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The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury
Open accessAbstract
During the transition from acute to chronic stages of recovery after spinal cord injury (SCI), there is an evolving state of immunologic dysfunction that exacerbates the problems associated with the more clinically obvious neurologic deficits. Since injury directly affects cells embedded within the “immune privileged/specialized” milieu of the spinal cord, maladaptive or inefficient responses are likely to occur. Collectively, these responses qualify as part of the continuum of “SCI disease” and are important therapeutic targets to improve neural repair and neurological outcome. Generic immune suppressive therapies have been largely unsuccessful, mostly because nflammation and immunity exert both beneficial (plasticity enhancing) and detrimental (e.g. glia- and neurodegenerative; secondary damage) effects and these functions change over time. Moreover, “compartmentalized” investigations, limited to only intraspinal inflammation and associated cellular or molecular changes in the spinal cord, neglect the reality that the structure and function of the CNS is influenced by systemic immune challenges and that the immune system is hardwired into the nervous system. Here, we consider this interplay during the progression from acute to chronic SCI. Specifically, we survey impaired/non-resolving intraspinal inflammation and the paradox of systemic inflammatory responses in the face of ongoing chronic immune suppression and autoimmunity. The concepts of systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS) and ‘neurogenic’ spinal cord injury-induced immune depression syndrome (SCI-IDS) are discussed as determinants of impaired ‘host-defense’ and trauma-induced autoimmunity.
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“which is impaired in individuals with UMNDs such as MS, BI, stroke, and SCI.46–50”
From Feasibility, Acceptability, and Efficacy of Mindfulness Training in People With Upper Motor Neuron Disorders: A Systematic Review (2022) · cites this paper as [50]
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“Immediately after injury the spinal cord undergoes massive cellular and molecular changes, including increased cell death [64, 65], infiltration of inflammation cells in the lesion [2–6], axon degeneration [7–10], and OL and myelin loss [13–16, 66, 67].”
From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [5]
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“This study establishes three main points: (1) time and level-matched laminectomy controls are essential for accurate data interpretation after SCI; (2) there exist both acute and chronic differences in plasma protein expression between cSCI and tSCI; and (3) splenic atrophy is not a robust phenomenon after incomplete…”
InfluentialInflammatory Stress Effects on Health and Function After Spinal Cord Injury
Noller, C. M., Groah, S. L., & Nash, M. S. (2017) · Topics in Spinal Cord Injury Rehabilitation · doi:10.1310/sci2303-207 · Cited by 42
“specific immune cells involved and the temporal response of those cells.(2,5,6,20,21) Suppression of acute inflammation is a legitimate clinical goal to preserve function after injury, but current”
BackgroundInfluentialAutonomic nervous system and neuroimmune interactions
Benarroch, E. E. (2019) · Neurology · doi:10.1212/wnl.0000000000006942 · Cited by 43
Biomaterial strategies for limiting the impact of secondary events following spinal cord injury
Ham, T. R., & Leipzig, N. D. (2017) · Biomedical Materials · doi:10.1088/1748-605x/aa9bbb · Cited by 41
Neuroimmunology of traumatic spinal cord injury: A brief history and overview
Popovich, P. G. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.05.001 · Cited by 42
Self-citationSpinal Cord Injury in Rats Disrupts the Circadian System
Gaudet, A. D., Fonken, L. K., Ayala, M. T., Bateman, E. M., Schleicher, W. E., Smith, E. J., D’Angelo, H. M., Maier, S. F., & Watkins, L. R. (2018) · eNeuro · doi:10.1523/eneuro.0328-18.2018 · Cited by 40
“For instance, SCI suppresses peripheral immunity, which increases susceptibility to infection (Schwab et al., 2014).”
BackgroundSpinal cord injury drives chronic brain changes
Labombarda, F., & Jure, I. (2017) · Neural Regeneration Research · doi:10.4103/1673-5374.211177 · Cited by 39
“On the one hand, the systemic immune function is markedly altered after SCI and this mechanism could affect the brain (Popovich and McTigue, 2009; Schwab et al., 2014) and on the other hand, corticosterone released in the acute phase after SCI could model the brain producing long-term alterations.”
Peripheral Immune Dysfunction: A Problem of Central Importance after Spinal Cord Injury
Jeffries, M. A., & Tom, V. J. (2021) · Biology · doi:10.3390/biology10090928 · Cited by 38
“While much research has focused on the resulting neuroinflammation in the spinal cord after SCI, there is also persistent, low-grade, peripheral inflammation that has been identified in SCI individuals (Figure 1) [6,7].”
BackgroundChen, X., Chen, X., Huang, X., Qin, C., Fang, Y., Liu, Y., Zhang, G., Pan, D., Wang, W., & Xie, M. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9118-1 · Cited by 35
“responses also substantially contribute to the secondary tissue degeneration and regeneration failure after SCI [3,37,38].”
Lee, C. Y., Chooi, W. H., Ng, S., & Chew, S. Y. (2022) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10389 · Cited by 38
System failure: Systemic inflammation following spinal cord injury
DiSabato, D. J., Marion, C. M., Mifflin, K. A., Alfredo, A. N., Rodgers, K. A., Kigerl, K. A., Popovich, P. G., & McTigue, D. M. (2023) · European Journal of Immunology · doi:10.1002/eji.202250274 · Cited by 40
“For a more detailed discussion on this overall immune system paradox, the reader is referred to the in-depth review published by Schwab et al. [29].”
BackgroundSelf-citationNarzo, A. F. D., Kozlenkov, A., Ge, Y., Zhang, B., Sanelli, L., May, Z., Li, Y., Fouad, K., Cardozo, C. P., Koonin, E. V., et al. (2015) · Scientific Reports · doi:10.1038/srep12615 · Cited by 35
Allicin protects traumatic spinal cord injury through regulating the HSP70/Akt/iNOS pathway in mice
Wang, S., & Ren, D. (2016) · Molecular Medicine Reports · doi:10.3892/mmr.2016.5651 · Cited by 34
“With high incidences of disability and other serious consequences, traumatic spinal cord injury (TSCI) can result in catastrophic damage to patients (1).”
BackgroundPediatric Spinal Cord Injury: A Review
Cunha, N., Malvea, A., Sadat, S., Fehlings, M. G., & Ibrahim, G. M. (2023) · Children · doi:10.3390/children10091456 · Cited by 35
Circulating T cell subsets are altered in individuals with chronic spinal cord injury
Monahan, R., Stein, A., Gibbs, K., Bank, M. A., & Bloom, O. (2015) · Immunologic Research · doi:10.1007/s12026-015-8698-1 · Cited by 34
“Taken together, the present findings of altered T cell subsets in individuals chronic SCI may be relevant to infection susceptibility among this population as well as to other manifestations of immunosuppression or immune system dysfunction observed in chronic SCI [4, 5].”
BackgroundInfluentialCentrally Synthesized Estradiol Is a Potent Anti-Inflammatory in the Injured Zebra Finch Brain
Pedersen, A. L., Nelson, L. H., & Saldanha, C. J. (2016) · Endocrinology · doi:10.1210/en.2015-1991 · Cited by 33
Characterization of the Antibody Response after Cervical Spinal Cord Injury
Ulndreaj, A., Τζέκου, Α., Mothe, A. J., Siddiqui, A. M., Dragas, R., Tator, C. H., Torlakovic, E., & Fehlings, M. G. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2016.4498 · Cited by 33
Riemann, L., Younsi, A., Scherer, M., Zheng, G., Skutella, T., Unterberg, A. W., & Zweckberger, K. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00428 · Cited by 33
“The inflammatory response likely plays a pivotal role in the pathophysiology of SCI and the neuroregeneration after SCI (5, 8).”
BackgroundConstitutive DAMPs in CNS injury: From preclinical insights to clinical perspectives
Castellanos-Molina, A., Bretheau, F., Boisvert, A., Bélanger, D., & Lacroix, S. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.07.047 · Cited by 35
“…of microglia, pericytes, fibroblasts, and astrocytes (concentric circles surrounding the secondary lesion). after clearance of debris, and in cases of SCI, they remain in the injured spinal cord for weeks to months, releasing additional waves of proinflammatory mediators (Schwab et al., 2014).”
Díaz, D., López‐Dolado, E., Haro, S., Monserrat, J., Martínez-Alonso, C., Balomeros, D., Albillos, A., & Álvarez‐Mon, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020744 · Cited by 32
“It is well known that acute SCI patients show an intense disturbance of immuneinflammatory responses, which includes hallmarks of inflammation and immunodeficiency [12,13].”
BackgroundJiang, S., Wu, Y., Wu, S., Ye, S., Kong, R., Chang, J., Xia, M., Bao, J.-P., Peng, X., Hong, X., et al. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00481-5 · Cited by 31
Sefiani, A., & Geoffroy, C. G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.682259 · Cited by 31
Pang, R., Wang, J., Xiong, Y.-S., Liu, J., Ma, X., Gou, X., He, X., Cheng, C., Wang, W., Zheng, J., et al. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.986480 · Cited by 30
“Based on previous findings (Beattie, 2004; Meisel et al., 2005; Popovich, 2014; Schwab et al., 2014) and our clinical experience, patients with SCI have decreased immunity, including immunosuppression, during acute phase, subacute phase, and even recovery periods, which is also the reason why patients are more likely…”
ResultLewis, N. E., Tabarestani, T. Q., Cellini, B. R., Zhang, N., Marrotte, E. J., Wang, H., Laskowitz, D. T., Abd‐El‐Barr, M. M., & Faw, T. D. (2022) · Neurospine · doi:10.14245/ns.2244476.238 · Cited by 30
Pleiotropic molecules in axon regeneration and neuroinflammation
Lang, B. T., Wang, J., Filous, A. R., Au, N. P. B., Ma, C. H. E., & Shen, Y. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.04.031 · Cited by 32
Chen, H., Li, J., Liang, S., Lin, B., Peng, Q., Zhao, P., Cui, J., & Rao, Y. (2017) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2017.4049 · Cited by 30
“However, one popular hypothesis is that the primary problem resulting from secondary spinal injury is chemical hypoxia (2), and further damage following SCI is caused by decreased local blood flow and hypoxia.”
BackgroundČížková, D., Devaux, S., Marrec‐Croq, F. L., Franck, J., Slovinská, L., Blaško, J., Rosocha, J., Špaková, T., Lefebvre, C., Fournier, I., et al. (2014) · Scientific Reports · doi:10.1038/srep07514 · Cited by 32
“The beneficial and detrimental effects of inflammation have been compared to glial scar, which is actively formed after spinal cord injury (SCI) 22 .”
Fang, Y., Huang, X., Wan, Y., Tian, H., Tian, Y., Wang, W., Zhu, S., & Xie, M. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.13980 · Cited by 32
Park, A., Anderson, D., Battaglino, R. A., Nguyen, N. M. H., & Morse, L. R. (2020) · Journal of Spinal Cord Medicine · doi:10.1080/10790268.2020.1773029 · Cited by 28
Bigford, G. E., & Garshick, E. (2022) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2022.102303 · Cited by 27
Tan, A. Q., Barth, S., & Trumbower, R. D. (2020) · Current Physical Medicine and Rehabilitation Reports · doi:10.1007/s40141-020-00270-8 · Cited by 27
Lagu, T. C., Schroth, S. L., Haywood, C., Heinemann, A. W., Kessler, A., Morse, L. R., Khan, S. S., Kershaw, K. N., & Nash, M. S. (2023) · Circulation · doi:10.1161/circulationaha.123.064859 · Cited by 27
Meng, X.-E., Zhang, Y., Li, N., Fan, D., Yang, C., Li, H., Guo, D. Z., & Pan, S. (2016) · Genetics and Molecular Research · doi:10.4238/gmr.15016933 · Cited by 26
Self-citationDynamic changes in the systemic immune responses of spinal cord injury model mice
Gao, T., Huang, F., Xie, Y., Wang, W.-Q., Wang, W., Mu, D., Cui, Y., & Wang, B. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.290910 · Cited by 28
Myeloid-derived suppressor cells mediate immune suppression in spinal cord injury
Wang, L., Yu, W.-B., Tao, L., & Xu, Q. R. (2015) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2015.11.023 · Cited by 25
“During the transition from an acute stage to a chronic stage of recovery after SCI, immune depression plays an important role that exacerbates the symptoms associated with the present neurologic deficits (Schwab et al., 2014).”
BackgroundMahmoudi, N., Mohamed, E., Dehnavi, S. S., Aguilar, L. M. C., Harvey, A. R., Parish, C. L., Williams, R. J., & Nisbet, D. R. (2023) · Advanced Science · doi:10.1002/advs.202303707 · Cited by 23
Metadata
- Authors
- Schwab, J. M., Zhang, Y., Kopp, M. A., Brommer, B., & Popovich, P. G.
- Affiliations
- Stiftung Charité (DE)
- The Ohio State University Wexner Medical Center (US)
- Corresponding author
- Schwab, Jan M.
- Popovich, Phillip G.
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 258
- Pages
- 121-129
- ISSN
- 0014-4886 (ISSN-L)
- PMC
- PMC4099970
- OpenAlex
- W1991275594
- Semantic Scholar
- 4a08f8b28fb79888e283c1be793ea654af48618a
- Cited by
- 260
- References
- 117
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 17 · 2023: 24 · 2022: 35 · 2021: 32 · 2020: 30 · 2019: 22 · 2018: 17 · 2017: 22 · 2016: 17 · 2015: 9 · 2014: 4
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-11-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS047175, R21NS067260)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Spinal Cord Injury Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- chronic spinal cord injury, neuroinflammation, systemic immune suppression, autoimmunity, traumatic spinal cord injury, systemic inflammatory response syndrome, compensatory anti-inflammatory response syndrome, immune privilege, secondary injury, glial activation, neurodegeneration, host defense
- MeSH terms
- Animals, Chronic Disease, Humans, Immune Tolerance, Inflammation, Spinal Cord Injuries, Autoimmunity, Inflammation Mediators
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