi.2022.924262
Liu, X., Zhang, M., Liu, H., Zhu, R., He, H., Zhou, Y., et al. (2021). Bone marrow mesenchymal stem cell-derived exosomes attenuate cerebral ischemia-reperfusion injury-induced neuroinflammation and pyroptosis by modulating microglia M1/M2 phenotypes. Exp. Neurol. 341, 113700. doi: 10.1016/j.expneurol.2021.113700
Mashkouri, S., Crowley, M. G., Liska, M. G., Corey, S., and Borlongan, C. V. (2016). Utilizing pharmacotherapy and mesenchymal stem cell therapy to reduce inflammation following traumatic brain injury. Neural Regen Res. 11, 1379–1384. doi: 10.4103/1673-5374.191197
Mazzitelli, J. A., Smyth, L., Cross, K. A., Dykstra, T., Sun, J., Du, S., et al. (2022). Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels. Nat. Neurosci. 25, 555–560. doi: 10.1038/s41593-022-01029-1
Misilimu, D., Li, W., Chen, D., Wei, P., Huang, Y., Li, S., et al. (2022). Intranasal salvinorin a improves long-term neurological function via immunomodulation in a mouse ischemic stroke model. J. Neuroimmune Pharmacol. 17, 350–366. doi: 10.1007/s11481-021-10025-4
Niraula, A., Wang, Y., Godbout, J. P., and Sheridan, J. F. (2018). Corticosterone production during repeated social defeat causes monocyte mobilization from the bone marrow, glucocorticoid resistance, and neurovascular adhesion molecule expression. J. Neurosci. 38, 2328–2340. doi: 10.1523/JNEUROSCI.2568-17.2018
Paolicelli, R. C., Sierra, A., Stevens, B., Tremblay, M. E., Aguzzi, A., Ajami, B., et al. (2022). Microglia states and nomenclature: a field at its crossroads. Neuron. 110, 3458–3483. doi: 10.1016/j.neuron.2022.10.020
Pengyue, Z., Tao, G., Hongyun, H., Liqiang, Y., and Yihao, D. (2017). Breviscapine confers a neuroprotective efficacy against transient focal cerebral ischemia by attenuating neuronal and astrocytic autophagy in the penumbra. Biomed. Pharmacother. 90, 69–76. doi: 10.1016/j.biopha.2017.03.039
Poller, W. C., Downey, J., Mooslechner, A. A., Khan, N., Li, L., Chan, C. T., et al. (2022). Brain motor and fear circuits regulate leukocytes during acute stress. Nature. 607, 578–584.doi: 10.1038/s41586-022-04890-z
Pulous, F. E., Cruz-Hernandez, J. C., Yang, C., Kaya, Z., Paccalet, A., Wojtkiewicz, G., et al. (2022). Cerebrospinal fluid can exit into the skull bone marrow and instruct cranial hematopoiesis in mice with bacterial meningitis. Nat. Neurosci. 25, 567–576. doi: 10.1038/s41593-022-01060-2
Rahimi, S., Dadfar, B., Tavakolian, G., Asadi, R. A., Rashid, S. A., and Siahposht-Khachaki, A. (2021). Morphine attenuates neuroinflammation and blood-brain barrier disruption following traumatic brain injury through the opioidergic system. Brain Res. Bull. 176, 103–111. doi: 10.1016/j.brainresbull.2021.08.010
Sha, R., Zhang, B., Han, X., Peng, J., Zheng, C., Zhang, F., et al. (2019). Electroacupuncture alleviates ischemic brain injury by inhibiting the miR-223/NLRP3 pathway. Med. Sci. Monit. 25, 4723–4733. doi: 10.12659/MSM.917213
Shen, J., Li, Y. Z., Yao, S., Zhu, Z. W., Wang, X., Sun, H. H., et al. (2022). Hu'po anshen decoction accelerated fracture-healing in a rat model of traumatic brain injury through activation of PI3K/AKT pathway. Front. Pharmacol. 13, 952696. doi: 10.3389/fphar.2022.952696
Shi, H., Wang, H. L., Pu, H. J., Shi, Y. J., Zhang, J., Zhang, W. T., et al. (2015). Ethyl pyruvate protects against blood-brain barrier damage and improves long-term neurological outcomes in a rat model of traumatic brain injury. CNS Neurosci. Ther. 21, 374–384. doi: 10.1111/cns.12366
Vera Quesada, C. L., Rao, S. B., Torp, R., and Eide, P. K. (2023). Immunohistochemical visualization of lymphatic vessels in human dura mater: methodological perspectives. Fluids Barriers CNS. 20, 23. doi: 10.1186/s12987-023-00426-3
Vidal-Itriago, A., Radford, R., Aramideh, J. A., Maurel, C., Scherer, N. M., Don, E. K., et al. (2022). Microglia morphophysiological diversity and its implications for the CNS. Front. Immunol. 13, 997786. doi: 10.3389/fimmu.2022.997786
Walter, H. L., Pikhovych, A., Endepols, H., Rotthues, S., Barmann, J., Backes, H., et al. (2022). Transcranial-direct-current-stimulation accelerates motor recovery after cortical infarction in mice: the interplay of structural cellular responses and functional recovery. Neurorehabil. Neural Repair. 36, 701–714. doi: 10.1177/15459683221124116
Wang, X., Zhang, C., Li, Y., Xu, T., Xiang, J., Bai, Y., et al. (2022). High-throughput mrna sequencing reveals potential therapeutic targets of febuxostat in secondary injury after intracerebral hemorrhage. Front. Pharmacol. 13, 833805. doi: 10.3389/fphar.2022.833805
Wei, P., Wang, K., Luo, C., Huang, Y., Misilimu, D., Wen, H., et al. (2021). Cordycepin confers long-term neuroprotection via inhibiting neutrophil infiltration and neuroinflammation after traumatic brain injury. J. Neuroinflammation. 18, 137. doi: 10.1186/s12974-021-02188-x
Xie, N., Fan, F., Jiang, S., Hou, Y., Zhang, Y., Cairang, N., et al. (2022). Rhodiola crenulate alleviates hypobaric hypoxia-induced brain injury via adjusting NF-kappaB/NLRP3-mediated inflammation. Phytomedicine. 103, 154240. doi: 10.1016/j.phymed.2022.154240
Xin, Y. Y., Wang, J. X., and Xu, A. J. (2022). Electroacupuncture ameliorates neuroinflammation in animal models. Acupunct. Med. 40, 474–483. doi: 10.1177/09645284221076515
Zhang, K. Y., Rui, G., Zhang, J. P., Guo, L., An, G. Z., Lin, J. J., et al. (2020). Cathodal tDCS exerts neuroprotective effect in rat brain after acute ischemic stroke. BMC Neurosci. 21, 21. doi: 10.1186/s12868-020-00570-8
Zhang, Q., Zhang, J., Yan, Y., Zhang, P., Zhang, W., and Xia, R. (2017). Proinflammatory cytokines correlate with early exercise attenuating anxiety-like behavior after cerebral ischemia. Brain Behav. 7, e00854. doi: 10.1002/brb3.854
Keywords: neuro-immune communication, inflammatory, brain injury, therapeutic strategy, neuroprotection
Citation: Zhang P, Bai Y, Zhang F, Zhang X, Deng Y and Ding Y (2023) Editorial: Therapeutic relevance and mechanisms of neuro-immune communication in brain injury. Front. Cell. Neurosci. 17:1209083. doi: 10.3389/fncel.2023.1209083
Received: 20 April 2023; Accepted: 20 July 2023;
Published: 01 August 2023.
Edited and reviewed by: Dirk M. Hermann, University of Duisburg-Essen, Germany
Copyright © 2023 Zhang, Bai, Zhang, Zhang, Deng and Ding. 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: Pengyue Zhang, enB5MTk4MDIwMDAmI3gwMDA0MDsxNjMuY29t