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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2015 Jun 12;173(4):681–691. doi: 10.1111/bph.13179

Progressive inflammation‐mediated neurodegeneration after traumatic brain or spinal cord injury

Alan I Faden 1,✉, Junfang Wu 1, Bogdan A Stoica 1, David J Loane 1
Editors: AG Stewart, PM Beart
PMCID: PMC4742301  PMID: 25939377

Abstract

Traumatic brain injury (TBI) has been linked to dementia and chronic neurodegeneration. Described initially in boxers and currently recognized across high contact sports, the association between repeated concussion (mild TBI) and progressive neuropsychiatric abnormalities has recently received widespread attention, and has been termed chronic traumatic encephalopathy. Less well appreciated are cognitive changes associated with neurodegeneration in the brain after isolated spinal cord injury. Also under‐recognized is the role of sustained neuroinflammation after brain or spinal cord trauma, even though this relationship has been known since the 1950s and is supported by more recent preclinical and clinical studies. These pathological mechanisms, manifested by extensive microglial and astroglial activation and appropriately termed chronic traumatic brain inflammation or chronic traumatic inflammatory encephalopathy, may be among the most important causes of post‐traumatic neurodegeneration in terms of prevalence. Importantly, emerging experimental work demonstrates that persistent neuroinflammation can cause progressive neurodegeneration that may be treatable even weeks after traumatic injury.

Linked Articles

This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2016.173.issue-4

Abbreviations

AD

Alzheimer's disease

CCI

controlled cortical impact

CTBI

chronic traumatic brain inflammation

CTE

chronic traumatic encephalopathy

CTIE

chronic traumatic inflammatory encephalopathy

DG

dentate gyrus

ERPs

event‐related potentials

SCI

spinal cord injury

TBI

traumatic brain injury

Tables of Links

TARGETS
Catalytic receptors a
IL‐4 receptor α
Enzymes b
Arginase 1
GPCR c
mGlu5 receptor
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LIGANDS
Aβ, β‐amyloid IL‐1β
CCL2 TGFβ
CCL3 TNFα
CCL21
CHPG, 2‐chloro‐5‐hydroxyphenylglycine
Ibudilast
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These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (a,b,cAlexander et al., 2013a), 2013b, 2013c).

Introduction

Neuroinflammation is a prominent feature of many neurodegenerative diseases (Eikelenboom et al., 2010; Perry et al., 2010), and is increasingly being recognized as an important pathophysiological mechanism underlying chronic neurodegeneration following traumatic brain injury (TBI) or spinal cord injury (SCI). As the primary mediators of the innate immune response in the CNS, microglia play a critical role in neuroinflammation and secondary injury following CNS injury. Their persistent activation towards the M1‐like neurotoxic phenotype may in part explain the progressive neuronal loss observed after CNS trauma.

Recent work, both experimental and clinical, has established that moderate or severe TBI may lead to chronic progressive neurodegeneration. A recent retrospective cohort study has shown that there is an increased risk of dementia after TBI (Gardner et al., 2014). Specifically, it demonstrated the influence of age at injury and injury severity on dementia risk after TBI, revealing that even mild TBI (mTBI) increases dementia risk in those aged ≥65 years. An important outstanding question is which type of dementia results from prior brain trauma? It has long been suggested that a prior history of TBI increases the likelihood of subsequent Alzheimer disease (AD) (Mortimer et al., 1985; 1991; Graves et al., 1990; Plassman et al., 2000). Moreover, consistent with the β‐amyloid (Aβ) hypothesis as a key mechanism of AD, brain trauma increases amyloid precursor protein, presenilins and β‐amyloid converting enzyme 1 in injured axons, and results in the deposition of the β‐amyloid fragment, Aβ1–42, in injured brain (see Johnson et al., 2010). However, more recent epidemiological studies involving much larger patient cohorts do not give much support to such an association between TBI and AD (Dams‐O'Connor et al., 2013; Nordstrom et al., 2014). In addition, recent clinical studies have increasingly called into question the role of Aβ as the major driver of cognitive decline in AD patients (Doody et al., 2014; Salloway et al., 2014; Murray et al., 2015). Rather, there is a significant association with non‐AD dementias (Wang et al., 2012; Lee et al., 2013; Barnes et al., 2014; Nordstrom et al., 2014; Faden and Loane, 2015).

Repeated mTBI, in boxers or athletes who participate in high contact sports, has been linked to later onset neurodegeneration. This chronic neurodegeneration may contribute to a pathologically distinct disease known as chronic traumatic encephalopathy (CTE) that has a significant τ pathology including phosphorylated τ in neurofibrillary tangles, neurites and glial deposits (Omalu et al., 2005; McKee et al., 2009; 2013). Some cases of CTE also demonstrate diffuse Aβ plaques and pathological accumulations of phosphorylated forms of the DNA‐binding protein TDP‐43 (McKee et al., 2013). Importantly, single TBI appears to have a different pathology. Acutely, it is associated with diffuse Aβ plaques (Roberts et al., 1991; 1994), whereas fibrillary Aβ plaques can be observed in the chronic phase (Johnson et al., 2012). Moreover, single TBI results in accumulation of phosphorylation‐independent TDP‐43 and a relative absence of pathological phosphorylated TDP‐43 (Johnson et al., 2011), which raises questions about whether the neuropathology following single, as distinct from repeated, TBI reflects poly‐pathologies rather than a single entity (e.g. tauopathy; Smith et al., 2013b).

Animal studies show that single moderate or severe TBI, or repeated mTBI, can cause progressive neurodegeneration with cognitive and other behavioural changes (Smith et al., 1997; Pierce et al., 1998; Dixon et al., 1999; Aungst et al., 2014; Loane et al., 2014; Mouzon et al., 2014). Delayed progressive pathological changes have been demonstrated in clinical TBI imaging studies (Trivedi et al., 2007; Bendlin et al., 2008; Ng et al., 2008; Sidaros et al., 2008; 2009; Kumar et al., 2009; Farbota et al., 2012). Post‐traumatic neurodegeneration and/or neurological deficits have been linked to persistent neuroinflammation in preclinical (Nonaka et al., 1999; Nagamoto‐Combs et al., 2007; Acosta et al., 2013; Aungst et al., 2014; Loane et al., 2014; Mouzon et al., 2014) and neuropathological (Johnson et al., 2013) studies. Microglial activation has been proposed as an important pathobiological mechanism in major neurodegenerative disorders, including AD (Eikelenboom et al., 2010; Perry et al., 2010). Such neuroinflammation has also been reported in several case reports of CTE that described the presence of activated microglia throughout the brain following neurotrauma (McKee et al., 2010; Goldstein et al., 2012; Saing et al., 2012). Although no formal studies of neuroinflammation in CTE have been conducted to date, these results are provocative, and the involvement of neuroinflammation in CTE, including pathological evidence of microglia and astrocytes activation, has been previously noted (Daneshvar et al., 2015). Preclinical studies strongly support a role for chronic neurotoxic neuroinflammation in post‐traumatic degeneration and associated neurological or psychiatric symptoms, and several recent experimental studies have demonstrated that delayed, targeted anti‐inflammatory treatments can limit behavioural and pathological changes (Byrnes et al., 2012; Piao et al., 2013; Rodgers et al., 2014).

The analysis of the effects of SCI has, for long, focused on sensorimotor deficits, or secondary complications such as neuropathic pain or bladder/bowel/sexual dysfunction. Most early research on the pathophysiological changes following SCI was predominantly focused on the spinal cord and its afferent and efferent pathways. In contrast, minimal work has addressed the potential effects of SCI on brain regions that regulate learning and memory or emotions, despite accumulating clinical evidence showing significant neuropsychological changes. Recent MRI studies suggest that SCI can cause progressive and widespread brain changes (Nicotra et al., 2006; Wrigley et al., 2009; Freund et al., 2013). Our recently published work demonstrates that SCI in both mouse and rat models causes a chronic neuroinflammatory response in the brain (Wu et al., 2014a, 2014b), similar to that observed experimentally and clinically after TBI. This chronic neuroinflammation is associated with progressive neurodegeneration in brain regions associated with cognitive decline and depressive‐like behaviour (Wu et al., 2014a, 2014b).

Progressive neurodegeneration after TBI

Increasing evidence, both experimental and clinical, indicates that TBI can result in progressive neurodegeneration (Smith et al., 1997; Dixon et al., 1999; Trivedi et al., 2007; Bendlin et al., 2008; Sidaros et al., 2008; Farbota et al., 2012; Loane et al., 2014). In the late 1990s, Smith et al. (1997) reported progressive brain atrophy and cell loss in multiple brain regions following fluid percussion induced injury in rats. More recently, Loane et al. (2014) found progressive lesion development and neuronal cell loss, using both repeated MRI and histological measurements, through 1 year after controlled cortical impact (CCI) injury in mice. An increasing number of clinical imaging TBI studies have shown progressive tissue loss and brain atrophy, which are likely to reflect chronic neurodegenerative changes, for months to years after TBI (Trivedi et al., 2007; Bendlin et al., 2008; Ng et al., 2008; Sidaros et al., 2008; 2009; Kumar et al., 2009; Farbota et al., 2012). Alterations have been identified in both grey and white matter. In several of these studies, imaging data were correlated with neurological deficits. Importantly, progressive neurodegeneration has been reported after mild as well as moderate or severe TBI (Trivedi et al., 2007; Kumar et al., 2009; Zhou et al., 2013). Furthermore, studies in children have also reported similar progressive degeneration after head injuries (Keightley et al., 2014).

Given the published reports on CTE and high‐impact sports, there has been considerable interest in whether repeated concussive or even sub‐concussive insults can lead to chronic neurodegeneration. A recent study used MRI to examine hippocampal size in relation to concussion history in collegiate football players (Singh et al., 2014). They demonstrated reduced hippocampal volumes in football players compared with age‐matched non‐football controls. The greatest changes were found in those with a documented concussion history and they reported an inverse relationship between hippocampal volumes or reaction times and years playing football. Other studies have also recently suggested that exposure to high‐impact sports can lead to brain imaging changes including hyperactivity in the default mode network (Johnson et al., 2014; Abbas et al., 2015) or delayed recovery of cerebral blood flow post‐concussion in slow‐to‐recover athletes (Meier et al., 2015), suggesting that even repeated sub‐concussive head exposures may lead to long‐term pathological alterations in the brain.

Chronic neuroinflammation after TBI

TBI is known to cause acute neuroinflammation that is associated with cytokine release (Loane and Byrnes, 2010; Ziebell and Morganti‐Kossmann, 2010). Indeed, many neuroprotective strategies have been directed at such inflammation or related factors (Kumar and Loane, 2012). Also well supported by clinical data, but less well appreciated is that clinical TBI can cause persistent microglial activation (Engel et al., 2000; Gentleman et al., 2004; Faden, 2011; Ramlackhansingh et al., 2011; Johnson et al., 2013; Smith et al., 2013a; Coughlin et al., 2015), and that such chronic neuroinflammation may contribute to neurodegeneration. Post‐mortem autopsy studies have revealed the presence of reactive microglia at months to years following a single TBI (Gentleman et al., 2004; Smith et al., 2013a). In fact, a recent study demonstrated the presence of CD68‐positive microglia in more than a quarter of brains examined with survival time of >1 year, and this was associated with white matter degeneration in these cases (Johnson et al., 2013). Another clinical TBI study used the PET translocator protein 18 kDa (TSPO) ligand ([11C]R‐PK11195) to examine chronic neuroinflammatory changes in patients months to years after a single head injury. Brain TSPO levels are increased after TBI in experimental models, likely due to increased expression by activated microglia during secondary neuroinflammation (Papadopoulos and Lecanu, 2009). Increased [11C]R‐PK11195 binding was found diffusely at sites distant from the trauma locus, indicating chronic neuroinflammatory changes in patients who suffered moderate‐to‐severe TBI (Ramlackhansingh et al., 2011). Moreover, localization of neuroinflammation in the diencephalon correlated with long‐term cognitive changes in these studies. Contrary to the neuropathological studies, [11C]R‐PK11195 binding was not observed in corpus callosum of TBI patients, which may be due to reduced sensitivity of the PET ligand for highly activated phagocytic (CD68 positive) microglia or other limitations in current methods to image neuroinflammation at high resolution in the human brain. However, another neuroimaging study using a second‐generation TSPO ligand, [11C]DPA‐713, in retired National Football Leagues (NFL) players supports the findings of Ramlackhansingh et al. and demonstrated increased radioligand binding in several brain regions, including supramarginal gyrus and right amygdala, in former NFL Players compared with age‐matched, healthy controls (Coughlin et al., 2015). Significant atrophy of the right hippocampus as well as varied performance on tests of verbal learning and memory in NFL players were reported, suggesting that neuroinflammatory changes may play a role in cognitive dysfunction and depression among former athletes exposed to sport‐related mTBI (Guskiewicz et al., 2005; Hart et al., 2013). In addition, recent biomarker studies have reported chronic increases of pro‐inflammatory cytokines either in serum or in CSF after head injury, with such changes associated with unfavourable neuropsychiatric outcomes (Juengst et al., 2014; Kumar et al., 2014).

Experimental studies strongly support these clinical observations and suggest both possible mechanisms involved and potential therapeutic strategies (Holmin and Mathiesen, 1999; Nonaka et al., 1999; Nagamoto‐Combs et al., 2007; Acosta et al., 2013; Aungst et al., 2014; Loane et al., 2014; Mouzon et al., 2014). We recently reported that moderate‐level CCI in mice caused persistent microglial activation through 1 year post‐trauma that was associated with progressively increased lesion volume and neurodegeneration (Loane et al., 2014). Chronically activated microglia expressed major histocompatibility complex class II (CR3/43), CD68 and NADPH oxidase (NOX2) at the lesion margins at 1 year, along with evidence of oxidative stress. Several groups have shown that repeated mTBI can also cause chronic neuroinflammation associated with pathological changes (Shitaka et al., 2011; Aungst et al., 2014; Mouzon et al., 2014). Utilizing a repeated closed head injury mouse model, Shitaka et al. (2011) reported that reactive microglia were identified adjacent to injured axons at 7 weeks after repetitive mTBI. Also using the repeated mTBI mouse model, Mouzon et al. (2014) demonstrated persistent neuroinflammation and related white matter degeneration, as well as chronic cognitive deficits through 18 months. Our group used a rat lateral fluid percussion model to show that repeated, but not single, mTBI resulted in chronic microglial activation and parallel behavioural deficits, electrophysiological changes and neuronal cell loss (Aungst et al., 2014); importantly, repeated mTBI simulated alterations induced by a single moderate insult, with similar degrees of neuroinflammation, neurodegeneration and associated neurological deficits.

Given that persistent post‐traumatic microglial activation is correlated with chronic neurodegeneration and functional deficits, several studies have addressed whether outcome can be improved by therapeutic targeting of such neuroinflammation late after the traumatic insult. Following CCI in mice, Byrnes et al. (2012) randomized animals at 1 month with the mGlu5 receptor agonist 2‐chloro‐5‐hydroxyphenylglycine (CHPG), vehicle or drug plus an allosteric mGlu5 receptor antagonist. Delayed treatment starting at 1 month post‐injury significantly improved cognitive and motor recovery, while decreasing neuroinflammation, lesion volume and neuronal loss at 4 months post‐injury; in addition, ex vivo diffusion tensor imaging demonstrated considerably greater preservation of white matter tracks in treated animals than vehicle‐treated TBI controls (Byrnes et al., 2012). The protective effects of CHPG were blocked by the mGlu5 receptor antagonist 3‐((2‐Methyl‐4‐thiazolyl)ethynyl)pyridine, indicating that the neuroprotection was mediated by actions at mGlu5 receptors . Similar protective actions and therapeutic mechanisms were reported by Piao et al. (2013) using a delayed 4 week voluntary exercise regimen initiated 5 weeks after mouse CCI. Late, but not early, exercise implementation decreased chronic microglial activation and associated neurodegeneration, and ameliorated behavioural deficits after TBI (Piao et al., 2013); protective effects were associated with an inhibition of NADPH oxidase (NOX2) in microglia. Recently, Rodgers et al. (2014) reported that anti‐inflammatory treatment with the phosphodiesterase inhibitor ibudilast, beginning 1 month following fluid percussion injury in rats, resulted in decreased chronic anxiety‐like behaviour as well as reactive gliosis at 6 months post‐injury.

Microglia and infiltrating macrophages in the CNS are heterogeneous, with diverse functional phenotypes that range from pro‐inflammatory (M1‐like) phenotypes to immunosuppressive (M2‐like) phenotypes (David and Kroner, 2011; Kumar and Loane, 2012). The ‘M1/M2’ paradigm has been increasingly studied in neurodegenerative diseases in an attempt to uncover mechanisms of immunopathogenesis, and advances in understanding of molecular and functional states of microglia/macrophages may provide a framework to help elucidate the relative beneficial versus destructive roles of microglia/macrophages after TBI. Although most studies to date underscore the neurotoxic actions of persistent M1‐like microglial activation following TBI, it is now well recognized that M2‐like phenotypes have anti‐inflammatory and neurorestorative effects (Cherry et al., 2014). For example, by removing cellular debris by phagocytosis and releasing neurotrophic factors and anti‐inflammatory cytokines, microglia can prevent neuronal injury and restore tissue integrity in the injured brain (David and Kroner, 2011; Kumar and Loane, 2012).

Experimental studies in various models of CNS injury (SCI, stroke/ischaemia and TBI) have shown that the majority of microglia and recruited macrophages at the injury site have an M2‐like profile, but that the M2‐like response is short‐lived, with a phenotypic shift towards an M1‐like dominant response within 1 week (Kigerl et al., 2009; Hu et al., 2012; Kumar et al., 2013; Wang et al., 2013; Loane et al., 2014). M1‐like cells that dominate the lesion have reduced phagocytic activity, and increased secretion of pro‐inflammatory and neurotoxic mediators (IL‐1β, TNFα, superoxide radicals, nitric oxide), that can exacerbate injury and contribute to pathology. Following focal TBI, there is a transient up‐regulation of M2‐like markers such as CD206, arginase 1, Ym1, CD163, Fizz1, IL‐4 receptor α and TGFβ (Hsieh et al., 2013; Kumar et al., 2013; Wang et al., 2013; Loane et al., 2014; Turtzo et al., 2014), and the M2‐like phenotype appears to peak between 3 and 5 days post‐injury before tapering off significantly. This coincides with the peak of macrophage infiltration after TBI (Jin et al., 2012). Such observations point to highly complex phenotypic and functional responses after TBI, with resident and infiltrating subsets of cells being activated dynamically to promote either anti‐inflammatory and neuroprotective (M2‐like) or chronic neurotoxic (M1‐like) effects. Importantly, NOX2 activation, which we and others have implicated in post‐traumatic neurotoxic neuroinflammation (Block et al., 2007; Byrnes et al., 2012; Gao et al., 2012; Loane et al., 2014), may serve as a switch that serves to increase M1 activation while suppressing M2 activation (Choi et al., 2012). The concept of microglia/macrophage phenotype switching following TBI is at an early stage of development. Further research is needed to determine key regulatory mechanisms that control phenotype switching in microglia in order to develop therapeutic strategies to optimize functional recovery following TBI.

Cognitive impairment and remote neurodegeneration after SCI

Although not well appreciated by clinicians, there have been multiple reports that SCI patients frequently develop long‐term cognitive impairments (Richards et al., 1988; Roth et al., 1989; Davidoff et al., 1992; Dowler et al., 1997; Lazzaro et al., 2013). Using a battery of neuropsychological tests studies in SCI patients have identified performance impairments in memory span, executive functioning, attention, processing speed and learning ability (Roth et al., 1989; Davidoff et al., 1992; Dowler et al., 1995; 1997; Strubreither et al., 1997; Jensen et al., 2007; Murray et al., 2007; Lazzaro et al., 2013). Moreover, central psychophysiological indices of information processing using scalp‐recorded, late component, event‐related potentials (ERPs) suggested that ERP alterations in SCI patients reflect impairments in distributed integrative cortical/subcortical networks that are engaged in stimulus detection, evaluation and executive functioning (Lazzaro et al., 2013). However, such observations were often discounted as probably reflecting unappreciated concurrent head injuries. Yet, studies clearly show that SCI patients who present without a history of TBI may develop cognitive decline and neurological dysfunction (Hess et al., 2003; Jensen et al., 2007). After SCI, the incidence rate of depression more than doubles, increasing to between 25 and 47% (Umlauf, 1992; Arango‐Lasprilla et al., 2011). An earlier experimental study suggested cognitive decline after SCI, using a projectile injury in pigs wearing body armour (Zhang et al., 2011). But the model, species and outcome used (conditioned feeding behaviour) make both interpretation and relevant comparison difficult. Our recent work revealed that SCI in both mouse and rat causes impairment of spatial and retention memory and depressive‐like behaviour as demonstrated by diminished performance in the Morris water maze, Y‐maze, novel objective recognition, sucrose preference and tail suspension tests (Wu et al., 2014a, 2014b). In addition to contributing to disability in their own right, these changes can also negatively affect rehabilitation and impair recovery. Remarkably, despite the clinical evidence showing SCI‐induced cognitive and affective changes, these changes have been assumed to be situational or reactive, and neither clinical nor experimental studies have addressed these changes at a mechanistic level with a view towards limiting such deficits or promoting recovery. Our results (Wu et al., 2014a, 2014b) suggest that SCI can result in physiological changes in the brain that can be modified by inhibiting the post‐traumatic neuroinflammatory response.

SCI can produce extensive long‐term reorganization of the cerebral cortex (Endo et al., 2007; Freund et al., 2011), and complete thoracic SCI patients have decreased grey matter volume in primary motor cortex that is consistent with neuronal loss and/or atrophy (Wrigley et al., 2009). Prospective longitudinal MRI studies show that SCI can cause progressive reduction in grey matter volume not only in the sensorimotor cortex but also in the regions not directly connected to the injury site, such as cerebellar cortex, medial prefrontal and anterior cingulate cortices that are critical for the processing of emotional relevant information and the modulation of attentional states (Nicotra et al., 2006; Wrigley et al., 2009; Freund et al., 2013). Crucially, myelin‐sensitive MRI parameters measured at 1 year were reduced within, but also beyond, the atrophic areas of the lesion (Freund et al., 2013). Collectively, these clinical studies suggest that SCI can cause progressive and widespread brain changes.

Until recently, assessment of neurodegeneration in the brain following experimental SCI focused on the sensorimotor cortex and medullary pyramid regions; results have been inconsistent, with outcomes ranging from no cell death to extensive retrograde degeneration (Kalil and Schneider, 1975; Feringa and Vahlsing, 1985; Ganchrow and Bernstein, 1985; Merline and Kalil, 1990; Bonatz et al., 2000; Hains et al., 2003a; Lee et al., 2004; Wannier et al., 2005; Kaas et al., 2008; Nielson et al., 2010; 2011). One of the limitations of these earlier SCI studies is that they were performed over poorly defined areas within the cerebral cortex and/or did not utilize rigorous quantitative assessment techniques. We used stereological methods with computer‐driven, random, systematic sampling to provide quantitative analysis of neuronal densities in defined brain regions after SCI. Isolated thoracic SCI in both rat and mouse models resulted in significant neuronal loss in the hippocampus, cortex and thalamus at 10–12 weeks post‐injury, but not at early time points (Wu et al., 2014a, 2014b). Importantly, significant long‐term reduction in neurogenesis in the dentate gyrus (DG) subregion of the hippocampus has been reported after chronic cervical/thoracic SCI (Felix et al., 2012; Wu et al., 2014a). In addition to inflammatory mechanisms (see below), cannabinoid CB1 receptors may be involved in such changes. CB1 receptor immunoreactivity was significantly increased in hippocampal subregions (CA3 and DG) following contusion SCI in rats (Knerlich‐Lukoschus et al., 2011), and this receptor has been implicated in regulation of adult neurogenesis in the hippocampus, including modulation of proliferation, survival and maturation of new neurons (Wolf et al., 2010).

Chronic neuroinflammation in the brain after SCI

SCI frequently causes neuropathic pain that is associated with chronic inflammation in both the dorsal horn and in spinothalamic projection sites in the thalamus (Schmitt et al., 2000; Hains et al., 2003b; Hains and Waxman, 2006; Zhao et al., 2007a, 2007b; Hulsebosch, 2008; Gwak et al., 2013; Wu et al., 2013a, 2013b). Felix et al. (2012) reported increased inflammation in the brain after rat cervical SCI. Changes included increased mRNA expression of the chemokine receptor CCR5 in the dorsal vagal complex and elevated TNFα in the subventricular zone and subgranular zone of the DG. After severe contusion induced SCI, the chemokines CCL2 and CCL3 were chronically expressed in thalamus, hippocampus (CA3 and DG subregions) and periaqueductal grey matter (Knerlich‐Lukoschus et al., 2011). Very recently, we used the TSPO ligand [125I]‐iodoDPA‐713 (Wang et al., 2009) that was used to analyse chronic neuroinflammation in retired NFL players (Coughlin et al., 2015), in autoradiography studies to assess brain inflammation after SCI in rats (Wu et al., 2014b). All brain regions examined (cortex, thalamus, hippocampus, cerebellum, caudate/putamen) showed significantly elevated [125I]‐iodoDPA‐713 binding. These data complemented microscopy data showing chronic microglial activation in the same brain regions after SCI that was associated with increased expression of markers for activated microglia, including TSPO, CD68 and the chemokine CCL21 (Wu et al., 2014a, 2014b). Notably, CCL21 is known to activate microglia at more distant sites following SCI (Zhao et al., 2007b; Hulsebosch et al., 2009). Collectively, these studies indicate that isolated SCI can cause chronic brain inflammation that is remarkably similar to that observed after TBI, resulting in progressive delayed neurodegeneration and functional deficits that include cognitive impairment and depressive‐like behaviour (Wu et al., 2014a, 2014b). The functional changes were associated with chronic microglial activation and concurrent activation of cell cycle pathways and CCL21 in the brain. Early treatment with a cell cycle inhibitor following SCI largely prevented both the post‐traumatic neuroinflammation in the brain and the long‐term cognitive dysfunction (Wu et al., 2014a, 2014b).

SCI in both rat and mouse models causes significant increases of M1‐like microglial activation genes and MHC II expression in the hippocampus, along with changes in M2‐like markers that are species dependent (Wu et al., 2014a, 2014b). M1/M2‐like phenotypic switching probably depends on the local signals in the microenvironment. However, as our analyses used tissue homogenates, the cellular origin of the gene expression changes remains to be determined.

Chronic traumatic inflammatory encephalopathy (CTIE): linking acute and chronic neurodegenerative disorders

Although acute neuroinflammation has been implicated in the pathophysiology of both TBI and SCI, a role for chronic brain inflammation and related neurodegeneration in neurotrauma has only recently been recognized (Faden and Loane, 2015). Neuroinflammation is implicated in the pathobiology of most chronic neurodegenerative disorders (Block et al., 2007), and may provide a mechanistic link to the chronic brain neurodegeneration observed after brain or spinal cord trauma ( Figure 1). There is no accepted nomenclature for persistent post‐traumatic neuroinflammation. Chronic traumatic encephalitis probably best describes the persistent M1‐like microglial activation and reactive astroglial changes that occur after TBI or SCI. It clearly shares key pathological features with other, better defined, non‐infectious forms of chronic encephalitis, such as autoimmune encephalitis or paraneoplastic limbic encephalitis (Leypoldt and Wandinger, 2014; Leypoldt et al., 2015). But the resulting abbreviation – CTE – would be confused with the well‐established abbreviation for the condition of chronic traumatic encephalopathy found after repeated head injuries (McKee et al., 2009; 2013). Chronic posttraumatic neuroinflammation or chronic traumatic inflammatory encephalopathy (CTIE) appear to be more accurate descriptions, with the latter better conveying the association with brain dysfunction. Finally, chronic traumatic brain inflammation is appropriately descriptive and would have the abbreviation CTBI, although this does not convey the pathological association with neurodegeneration or dysfunction. Thus, either CTIE or CTBI would serve as reasonable descriptors for this important condition. Whatever term is used, this disorder may be a more common cause of progressive neuropsychiatric dysfunction after TBI than CTE. Unlike CTE, chronic neuroinflammation occurs following single moderate or severe TBI, as well as after repeated brain trauma. Moreover, as supported by recent research, CTIE/CTBI can be treated effectively weeks after injury (Byrnes et al., 2012; Piao et al., 2013; Rodgers et al., 2014), which suggests the possibility of effective targeted clinical neuroprotection long after a traumatic insult.

Figure 1.

figure

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Chronic inflammation‐mediated neurodegeneration after TBI and SCI. In the acute phase after TBI, M1‐ and M2‐like microglia are activated to limit the primary injury by removing damaged tissue by phagocytosis and resolving destructive pro‐inflammatory responses to improve brain repair and promote neurorestoration. However, repeated mTBI or moderate‐to‐severe TBI results in chronic microglial activation characterized by a predominant M1‐like activation state (i.e. NOX2‐positive neurotoxic phenotype) that contributes to progressive neurodegeneration and loss of neurological function. Similarly, isolated SCI can cause chronic neuroinflammation in the cortex, hippocampus and thalamus at delayed time points after injury. CCL21 expression is up‐regulated in the brain and is associated with increased microglial activation and neurodegeneration, which can cause long‐term neurological deficits after SCI.

Conclusions

Although CTE and AD have received the most attention as chronic brain disorders following TBI, CTIE/CTBI appears to be a more frequent and more likely contributing mechanism for progressive neurodegeneration and related cognitive decline. Surprisingly, SCI may also not uncommonly cause chronic brain inflammation and progressive neurodegeneration, with functional impairments. Thus, both TBI and SCI should be considered chronic, as well as acute, neurodegenerative disorders, in which potentially treatable chronic neuroinflammation plays a critical role.

Conflict of interest

The authors declare they have no conflict of interest.

Acknowledgement

This work was supported by NIH grants R01NS037313, R01NS052568, R01NR013601 (A. I. F.) and R01NS082308 (D. J. L.).

Faden, A. I. , Wu, J. , Stoica, B. A. , and Loane, D. J. (2016) Progressive inflammation‐mediated neurodegeneration after traumatic brain or spinal cord injury. British Journal of Pharmacology, 173: 681–691. doi: 10.1111/bph.13179.

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