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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Hypothalamic-pituitary-adrenal axis function is impaired in individuals with upper motor neuron disorders such as multiple sclerosis, brain injury, stroke, and spinal cord injury.
“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]
The SCI-IDS and infection section reports dysregulation of the HPA axis after spinal cord injury, particularly with higher-level injuries (T3 rather than T9). It does not establish impaired HPA-axis function in multiple sclerosis, brain injury, or stroke, so it supports only the spinal-cord-injury portion of the claim. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredImmediately after injury the spinal cord undergoes massive cellular and molecular changes, including increased cell death, infiltration of inflammation cells, axon degeneration, and OL and myelin loss.
“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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“Activation of SPNs causes release of norepinephrine (NE) and GCs from postganglionic nerve terminals and the adrenal gland (Engeland and Arnhold, 2005).”
BackgroundFunctional neurological recovery after spinal cord injury is impaired in patients with infections
Failli, V., Kopp, M. A., Gericke, C., Martus, P., Klingbeil, S., Brommer, B., Laginha, I., Chen, Y., DeVivo, M. J., Dirnagl, U., et al. (2012) · Brain · doi:10.1093/brain/aws267 · Cited by 175 · cited 6× · see citing works
“Thus, infections qualify as independent neurobiological rehabilitation confounders that impair the endogenous recovery potential after SCI (Dietz and Fouad, 2014; Failli et al., 2012).”
BackgroundInfluentialSelf-citationAnkeny, D. P., Lucin, K. M., Sanders, V. M., McGaughy, V. M., & Popovich, P. G. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04147.x · Cited by 171 · cited 3× · see citing works
“…intraspinal inflammation persists indefinitely (Popovich et al., 1997; Prüss et al., 2011; Rosenberg et al., 2005) and depending on injury level, anti-inflammatory or even autoimmune pathologies develop (Ankeny et al., 2006; Hayes et al., 2002; Popovich et al., 1997; Zajarías-Fainsod et al., 2012).”
BackgroundSelf-citationVargas, M. E., Watanabe, J., Singh, S. J., Robinson, W. H., & Barres, B. A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001948107 · Cited by 168 · cited 1× · see citing works
“Mouse S and CSF Propagated myelin clearance and regeneration (after PNS-injury) (Vargas et al., 2010)”
BackgroundImmune depression syndrome following human spinal cord injury (SCI): A pilot study
Riegger, T., Conrad, S., Schluesener, H. J., Kaps, H.-P., Badke, A., Baron, C., Gerstein, J., Dietz, K., Abdizahdeh, M., & Schwab, J. M. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.08.021 · Cited by 168 · cited 2× · see citing works
“…response evolves in parallel including potent anti-inflammatory mechanisms both within and outside the spinal cord, presumably to regulate ongoing inflammation initiated by trauma (Lucin et al., 2007, 2009; Riegger et al., 2007, 2009, for review see Irwin and Cole, 2011; Meisel et al., 2005) (Fig.”
BackgroundSelf-citationBlight, A. R. (1991) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(91)90159-5 · Cited by 162 · cited 4× · see citing works
“, 2005), that is conserved in different species including humans (Blight, 1991; Dulin et al., 2013; Fleming et al., 2006; Kigerl et al., 2006; Popovich et al., 1997).”
BackgroundInfluentialBlockade of adrenoreceptors inhibits the splenic response to stroke
Ajmo, C. T., Collier, L. A., Leonardo, C. C., Hall, A. A., Green, S. M., Womble, T. A., Cuevas, J., Willing, A. E., & Pennypacker, K. R. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.03.044 · Cited by 150 · cited 3× · see citing works
“Contents lists available at ScienceDirect Experimental Neurology j ourna l homepage: www.e lsev ie r .com/ locate /yexnr Review The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury Jan M. Schwab a,b,⁎,1, Yi Zhang c,1, Marcel A. Kopp a, Benedikt…”
BackgroundInfluentialEnouz, S., Carrié, L., Merkler, D., Bevan, M. J., & Zehn, D. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20120905 · Cited by 142 · cited 2× · see citing works
“…a dynamic process, which is likely to be a function of the extent of SCI-IDS (Kopp et al., 2013; Meisel et al., 2005) and consecutive infections (Enouz et al., 2012) supported by clinical observations demonstrating elevated auto-antibody titers in patients with concomitant infections (Davies et…”
BackgroundSpinal cord injury‐induced immune depression syndrome (SCI‐IDS)
Riegger, T., Conrad, S., Liu, K., Schluesener, H. J., Adibzahdeh, M., & Schwab, J. M. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05447.x · Cited by 141 · cited 2× · see citing works
“…response evolves in parallel including potent anti-inflammatory mechanisms both within and outside the spinal cord, presumably to regulate ongoing inflammation initiated by trauma (Lucin et al., 2007, 2009; Riegger et al., 2007, 2009, for review see Irwin and Cole, 2011; Meisel et al., 2005) (Fig.”
BackgroundSelf-citationTeeling, J. L., Cunningham, C., Newman, T. A., & Perry, V. H. (2010) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2009.11.006 · Cited by 139 · cited 2× · see citing works
“, 2011) but also “sickness behavior” (Teeling et al., 2010) were reported after systemic endotoxin challenge as a model of systemic infections (Perry et al.”
BackgroundGold, R., Stangel, M., & Dalakas, M. C. (2007) · Nature Clinical Practice Neurology · doi:10.1038/ncpneuro0376 · Cited by 139 · cited 1× · see citing works
“IgG Rat Human Immunomodulatory effect in human autoimmune disease (Gold et al., 2007)”
BackgroundOhri, S., Maddie, M. A., Zhao, Y.-M., Qiu, M., Hetman, M., & Whittemore, S. (2011) · Glia · doi:10.1002/glia.21191 · Cited by 119 · cited 1× · see citing works
“For example, the oxidative lesion microenvironment may damage leukocyte (and glial) mitochondria, which could impair normal cellular functions including the ability to sustain selfrepair or maintenance functions (Lin et al., 2007; Ohri et al., 2011; Sullivan et al., 2005).”
BackgroundSystemic inflammation induces axon injury during brain inflammation
Moreno, B., Jukes, J., Vergara‐Irigaray, N., Errea, O., Villoslada, P., Perry, V. H., & Newman, T. A. (2011) · Annals of Neurology · doi:10.1002/ana.22550 · Cited by 118 · cited 2× · see citing works
“, 2005) and axonal injury (Moreno et al., 2011) but also “sickness behavior” (Teeling et al.”
BackgroundB cells and autoantibodies: Complex roles in CNS injury
Ankeny, D. P., & Popovich, P. G. (2010) · Trends in Immunology · doi:10.1016/j.it.2010.06.006 · Cited by 116 · cited 1× · see citing works
“Each has been implicated in progression of secondary injury after SCI (Ankeny and Popovich, 2010).”
BackgroundThe systemic response to CNS injury
Anthony, D. C., & Couch, Y. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.03.013 · Cited by 116 · cited 1× · see citing works
“Although distinct from sepsis, “sterile” inflammatory lesions in the lesioned CNS (e.g. after SCI) trigger a host response resembling SIRS (see Anthony and Couch, 2014-in this issue).”
BackgroundImmunological regulation of neuronal degeneration and regeneration in the injured spinal cord
Popovich, P. G. (2000) · Progress in brain research · doi:10.1016/s0079-6123(00)28006-0 · Cited by 112 · cited 2× · see citing works
“…the pathogenesis of post-traumatic secondary injury, a delayed and progressive form of neurodegeneration that exacerbates cell death beyond the site of primary mechanical trauma (Blight, 1991; Dulin et al., 2013; Dusart and Schwab, 1994; Fleming et al., 2006; Popovich, 2000; Schwab et al., 2006).”
BackgroundSelf-citationPrüß, H., Kopp, M. A., Brommer, B., Gatzemeier, N., Laginha, I., Dirnagl, U., & Schwab, J. M. (2011) · Brain Pathology · doi:10.1111/j.1750-3639.2011.00488.x · Cited by 111 · cited 9× · see citing works
“…aim of reducing dwell time of inflammatory cells at the CNS lesion or in peripheral tissues (see Anthony, 2014-in this issue) is an alternative to the conventional anti-inflammatory strategies, which solely aim to reduce infiltrating leukocyte cell numbers at the lesion site (Prüss et al., 2011).”
BackgroundInfluentialSelf-citationMeuth, S. G., Simon, O. J., Grimm, A. M., Melzer, N., Herrmann, A. M., Spitzer, P., Landgraf, P., & Wiendl, H. (2008) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2007.11.013 · Cited by 107 · cited 1× · see citing works
“As a consequence of SCI and subsequent neurodegeneration, such control is lost and microglia become activated (Cardona et al., 2006; Meuth et al., 2008).”
BackgroundPrüß, H., Rosche, B., Sullivan, A. B., Brommer, B., Wengert, O., Gronert, K., & Schwab, J. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055859 · Cited by 103 · cited 1× · see citing works
“This appears to be true even in patients with multiple sclerosis (MS), an inflammatory human CNS disease with comparatively less tissue damage (Prüss et al., 2013).”
BackgroundSelf-citationSchwab, J., Frei, E., Klusman, I., Schnell, L., Schwab, M., & Schluesener, H. (2001) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(01)00375-7 · Cited by 102 · cited 1× · see citing works
“Injury to the spinal cord elicits a robust intraspinal inflammatory response (Fleming et al., 2006; Popovich et al., 1996a,b; Rice et al., 2007; Schwab et al., 2001).”
BackgroundSelf-citationStress hormones collaborate to induce lymphocyte apoptosis after high level spinal cord injury
Lucin, K. M., Sanders, V. M., & Popovich, P. G. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06232.x · Cited by 102 · cited 4× · see citing works
“…response evolves in parallel including potent anti-inflammatory mechanisms both within and outside the spinal cord, presumably to regulate ongoing inflammation initiated by trauma (Lucin et al., 2007, 2009; Riegger et al., 2007, 2009, for review see Irwin and Cole, 2011; Meisel et al., 2005) (Fig.”
BackgroundInfluentialSelf-citationCharacterization of the Early Neuroinflammation After Spinal Cord Injury in Mice
Rice, T. K., Larsen, J., Rivest, S., & Yong, V. W. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000248552.07338.7f · Cited by 98 · cited 1× · see citing works
“Injury to the spinal cord elicits a robust intraspinal inflammatory response (Fleming et al., 2006; Popovich et al., 1996a,b; Rice et al., 2007; Schwab et al., 2001).”
BackgroundVallières, N., Berard, J. L., David, S., & Lacroix, S. (2005) · Glia · doi:10.1002/glia.20266 · Cited by 95 · cited 1× · see citing works
“Cellular and myelin debris are potent inflammatory signals that persist indefinitely at and nearby the injury site because of inefficient or impaired phagocytosis (George and Griffin, 1994; Magnus et al., 2002; Vallières et al., 2006).”
BackgroundSpinal cord injury induces early and persistent lesional P2X4 receptor expression
Schwab, J. M., Guo, L., & Schluesener, H. J. (2005) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2005.02.016 · Cited by 90 · cited 1× · see citing works
“Chronic remote activation of microglia has been implicated in the onset and progression of neuropathic pain (Detloff et al., 2008; Hains and Waxman, 2006; Schwab et al., 2005; Zhao et al., 2007).”
BackgroundSelf-citationJones, T. B., Hart, R. P., & Popovich, P. G. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0305-05.2005 · Cited by 87 · see citing works
Self-citationQiao, F., Atkinson, C., Song, H., Pannu, R., Singh, I., & Tomlinson, S. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.060248 · Cited by 86 · cited 1× · see citing works
“Also, axon loss, demyelination and inflammatory cell accumulation are reduced and functional recovery is improved in SCI mice that are deficient in complement C3 (Qiao et al., 2006).”
BackgroundImproved regeneration after spinal cord injury in mice lacking functional T- and B-lymphocytes
Wu, B., Matić, D. R., Djogo, N., Szpotowicz, E., Schachner, M., & Jakovčevski, I. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.07.016 · Cited by 84 · cited 2× · see citing works
“Lacking functional Mice RAG2-/Reduced demyelinization (Wu et al., 2012).”
BackgroundT cell responses to myelin basic protein in patients with spinal cord injury and multiple sclerosis
Kil, K., Zang, Y. C. Q., Yang, D., Markowski, J., Fuoco, G. S., Vendetti, G. C., Rivera, V. M., & Zhang, J. Z. (1999) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(99)00057-0 · Cited by 83 · cited 1× · see citing works
“SCI also triggers autoimmune T- and B-cell responses in humans but the pathogenic significance of these responses remains uncertain (Kil et al., 1999; Saltzman et al., 2013).”
BackgroundPrimary progressive multiple sclerosis: progress and challenges
Rice, C. M., Cottrell, D., Wilkins, A., & Scolding, N. J. (2013) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2012-304140 · Cited by 74 · cited 1× · see citing works
“In the progressive phase of MS, new demyelinating lesions are rare but diffuse atrophy of the gray and white matter and changes in the macroscopically “normal-appearing white matter” (NAWM) become prominent (Lassmann et al., 2007; Rice et al., 2013).”
BackgroundLin, Y., Vreman, H. J., Wong, R. J., Tjoa, T., Yamauchi, T., & Noble‐Haeusslein, L. J. (2006) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600412 · Cited by 73 · cited 1× · see citing works
“For example, the oxidative lesion microenvironment may damage leukocyte (and glial) mitochondria, which could impair normal cellular functions including the ability to sustain selfrepair or maintenance functions (Lin et al., 2007; Ohri et al., 2011; Sullivan et al., 2005).”
BackgroundLymphocytes and autoimmunity after spinal cord injury
Jones, T. B. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.03.003 · Cited by 72 · cited 2× · see citing works
“…robust activation of myeloid cells (e.g., neutrophils, monocytes/macrophages; also see Kigerl et al., 2014-in this issue) and the latter activation of self-reactive lymphocytes and enhanced synthesis of autoantibodies (Hayes et al., 2002; Davies et al., 2007; also see Jones, 2014-in this issue).”
BackgroundImmune system-neuroendocrine dysregulation in spinal cord injury
Cruse, J. M., Keith, J. C., Bryant, M. L., & Lewis, R. E. (1996) · Immunologic Research · doi:10.1007/bf02935314 · Cited by 72 · cited 1× · see citing works
“…results from the loss of descending modulation of spinal sympathetic pre-ganglionic neurons (SPNs) lying caudal to the lesion, as well as the exaggerated spinal circuitry/ autonomic reflex triggered by a strong sensory input (Cruse et al., 1993, 1996; Lucin et al., 2007, 2009; Zhang et al., 2013).”
BackgroundSchwab, J. M., Brechtel, K., Nguyen, T. D., & Schluesener, H. J. (2000) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(00)00372-6 · Cited by 71 · cited 4× · see citing works
“Although inflammatory cells persist at/nearby the injury site for months post-injury, none are as prominent as activated microglia and monocyte-derived macrophages, which persistently synthesize inflammatory enzymes that have been linked with chronic pathology and loss of function (Dulin et al., 2013; Schwab et al., 2…”
BackgroundInfluentialSelf-citationGilbert, O. N., Croffoot, J. R., Taylor, A. J., Nash, M. S., Schomer, K. G., & Groah, S. L. (2013) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2013.11.028 · Cited by 69 · cited 2× · see citing works
“…as obesity and associated metabolic syndromes contribute to atherosclerosis, another form of chronic inflammation (Nathan and Ding, 2010), a cardiometabolic syndrome develops after SCI and could exacerbate neuroinflammation and neurologic dysfunction (Bigford et al., 2013; Gilbert et al., 2014).”
BackgroundNguyen, D. H., Cho, N., Satkunendrarajah, K., Austin, J. W., Wang, J., & Fehlings, M. G. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-224 · Cited by 65 · cited 1× · see citing works
“Unspecific, derived from healthy donors Neuroprotective in xenogenous application after compression SCI in rats (Nguyen et al., 2012).”
BackgroundDamage control in the nervous system: beware the immune system in spinal cord injury
Popovich, P. G., & McTigue, D. M. (2009) · Nature Medicine · doi:10.1038/nm0709-736 · Cited by 63 · cited 1× · see citing works
“Dynamic interactions between the “immune-privileged/-specialized” spinal cord and systemic immune organs innervated by the CNS are critical considerations for the evolution of the “SCI-disease”-state that is initiated by traumatic SCI (Popovich and McTigue, 2009).”
BackgroundSelf-citationROSENBERG, L. J., Zai, L. J., & Wrathall, J. R. (2004) · Glia · doi:10.1002/glia.20096 · Cited by 60 · cited 4× · see citing works
“Nevertheless, intraspinal inflammation after SCI includes a non self-limiting, smoldering inflammatory cascade (Prüss et al., 2011; Rosenberg et al., 2005), that is conserved in different species including humans (Blight, 1991; Dulin et al.”
BackgroundInfluentialCellular Mechanisms of Central Nervous System Repair by Natural Autoreactive Monoclonal Antibodies
Wright, B. R., Warrington, A. E., Edberg, D., & Rodriguez, M. (2009) · Archives of Neurology · doi:10.1001/archneurol.2009.262 · Cited by 57 · see citing works
Rabchevsky, A. G., Patel, S. P., Lyttle, T. S., Eldahan, K. C., O'Dell, C. R., Zhang, Y., Popovich, P. G., Kitzman, P. H., & Donohue, K. D. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00329 · Cited by 54 · cited 1× · see citing works
“For example, gabapentin, a GABA (gamma-aminobutyric acid) analogue used clinically to treat neuropathic pain, has also been shown in experimental models to significantly reduce tail spasticity and autonomic dysreflexia after severe SCI (Rabchevsky et al., 2012).”
BackgroundSelf-citationDulin, J. N., Karoly, E. D., Wang, Y., Strobel, H. W., & Grill, R. J. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.6128-11.2013 · Cited by 52 · cited 7× · see citing works
“…persist at/nearby the injury site for months post-injury, none are as prominent as activated microglia and monocyte-derived macrophages, which persistently synthesize inflammatory enzymes that have been linked with chronic pathology and loss of function (Dulin et al., 2013; Schwab et al., 2000).”
BackgroundInfluentialMagnus, T., Chan, A., Savill, J., Toyka, K. V., & Gold, R. (2002) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00212-6 · Cited by 52 · cited 1× · see citing works
“Cellular and myelin debris are potent inflammatory signals that persist indefinitely at and nearby the injury site because of inefficient or impaired phagocytosis (George and Griffin, 1994; Magnus et al., 2002; Vallières et al., 2006).”
BackgroundSystemic humoral factors participating in the course of spinal cord injury
Mizrachi, Y., Ohry, A., Aviel, A., Rozin, R., Brooks, M. E., & Schwartz, M. (1983) · Spinal Cord · doi:10.1038/sc.1983.48 · Cited by 51 · see citing works
The role of trauma in the pathogenesis of multiple sclerosis: a review.
Poser, C. (1994) · Clinical neurology and neurosurgery (Dutch-Flemish ed. Print) · doi:10.1016/0303-8467(94)90042-6 · Cited by 50 · cited 2× · see citing works
“Even though trauma and subsequent injury to the blood–spinal cord barrier (BSB) can be linked to neurologic relapses in multiple sclerosis (MS) patients associated with exacerbated neuropathology and loss of function in predisposed rodent models (Jones et al., 2002; Poser, 1994), this de novo autoimmunity elicited by…”
BackgroundCruse, J. M., Lewis, R. E., Bishop, R., Kliesch, W. F., Gaitán, E., & Britt, R. E. (2008) · Pathobiology · doi:10.1159/000163790 · Cited by 50 · cited 1× · see citing works
“…results from the loss of descending modulation of spinal sympathetic pre-ganglionic neurons (SPNs) lying caudal to the lesion, as well as the exaggerated spinal circuitry/ autonomic reflex triggered by a strong sensory input (Cruse et al., 1993, 1996; Lucin et al., 2007, 2009; Zhang et al., 2013).”
BackgroundIMPAIRED PHAGOCYTOSIS OF STAPHYLOCOCCUS AUREUS IN COMPLETE TETRAPLEGICS1
Campagnolo, D. I., Bartlett, J. A., Keller, S. E., Sánchez, W., & Oza, R. (1997) · American Journal of Physical Medicine & Rehabilitation · doi:10.1097/00002060-199707000-00005 · Cited by 50 · cited 2× · see citing works
“…of high dose corticosteroids and is analogously represented in animal and human SCI justifying its translational relevance and extends into the chronic phase after SCI (Campagnolo et al., 1997; Furlan et al., 2006; Lucin et al., 2007, 2009; Riegger et al., 2007, 2009; Zhang et al., 2013).”
BackgroundKopp, M. A., Druschel, C., Meisel, C., Liebscher, T., Prilipp, E., Watzlawick, R., Cinelli, P., Niedeggen, A., Schaser, K.-D., Wanner, G. A., et al. (2013) · BMC Neurology · doi:10.1186/1471-2377-13-168 · Cited by 47 · see citing works
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“…of high dose corticosteroids and is analogously represented in animal and human SCI justifying its translational relevance and extends into the chronic phase after SCI (Campagnolo et al., 1997; Furlan et al., 2006; Lucin et al., 2007, 2009; Riegger et al., 2007, 2009; Zhang et al., 2013).”
BackgroundBradl, M., Bauer, J., Flügel, A., Wekerle, H., & Lassmann, H. (2005) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)62361-9 · Cited by 43 · cited 1× · see citing works
“CD8 N CD4 Rat Immune surveillance (Bradl et al., 2005), preferentially grey matter”
BackgroundSaltzman, J. W., Battaglino, R. A., Salles, L. P., Jha, P., Sudhakar, S., Garshick, E., Stott, H. L., ZAFONTE, R. D., & Morse, L. R. (2012) · Journal of Neurotrauma · doi:10.1089/neu.2012.2501 · Cited by 37 · cited 1× · see citing works
“SCI also triggers autoimmune T- and B-cell responses in humans but the pathogenic significance of these responses remains uncertain (Kil et al., 1999; Saltzman et al., 2013).”
BackgroundAutoreactivity against myelin basic protein in patients with chronic paraplegia
Zajarias-Fainsod, D., Carrillo-Ruiz, J. D., Mestre, H., Grijalva, I., Madrazo, I., & Ibarra, A. (2011) · European Spine Journal · doi:10.1007/s00586-011-2060-7 · Cited by 34 · cited 3× · see citing works
“…intraspinal inflammation persists indefinitely (Popovich et al., 1997; Prüss et al., 2011; Rosenberg et al., 2005) and depending on injury level, anti-inflammatory or even autoimmune pathologies develop (Ankeny et al., 2006; Hayes et al., 2002; Popovich et al., 1997; Zajarías-Fainsod et al., 2012).”
BackgroundSchwartz, M., & Kipnis, J. (2005) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1361.114 · Cited by 31 · cited 1× · see citing works
“Despite the encephalitogenic potential of SCI-activated lymphocytes, protective T cells also are activated after SCI and a subset of endogenous autoreactive cells may exert “repairing” effects the injured CNS (Schwartz and Kipnis, 2005; also see Jones, 2014- in this issue).”
BackgroundBigford, G. E., Bracchi-Ricard, V. C., Keane, R. W., Nash, M. S., & Bethea, J. R. (2013) · ASN NEURO · doi:10.1042/an20130021 · Cited by 29 · cited 2× · see citing works
“…as obesity and associated metabolic syndromes contribute to atherosclerosis, another form of chronic inflammation (Nathan and Ding, 2010), a cardiometabolic syndrome develops after SCI and could exacerbate neuroinflammation and neurologic dysfunction (Bigford et al., 2013; Gilbert et al., 2014).”
BackgroundA human IgM signals axon outgrowth: coupling lipid raft to microtubules
Xu, X., Warrington, A. E., Wright, B. R., Bieber, A. J., Keulen, V. P. V., Pease, L. R., & Rodriguez, M. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07416.x · Cited by 28 · cited 1× · see citing works
“β3-tubulin-reactive? Mouse Recomb Propagated neurite outgrowth/stabilization (Xu et al., 2011)”
Bigford, G. E., Bracchi-Ricard, V. C., Nash, M. S., & Bethea, J. R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041073 · Cited by 20 · see citing works
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Chemical and bio-warfare detection system piloted at US airport
Larkin, M. (2003) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(03)00621-2 · Cited by 4 · see citing works
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Ahuja, C. S., Wilson, J. R., Nori, S., Kotter, M. R. N., Druschel, C., Curt, A., & Fehlings, M. G. (2017) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.18 · Cited by 2,441 · see citing works
Cell biology of spinal cord injury and repair
O’Shea, T. M., Burda, J. E., & Sofroniew, M. V. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90608 · Cited by 590 · see citing works
Immune cell regulation of glia during CNS injury and disease
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Recent update on basic mechanisms of spinal cord injury
Quadri, S. A., Farooqui, M., Ikram, A., Zafar, A., Khan, M. A., Suriya, S. S., Claus, C. F., Fiani, B., Rahman, M. S., Ramachandran, A., et al. (2018) · Neurosurgical Review · doi:10.1007/s10143-018-1008-3 · Cited by 344 · see citing works
Transplanting neural progenitor cells to restore connectivity after spinal cord injury
Fischer, I., Dulin, J. N., & Lane, M. A. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-0314-2 · Cited by 297 · see citing works
Cell-based and stem-cell-based treatments for spinal cord injury: evidence from clinical trials.
Zipser, C., Cragg, J., Guest, J., Fehlings, M., Jutzeler, C., Anderson, A., & Curt, A. (2022) · Lancet Neurology · doi:10.1016/s1474-4422(21)00464-6 · Cited by 212 · see citing works
Reactive astrocytes undergo M1 microglia/macrohpages-induced necroptosis in spinal cord injury
Fan, H., Zhang, K., Shan, L., Kuang, F., Chen, K., Zhu, K., Ma, H., Ju, G., & Wang, Y. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0081-8 · Cited by 225 · see citing works
“Background One unique pathological change after primarily spinal cord injury (SCI) is the secondary injury, which is characterized by continuous tissue loss, reactive astrogliosis and chronic inflammation, and usually leads to gradual expansion of the lesion center and formation of a spinal cavity [1, 2].”
BackgroundMorganti-Kossmann, M. C., Semple, B. D., Hellewell, S. C., Bye, N., & Ziebell, J. M. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1944-6 · Cited by 221 · see citing works
Acute and non-resolving inflammation associate with oxidative injury after human spinal cord injury
Zrzavy, T., Schwaiger, C., Wimmer, I., Berger, T., Bauer, J., Butovsky, O., Schwab, J. M., Lassmann, H., & Höftberger, R. (2020) · Brain · doi:10.1093/brain/awaa360 · Cited by 212 · see citing works
Self-citationGreenhalgh, A. D., Zarruk, J. G., Healy, L. M., Jesudasan, S. J. B., Jhelum, P., Salmon, C. K., Formanek, A., Russo, M. V., Antel, J. P., McGavern, D. B., et al. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2005264 · Cited by 212 · see citing works
“It is still controversial as to whether the net effect of microglia is beneficial or detrimental to CNS injury [4, 5, 60]; however, the kinetics of the microglial response must be considered.”
BackgroundInflammation: A Target for Treatment in Spinal Cord Injury
Freyermuth-Trujillo, X., Segura-Uribe, J. J., Salgado‐Ceballos, H., Orozco-Barrios, C. E., & Coyoy-Salgado, A. (2022) · Cells · doi:10.3390/cells11172692 · Cited by 210 · see citing works
Sun, X., Jones, Z., Chen, X.-M., Zhou, L., So, K., & Ren, Y. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0736-y · Cited by 201 · see citing works
“SCI-IDS, indicated by the loss of splenocytes and leukopenia, is a putative self-defense mechanism that lowers potential autoimmunity to self-antigens produced by damage in the central nervous system [22, 23].”
BackgroundMa, E. L., Smith, A. D., Desai, N., Cheung, L., Hanscom, M., Stoica, B. A., Loane, D. J., Shea‐Donohue, T., & Faden, A. I. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.06.018 · Cited by 173 · see citing works
Aging and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe?
Mayne, K., White, J. A., McMurran, C. E., Rivera, F. J., & de la Fuente, A. G. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.572090 · Cited by 167 · see citing works
The neuroanatomical–functional paradox in spinal cord injury
Fouad, K., Popovich, P. G., Kopp, M. A., & Schwab, J. M. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-00436-x · Cited by 160 · see citing works
Self-citationCytokine and Growth Factor Activation In Vivo and In Vitro after Spinal Cord Injury
García, E., Aguilar-Cevallos, J., Silva‐García, R., & Ibarra, A. (2016) · Mediators of Inflammation · doi:10.1155/2016/9476020 · Cited by 152 · see citing works
“cells are responsible for the generation of autoimmunity in individuals with genetic susceptibility [89, 158, 159].”
BackgroundKim, J., Mahapatra, C., Hong, J., Kim, M. S., Leong, K. W., Kim, H., & Hyun, J. K. (2017) · Advanced Science · doi:10.1002/advs.201700034 · Cited by 147 · see citing works
Intermittent hypoxia and neurorehabilitation
Gonzalez‐Rothi, E. J., Lee, K., Dale, E. A., Reier, P. J., Mitchell, G. S., & Fuller, D. D. (2015) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00235.2015 · Cited by 143 · see citing works
“Systemic inflammation persists for months and even years after SCI and can have considerable impact on the degree of motor recovery (1, 88).”
BackgroundHayta, E., & Elden, H. (2017) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2017.08.001 · Cited by 124 · see citing works
Systemic inflammation in traumatic spinal cord injury
Bloom, O., Herman, P. E., & Spungen, A. M. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.113143 · Cited by 120 · see citing works
Fecal transplant prevents gut dysbiosis and anxiety-like behaviour after spinal cord injury in rats
Schmidt, E. K. A., Torres-Espin, A., Raposo, P. J. F., Madsen, K. L., Kigerl, K. A., Popovich, P. G., Fenrich, K. K., & Fouad, K. (2020) · PLoS ONE · doi:10.1371/journal.pone.0226128 · Cited by 119 · see citing works
“Given the acute and chronic inflammatory state associated with SCI [59,60], it is likely that inflammation plays a role in the etiology of mental health disorders following SCI [6].”
BackgroundSelf-citationO’Connor, G., Jeffrey, E., Madorma, D., Marcillo, A. E., Abreu, M. T., Deo, S. K., Dietrich, W. D., & Daunert, S. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2017.5349 · Cited by 110 · see citing works
Long-term functional outcome in patients with acquired infections after acute spinal cord injury
Kopp, M. A., Watzlawick, R., Martus, P., Failli, V., Finkenstaedt, F. W., Chen, Y., DeVivo, M. J., Dirnagl, U., & Schwab, J. M. (2017) · Neurology · doi:10.1212/wnl.0000000000003652 · Cited by 109 · see citing works
Self-citationConsiderations for Studying Sex as a Biological Variable in Spinal Cord Injury
Stewart, A. N., MacLean, S. M., Stromberg, A. J., Whelan, J. P., Bailey, W. M., Gensel, J. C., & Wilson, M. E. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00802 · Cited by 110 · see citing works
Neuroimmunological therapies for treating spinal cord injury: Evidence and future perspectives
Chio, J. C. T., Xu, K. J., Popovich, P. G., David, S., & Fehlings, M. G. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113704 · Cited by 108 · see citing works
Self-citationRole of microglia in spinal cord injury
Kroner, A., & Almanza, J. R. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134370 · Cited by 100 · see citing works
Jung, W., Lévesque, J.-P., & Ruitenberg, M. J. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.08.010 · Cited by 98 · see citing works
Pathophysiology, Classification and Comorbidities after Traumatic Spinal Cord Injury
Guest, J. D., Datta, N., Jimsheleishvili, G., & Gater, D. R. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12071126 · Cited by 98 · see citing works
“An added layer of systemic complexity is the evolving understanding of the immune system, including discovering the post-SCI immune deficiency syndrome [72] whereas there is potential induced autoimmunity due to exposure of SCI exposed antigens such as myelin basic protein [73,74].”
BackgroundEngineering challenges for brain tumor immunotherapy
Lyon, J. G., Mokarram, N., Saxena, T. K., Carroll, S. L., & Bellamkonda, R. V. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.06.006 · Cited by 96 · see citing works
Yavne, Y., Amital, D., Watad, A., Tiosano, S., & Amital, H. (2018) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2017.12.011 · Cited by 99 · see citing works
“Chronic immune-mediated neuroinflammation following spinal cord injury could be a possible mechanism explaining FM development after spinal injuries[52].”
BackgroundDefining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation
Ropper, A. E., Thakor, D. K., Han, I., Yu, D., Zeng, X., Anderson, J. E., Aljuboori, Z., Kim, S., Wang, H., Sidman, R. L., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1616340114 · Cited by 90 · see citing works
“The inflammatory cascade paradoxically contributes to both postinjury neural damage and repair (23, 31), so that subtly tuned antiinflammation capability has become a focus for treating CNS trauma (32–34).”
BackgroundGaudet, A. D., Mandrekar-Colucci, S., Hall, J. C. E., Sweet, D. R., Schmitt, P., Xu, X., Guan, Z., Mo, X. M., Guerau‐de‐Arellano, M., & Popovich, P. G. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.0735-16.2016 · Cited by 87 · see citing works
“Scale bars: C, 100 m; F, 50 m; inset, 5 m. tive effects of miR-155 deletion may also benefit SCI-induced neuropathic pain or autonomic dysfunction (Gris et al., 2004; Detloff et al., 2008; Schwab et al., 2014; Allison and Ditor, 2015; Tan et al., 2015; Brommer et al., 2016; Offiah et al., 2016).”
BackgroundSelf-citationLymphocytes and autoimmunity after spinal cord injury
Jones, T. B. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.03.003 · Cited by 72 · see citing works
Arginase-1 is expressed exclusively by infiltrating myeloid cells in CNS injury and disease
Greenhalgh, A. D., dos Santos, R. P., Zarruk, J. G., Salmon, C. K., Kroner, A., & David, S. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.04.013 · Cited by 72 · see citing works
“Inflammation may be both detrimental and beneficial depending on the timing after injury and context of the damage (Schwab et al., 2014; Shechter and Schwartz, 2013).”
BackgroundKigerl, K. A., Zane, K., Adams, K., Sullivan, M. B., & Popovich, P. G. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.113085 · Cited by 70 · see citing works
“However, it may be useful to think of TIA as a continuum of a non-resolving inflammatory response, dominated by innate immune cells, that is set in motion by SCI (Schwab et al., 2014).”
BackgroundSelf-citationImmune response after central nervous system injury
Salvador, A. F., & Kipnis, J. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101629 · Cited by 69 · see citing works
Herman, P. E., Papatheodorou, A., Bryant, S. A., Waterbury, C. K. M., Herdy, J. R., Arcese, A. A., Buxbaum, J. D., Smith, J. J., Morgan, J. R., & Bloom, O. (2018) · Scientific Reports · doi:10.1038/s41598-017-18757-1 · Cited by 67 · see citing works
Papatheodorou, A., Stein, A., Bank, M. A., Sison, C. P., Gibbs, K., Davies, P., & Bloom, O. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2016.4596 · Cited by 67 · see citing works
“flammation acutely after SCI also is widely appreciated to exacerbate neuronal loss and induce secondary damage after SCI.(2)”
BackgroundInfluentialDePaul, M. A., Palmer, M., Lang, B. T., Cutrone, R., Tran, A. P., Madalena, K. M., Bogaerts, A., Hamilton, J. A., Deans, R., Mays, R. W., et al. (2015) · Scientific Reports · doi:10.1038/srep16795 · Cited by 63 · see citing works
Leister, I., Haider, T. T., Mattiassich, G., Kramer, J. L. K., Linde, L. D., Pajalic, A., Grassner, L., Altendorfer, B., Resch, H., Wallner, S., et al. (2020) · Neurorehabilitation and neural repair · doi:10.1177/1545968319899920 · Cited by 63 · see citing works
Cardiovascular Autonomic Dysfunction in Spinal Cord Injury: Epidemiology, Diagnosis, and Management
Wecht, J. M., Harel, N. Y., Guest, J. D., Kirshblum, S., Forrest, G. F., Bloom, O., Ovechkin, A. V., & Harkema, S. J. (2020) · Seminars in Neurology · doi:10.1055/s-0040-1713885 · Cited by 61 · see citing works
Santo, C. C. D. E., Fiorin, F. D. S., Ilha, J., Duarte, M. M. M. F., Duarte, T., & Santos, A. R. S. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.01.012 · Cited by 61 · see citing works
Huang, F., Gao, T., Wang, W., Wang, L., Xie, Y., Tai, C., Liu, S., Cui, Y., & Wang, B. (2021) · Stem Cell Research & Therapy · doi:10.1186/s13287-021-02537-w · Cited by 59 · see citing works
Lee, S., Mattingly, A. J., Lin, A., Sacramento, J. A., Mannent, L., Castel, M., Canolle, B., Delbary-Gossart, S., Ferzaz, B., Morganti, J. M., et al. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0544-4 · Cited by 55 · see citing works
“2008;28(39):9870–9. doi:10.1523/ JNEUROSCI.2841-08.2008.”
BackgroundInfluentialSpinal Cord Injury Impairs Neurogenesis and Induces Glial Reactivity in the Hippocampus
Jure, I., Pietranera, L., Nicola, A. F. D., & Labombarda, F. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2225-9 · Cited by 55 · see citing works
“On the other hand, the systemic immune function is markedly altered after SCI and this mechanism could affect the brain [66, 67].”
BackgroundPrognostic value of early leukocyte fluctuations for recovery from traumatic spinal cord injury
Jogia, T., Lübstorf, T., Jacobson, E., Scriven, E., Atresh, S. S., Nguyen, Q. H., Liebscher, T., Schwab, J. M., Kopp, M. A., Walsham, J., et al. (2021) · Clinical and Translational Medicine · doi:10.1002/ctm2.272 · Cited by 55 · see citing works
Self-citationHerman, P. E., Stein, A., Gibbs, K., Korsunsky, I., Gregersen, P. K., & Bloom, O. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2017.5519 · Cited by 56 · see citing works
“Another immunological alteration post-SCI is systemic inflammation, which has been observed in both pre-clinical and clinical studies.(13,15) Kwon and others have demonstrated elevated systemic inflammatory mediators in persons with acute SCI, where some appear to correlate with injury severity and/or neurological rec…”
BackgroundSchmidt, E. K. A., Raposo, P. J. F., Espin, A. T., Fenrich, K. K., & Fouad, K. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02123-0 · Cited by 53 · see citing works
Bastidas, J. C., Athauda, G., la Cruz, G. D., Chan, W., Golshani, R., Berrocal, Y. A., Henao, M., Lalwani, A. K., Mannoji, C., Assi, M., et al. (2017) · Glia · doi:10.1002/glia.23161 · Cited by 53 · see citing works
Spejo, A. B., Chiarotto, G. B., Ferreira, A. D. F., Gomes, D. A., Ferreira, R. S., Barraviera, B., & de Oliveira, A. L. R. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1268-4 · Cited by 53 · see citing works
Ortega, M. A., Fraile‐Μartinez, O., Montero, C. G., Haro, S., Álvarez-Mon, M. Á., León-Oliva, D. D., Gomez-Lahoz, A. M., Monserrat, J., Atienza-Pérez, M., Díaz, D., et al. (2023) · Military Medical Research · doi:10.1186/s40779-023-00461-z · Cited by 53 · see citing works
“SCI-IDS is characterized by several alterations in the function, number and modulation of virtually all immune cell populations, which is equally tightly linked to enhanced susceptibility to infections [135].”
BackgroundInfluentialPrognostic Value of Malondialdehyde (MDA) in the Temporal Progression of Chronic Spinal Cord Injury
Haro, S., Monserrat, J., Ortega, M. A., Montero, C. G., Fraile‐Μartinez, O., Gomez-Lahoz, A. M., Boaru, D. L., León-Oliva, D. D., Guijarro, L. G., Atienza-Pérez, M., et al. (2023) · Journal of Personalized Medicine · doi:10.3390/jpm13040626 · Cited by 55 · see citing works
The Damaged Spinal Cord Is a Suitable Target for Stem Cell Transplantation
Curt, A. E. P., Hsieh, J., Schubert, M. J. W., Hupp, M., Friedl, S., Freund, P., Huber, E., Pfyffer, D., Sutter, R., Jutzeler, C. R., et al. (2020) · Neurorehabilitation and neural repair · doi:10.1177/1545968320935815 · Cited by 50 · see citing works
When friend turns foe: central and peripheral neuroinflammation in central nervous system injury
Marcet, P. A., Santos, N., & Borlongan, C. V. (2017) · Neuroimmunology and Neuroinflammation · doi:10.20517/2347-8659.2017.07 · Cited by 49 · see citing works
“It is known that the concentration of neutrophils peaks around 3–24 h after injury, and the concentration of monocytes peaks around 1–2 days after spinal cord injury.[63] Marcet et al.”
BackgroundLi, X., Lou, X., Xu, S., Du, J., & Wu, J. (2020) · Biological Research · doi:10.1186/s40659-020-00302-6 · Cited by 49 · see citing works
Zhang, L., Zhuang, X., Kotitalo, P., Keller, T., Krzyczmonik, A., Haaparanta‐Solin, M., Solin, O. H., Forsback, S. J., Grönroos, T. J., Han, C., et al. (2020) · Theranostics · doi:10.7150/thno.52197 · Cited by 48 · see citing works
“After the initial insult to the spinal cord, the injury triggers a cascade of pathological events [2], including neuroinflammation, which has been described as a pathological hallmark leading to further neuronal death.”
BackgroundBao, G., Li, C., Qi, L., Wang, N., & He, B. (2016) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2016.10.007 · Cited by 48 · see citing works
Novel innovations in cell and gene therapies for spinal cord injury
Zavvarian, M.-M., Toossi, A., Khazaei, M., Hong, J., & Fehlings, M. G. (2020) · F1000Research · doi:10.12688/f1000research.21989.1 · Cited by 47 · see citing works
Mokhtari, T., & Uludağ, K. (2023) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00596 · Cited by 46 · see citing works
Controlled release strategies for modulating immune responses to promote tissue regeneration
Dumont, C. M., Park, J., & Shea, L. D. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.08.014 · Cited by 45 · see citing works
Elevated Autoantibodies in Subacute Human Spinal Cord Injury Are Naturally Occurring Antibodies
Arévalo‐Martín, Á., Grassner, L., García‐Ovejero, D., Paniagua‐Torija, B., Barroso-García, G., Gonzalez, A., Mach, O., Turrero, Á., Vargas, E., Alcobendas, M., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02365 · Cited by 46 · see citing works
Wu, C., Wang, L., Chen, S., Shi, L., Liu, M., Tu, P., Sun, J., Zhao, R., Zhang, Y., Wang, J., et al. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02848-0 · Cited by 45 · see citing works
Self-citationGiles, J. A., Greenhalgh, A. D., Dénes, Á., Nieswandt, B., Coutts, G., McColl, B. W., & Allan, S. M. (2018) · Immunology · doi:10.1111/imm.12892 · Cited by 44 · see citing works
“This may be especially important when targeting components of the immune system that are particularly susceptible to infections, such as after stroke and spinal cord injury (10,11).”
BackgroundMetabolites of neuroinflammation relate to neuropathic pain after spinal cord injury
Pfyffer, D., Wyss, P. O., Huber, E., Curt, A. E. P., Henning, A., & Freund, P. (2020) · Neurology · doi:10.1212/wnl.0000000000010003 · Cited by 43 · see citing works
Hong, J., Chang, A., Zavvarian, M.-M., Wang, J., Liu, Y., & Fehlings, M. G. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082167 · Cited by 43 · see citing works
“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 · see citing works
“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 42 · see citing works
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 · see citing works
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 41 · see citing works
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 · see citing works
“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 · see citing works
“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 36 · see citing works
“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 · see citing works
“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 37 · see citing works
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 38 · see citing works
“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 34 · see citing works
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 · see citing works
“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 34 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“…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 · see citing works
“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 · see citing works
Sefiani, A., & Geoffroy, C. G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.682259 · Cited by 31 · see citing works
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 · see citing works
“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 · see citing works
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 30 · see citing works
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“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.”
BackgroundČı́žková, 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 29 · see citing works
“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 29 · see citing works
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 · see citing works
Bigford, G. E., & Garshick, E. (2022) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2022.102303 · Cited by 27 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 26 · see citing works
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 · see citing works
“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 · see citing works
- 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 › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › 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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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