The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury

“In response to injury or infection, SIRS develops but in parallel CARS is triggered to terminate inflammation (Hotchkiss et al., 2013a, b).”

“Failure to resolve inflammation results in aberrant tissue remodeling and organ dysfunction (Nathan and Ding, 2010; Serhan and Savill, 2005; Serhan et al., 2007).”

“Functional cross-talk between the nervous and immune systems is achieved by the autonomic nervous system (ANS) and the hypothalamic–pituitary–adrenal (HPA) axis (Elenkov et al., 2000).”

“The immunologically silent, non-phlogistic clearance of apoptotic cells is crucial for maintaining tolerance to self-antigens (Savill et al., 2002; Uderhardt et al., 2012).”

“As a consequence of SCI and subsequent neurodegeneration, such control is lost and microglia become activated (Cardona et al., 2006; Meuth et al., 2008).”

“In classical CNS inflammatory diseases (e.g., MS), ectopic lymphoidlike follicles form adjacent to large intraparenchymal inflammatory lesions (Magliozzi et al., 2007; Franciotta et al., 2008).”

“In response to injury or infection, SIRS develops but in parallel CARS is triggered to terminate inflammation (Hotchkiss et al., 2013a, b).”

“Besides anti-inflammatory strategies, which aim to reduce leukocyte infiltration or survival at site of inflammation, naturally occurring resolution-promoting agonists, including resolvin E1 and protectin D1, exert similar effects (Schwab et al., 2007).”

“Such a compartmentalized inflammatory reaction in the spinal cord may drive chronic progression of neurodegeneration and demyelination (Lassmann et al., 2007).”

“Instead, it is associated with excessive parenchyma destruction and functio laesa (Serhan et al., 2007).”

“, BAFF andAPRIL) have or are being tested as therapies for classical forms of autoimmune disease (Mackay et al., 2003), similar strategies have not been tested in stroke, CNS injury or neurodegenerative disease.”

“…for each of the above components of intraspinal inflammation and the significance of these events are described throughout other reviews in this special issue and also in previous reviews (Ankeny et al., 2009; Donnelly and Popovich, 2008; Lucin and Wyss-Coray, 2009; Popovich and Longbrake, 2008).”

“Cytokines are known to affect the survival and function of neurons and glia and can activate both the SNS and the HPA axis through a complex corticotropin-releasing hormone (CRH)-dependent pathway (long feedback loop between the immune system and the brain (hypothalamus) (Meisel et al., 2005).”

“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…”

“…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.”

“Physiological concentrations of GCs and NE ensure normal immune function but recurrent or prolonged activation of glucocorticoid receptors (GRs) or beta-2 adrenergic receptors (β2AR) is immunosuppressive (Nance and Sanders, 2007).”

“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).”

“Autoimmunity can be viewed as a continuumof autoinflammatory (self-directed tissue inflammation dominated by innate immune system) and autoimmune reactions (loss of immunological tolerancewith activation of selfdirected adaptive immune responses) reactions (McGonagle and McDermott, 2006).”

“Among others, exacerbated neurodegeneration (Cunningham et al., 2005) and axonal injury (Moreno et al.”

“Recent data show that in cases of MS, ectopic CNS B-cell follicles co-localized with a corresponding gradient of neuronal loss (Magliozzi et al., 2010).”

“…for each of the above components of intraspinal inflammation and the significance of these events are described throughout other reviews in this special issue and also in previous reviews (Ankeny et al., 2009; Donnelly and Popovich, 2008; Lucin and Wyss-Coray, 2009; Popovich and Longbrake, 2008).”

“The autoimmune pathogenesis of systemic lupus erythematosus (SLE), in humans and mouse models, has been attributed in parts to failed clearance of apoptotic cells (Muñoz et al., 2010; Nagata et al., 2010).”

“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).”

“…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).”

“, 2010) were reported after systemic endotoxin challenge as a model of systemic infections (Perry et al., 2003).”

“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).”

“Most experimental data indicate that SCI autoantibodies can cause tissue damage; therefore, strategies to remove or deplete autoantibodies or suppress B-cell activation could be neuroprotective (Martin and Chan, 2006).”

“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).”

“Thus, infections qualify as independent neurobiological rehabilitation confounders that impair the endogenous recovery potential after SCI (Dietz and Fouad, 2014; Failli et al., 2012).”

“…for each of the above components of intraspinal inflammation and the significance of these events are described throughout other reviews in this special issue and also in previous reviews (Ankeny et al., 2009; Donnelly and Popovich, 2008; Lucin and Wyss-Coray, 2009; Popovich and Longbrake, 2008).”

“In classical CNS inflammatory diseases (e.g., MS), ectopic lymphoidlike follicles form adjacent to large intraparenchymal inflammatory lesions (Magliozzi et al., 2007; Franciotta et al., 2008).”

“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).”

“Likewise, in human SCI, a greater magnitude of progressive atrophy in exofocal gray and white matter over a period of ~1 year correlates with significantly impaired neurological function (Freund et al., 2013).”

“, 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).”

“Infection is the leading cause of morbidity and mortality in patients with SCI (DeVivo et al., 1989; Soden et al., 2000).”

“Residual activated microglia/macrophages are likely to undermine blood–spine barrier closure after SCI thereby thwarting reconstitution of a critical feature of CNS immune privilege (Dulin et al., 2013; Popovich et al., 1996b; Schwab et al., 2000).”

“…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).”

“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).”

“Activated B and T cells also infiltrate and accumulate within the traumatically injured spinal cord where they form large cellular clusters that are reminiscent of germinal centers with follicles that are normally found in spleen and lymph nodes (Ankeny et al., 2006, 2009) (Fig.”

“…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).”

“…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).”

“…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).”

“Infection is the leading cause of morbidity and mortality in patients with SCI (DeVivo et al., 1989; Soden et al., 2000).”

“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…”

“A decentralized, non-regulated SNS is also involved in the occurrence of autonomic dysreflexia (AD), which was recently identified as a cause/mechanism of secondary immune deficiency after SCI (Zhang et al., 2013).”

“Activation of SPNs causes release of norepinephrine (NE) and GCs from postganglionic nerve terminals and the adrenal gland (Engeland and Arnhold, 2005).”

“Thus, infections qualify as independent neurobiological rehabilitation confounders that impair the endogenous recovery potential after SCI (Dietz and Fouad, 2014; Failli et al., 2012).”

“…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.”

“…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).”

“Mouse S and CSF Propagated myelin clearance and regeneration (after PNS-injury) (Vargas et al., 2010)”

“, 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).”

“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…”

“…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…”

“…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.”

“, 2011) but also “sickness behavior” (Teeling et al., 2010) were reported after systemic endotoxin challenge as a model of systemic infections (Perry et al.”

“IgG Rat Human Immunomodulatory effect in human autoimmune disease (Gold et al., 2007)”

“, 2005) and axonal injury (Moreno et al., 2011) but also “sickness behavior” (Teeling et al.”

“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).”

“Each has been implicated in progression of secondary injury after SCI (Ankeny and Popovich, 2010).”

“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).”

“…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).”

“…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).”

“As a consequence of SCI and subsequent neurodegeneration, such control is lost and microglia become activated (Cardona et al., 2006; Meuth et al., 2008).”

“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).”

“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).”

“…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.”

“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).”

“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).”

“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).”

“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).”

“Lacking functional Mice RAG2-/Reduced demyelinization (Wu et al., 2012).”

“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).”

“…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).”

“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).”

“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).”

“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…”

“…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).”

“…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).”

“Unspecific, derived from healthy donors Neuroprotective in xenogenous application after compression SCI in rats (Nguyen et al., 2012).”

“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).”

“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.”

“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).”

“…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).”

“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).”

“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…”

“…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).”

“…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).”

“…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).”

“CD8 N CD4 Rat Immune surveillance (Bradl et al., 2005), preferentially grey matter”

“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).”

“…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).”

“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).”

“…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).”

“β3-tubulin-reactive? Mouse Recomb Propagated neurite outgrowth/stabilization (Xu et al., 2011)”