The inflammatory response in the CNS

In recent years it has been recognized that cells of the mononuclear phagocyte lineage, macrophages and microglia, are a major component of gliosis. We review here studies on the kinetics of the myelomonocytic response to acute excitotoxin induced neuronal degeneration and following the injection of endotoxin (LPS) into the parenchyma of the central nervous system. These studies have shown that the kinetics of myelomonocytic recruitment to the parenchyma of the central nervous system is quite unlike that of other tissues; the polymorphonuclear cells are largely excluded and monocytes are only recruited after a delay of several days. The unusual nature of the inflammatory response in the central nervous system needs to be considered when drawing parallels with the acute inflammatory response in other tissues.     

Neutralization of interleukin-1β modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice

Interleukin-1β (IL-1β) may play a central role in the inflammatory response following traumatic brain injury (TBI). We subjected 91 mice to controlled cortical impact (CCI) brain injury or sham injury. Beginning 5 min post-injury, the IL-1β neutralizing antibody IgG2a/k (1.5 μg/mL) or control antibody was infused at a rate of 0.25 μL/h into the contralateral ventricle for up to 14 days using osmotic minipumps. Neutrophil and T-cell infiltration and microglial activation was evaluated at days 1–7 post-injury. Cognition was assessed using Morris water maze, and motor function using rotarod and cylinder tests. Lesion volume and hemispheric tissue loss were evaluated at 18 days post-injury. Using this treatment strategy, cortical and hippocampal tissue levels of IgG2a/k reached 50 ng/mL, sufficient to effectively inhibit IL-1β in vitro . IL-1β neutralization attenuated the CCI-induced cortical and hippocampal microglial activation ( P  <   0.05 at post-injury days 3 and 7), and cortical infiltration of neutrophils ( P  <   0.05 at post-injury day 7). There was only a minimal cortical infiltration of activated T-cells, attenuated by IL-1β neutralization ( P  <   0.05 at post-injury day 7). CCI induced a significant deficit in neurological motor and cognitive function, and caused a loss of hemispheric tissue ( P  <   0.05). In brain-injured animals, IL-1β neutralizing treatment resulted in reduced lesion volume, hemispheric tissue loss and attenuated cognitive deficits ( P  <   0.05) without influencing neurological motor function. Our results indicate that IL-1β is a central component in the post-injury inflammatory response that, in view of the observed positive neuroprotective and cognitive effects, may be a suitable pharmacological target for the treatment of TBI.     

Sexual dimorphism in the inflammatory response to traumatic brain injury

The activation of resident microglial cells, alongside the infiltration of peripheral macrophages, are key neuroinflammatory responses to traumatic brain injury (TBI) that are directly associated with neuronal death. Sexual disparities in response to TBI have been previously reported; however it is unclear whether a sex difference exists in neuroinflammatory progression after TBI. We exposed male and female mice to moderate‐to‐severe controlled cortical impact injury and studied glial cell activation in the acute and chronic stages of TBI using immunofluorescence and in situ hybridization analysis. We found that the sex response was completely divergent up to 7 days postinjury. TBI caused a rapid and pronounced cortical microglia/macrophage activation in male mice with a prominent activated phenotype that produced both pro‐ (IL‐1β and TNFα) and anti‐inflammatory (Arg1 and TGFβ) cytokines with a single‐phase, sustained peak from 1 to 7 days. In contrast, TBI caused a less robust microglia/macrophage phenotype in females with biphasic pro‐inflammatory response peaks at 4 h and 7 days, and a delayed anti‐inflammatory mRNA peak at 30 days. We further report that female mice were protected against acute cell loss after TBI, with male mice demonstrating enhanced astrogliosis, neuronal death, and increased lesion volume through 7 days post‐TBI. Collectively, these findings indicate that TBI leads to a more aggressive neuroinflammatory profile in male compared with female mice during the acute and subacute phases postinjury. Understanding how sex affects the course of neuroinflammation following brain injury is a vital step toward developing personalized and effective treatments for TBI.     

Systemic hypoglycemia following central injection of endotoxin in mice

Intracerebroventricular microinjection of endotoxin in mice resulted in powerful hypoglycemia. The effect was reproduced by the biologically active moiety of endotoxin, lipid A, and prevented by coadministration of the polycationic peptide antibiotic polymyxin B (PMB) or by detoxification of endotoxin by means of mild alkaline hydrolysis. Central treatment with PMB also attenuated the hypoglycemic response to systemic administration of endotoxin or lipid A. These results suggest a direct role of the CNS in the mechanism of endotoxin hypoglycemia.     

Altered immune response to CNS viral infection in mice with a conditional knock-down of macrophage-lineage cells

Neuroadapted Sindbis Virus (NSV) is a neuronotropic virus that causes hindlimb paralysis in susceptible mice and rats. The authors and others have demonstrated that though death of infected motor neurons occurs, bystander death of uninfected neurons also occurs and both contribute to the paralysis that ensues following infection. The authors have previously shown that the treatment of NSV-infected mice with minocycline, an inhibitor that has many functions within the central nervous system (CNS), including inhibiting microglial activation, protects mice from paralysis and death. The authors, therefore, proposed that microglial activation may contribute to bystander death of motor neurons following NSV infection. Here, the authors tested the hypothesis using a conditional knock-out of activated macrophage-lineage cells, including endogenous CNS macrophage cells. Surprisingly, ablation of these cells resulted in more rapid death and similar weakness in the hind limbs of NSV-infected animals compared with that of control animals. Several key chemokines including IL-12 and monocyte chemoattractant protein-1 (MCP-1) did not become elevated in these animals, resulting in decreased infiltration of T lymphocytes into the CNS of the knock-down animals. Either because of the decreased macrophage activation directly or because of the reduced immune cell influx, viral replication persisted longer within the nervous system in knock-down mice than in wild type mice. The authors, therefore, conclude that although macrophage-lineage cells in the CNS may contribute to neurodegeneration in certain situations, they also serve a protective role, such as control of viral replication.     

IL-10 deficiency exacerbates the brain inflammatory response to permanent ischemia without preventing resolution of the lesion

Stroke induces inflammation that can aggravate brain damage. This work examines whether interleukin-10 (IL-10) deficiency exacerbates inflammation and worsens the outcome of permanent middle cerebral artery occlusion (pMCAO). Expression of IL-10 and IL-10 receptor (IL-10R) increased after ischemia. From day 4, reactive astrocytes showed strong IL-10R immunoreactivity. Interleukin-10 knockout (IL-10 KO) mice kept in conventional housing showed more mortality after pMCAO than the wild type (WT). This effect was associated with the presence of signs of colitis in the IL-10 KO mice, suggesting that ongoing systemic inflammation was a confounding factor. In a pathogen-free environment, IL-10 deficiency slightly increased infarct volume and neurologic deficits. Induction of proinflammatory molecules in the IL-10 KO brain was similar to that in the WT 6 hours after ischemia, but was higher at day 4, while differences decreased at day 7. Deficiency of IL-10 promoted the presence of more mature phagocytic cells in the ischemic tissue, and enhanced the expression of M2 markers and the T-cell inhibitory molecule CTLA-4. These findings agree with a role of IL-10 in attenuating local inflammatory reactions, but do not support an essential function of IL-10 in lesion resolution. Upregulation of alternative immunosuppressive molecules after brain ischemia can compensate, at least in part, the absence of IL-10.     

Resident microglia die and infiltrated neutrophils and monocytes become major inflammatory cells in lipopolysaccharide-injected brain

Generally, it has been accepted that microglia play important roles in brain inflammation. However, recently several studies suggested possible infiltration of blood neutrophils and monocytes into the brain. To understand contribution of microglia and blood inflammatory cells to brain inflammation, the behavior of microglia, neutrophils, and monocytes was investigated in LPS (lipopolysaccharide)-injected substantia nigra pars compacta, cortex, and hippocampus of normal and/or leukopenic rats using specific markers of neutrophils (myeloperoxidase, MPO), and microglia and monocytes (ionized calcium binding adaptor molecule-1, Iba-1), as well as a general marker for these inflammatory cells (CD11b). CD11b-immunopositive (CD11b(+)) cells and Iba-1(+) cells displayed similar behavior in intact and LPS-injected brain at 6 h after the injection. Interestingly, however, CD11b(+) cells and Iba-1(+) cells displayed significantly different behavior at 12 h: Iba-1(+) cells disappeared while CD11b(+) cells became round in shape. We found that CD11b/Iba-1-double positive (CD11b(+)/Iba-1(+)) ramified microglia died within 6 h after LPS injection. The round CD11b(+) cells detected at 12 h were MPO(+). These CD11b(+)/MPO(+) cells were not found in leukopenic rats, suggestive of neutrophil infiltration. MPO(+) neutrophils expressed inducible nitric oxide synthase, interleukin-1beta, cyclooxygenase-2, and monocyte chemoattractant protein-1, but died within 18 h. CD11b(+) cells detected at 24 h appeared to be infiltrated monocytes, since these cells were once labeled with Iba-1 and were not found in leukopenic rats. Furthermore, transplanted monocytes were detectable in LPS-injected brain. These results suggest that at least a part of neutrophils and monocytes could have been misinterpreted as activated microglia in inflamed brain.     

Interleukin 15 expression in the CNS: blockade of its activity prevents glial activation after an inflammatory injury

Although reactive glia formation after neuronal degeneration or traumatic damage is one of the hallmarks of central nervous system (CNS) injury, we have little information on the signals that direct activation of resting glia. IL-15, a pro-inflammatory cytokine involved in regulating the response of T and B cells, may be also key for the regulation of early inflammatory events in the nervous system. IL-15 was expressed in the CNS, most abundantly in cerebellum and hippocampus, mainly in astrocytes and in some projection neurons. Using a rodent model of acute inflammatory injury [lipopolysaccharide (LPS) injection], we found enhanced expression of IL-15 in both reactive astroglia and microglia, soon after CNS injury. Blockade of IL-15 activity with an antibody to the cytokine, reversed activation of both glial types, suggesting that IL-15 has a major role in the generation of gliotic tissue and in the regulation of neuroimmune responses. Because IL-15 appears to modulate the inflammatory environment acutely generated after CNS injury, regulating IL-15 expression seems a clear antiinflammatory therapy to improve the outcome of neurodegenerative diseases and CNS trauma.     

Lack of NG2 exacerbates neurological outcome and modulates glial responses after traumatic brain injury

Traumatic brain injury (TBI) is a major cause of death and disability. The underlying pathophysiology is characterized by secondary processes including neuronal death and gliosis. To elucidate the role of the NG2 proteoglycan we investigated the response of NG2‐knockout mice (NG2‐KO) to TBI. Seven days after TBI behavioral analysis, brain damage volumetry and assessment of blood brain barrier integrity demonstrated an exacerbated response of NG2‐KO compared to wild‐type (WT) mice. Reactive astrocytes and expression of the reactive astrocyte and neurotoxicity marker Lcn2 (Lipocalin‐2) were increased in the perilesional brain tissue of NG2‐KO mice. In addition, microglia/macrophages with activated morphology were increased in number and mRNA expression of the M2 marker Arg1 (Arginase 1) was enhanced in NG2‐KO mice. While TBI‐induced expression of pro‐inflammatory cytokine genes was unchanged between genotypes, PCR array screening revealed a marked TBI‐induced up‐regulation of the C‐X‐C motif chemokine 13 gene Cxcl13 in NG2‐KO mice. CXCL13, known to attract immune cells to the inflamed brain, was expressed by activated perilesional microglia/macrophages seven days after TBI. Thirty days after TBI, NG2‐KO mice still exhibited more pronounced neurological deficits than WT mice, up‐regulation of Cxcl13, enhanced CD45+ leukocyte infiltration and a relative increase of activated Iba‐1+/CD45+ microglia/macrophages. Our study demonstrates that lack of NG2 exacerbates the neurological outcome after TBI and associates with abnormal activation of astrocytes, microglia/macrophages and increased leukocyte recruitment to the injured brain. These findings suggest that NG2 may counteract neurological deficits and adverse glial responses in TBI. GLIA 2016;64:507–523     

Neuroprotective effects of resident microglia following acute brain injury

Microglia quickly react to various neurodegenerative processes by producing cytokines and eliminating cellular debris via phagocytosis. These events are also associated with an increased proliferation of microglia, which derive from resident progenitors and those present in the bone marrow. However, it is not clear whether the innate immune response by resident or newly differentiated microglia is beneficial or detrimental to the central nervous system. The aim of this study was to determine the impact of an altered immune response following acute excitotoxicity. Sodium nitroprusside (SNP) or kainic acid (KA) was administered in the brain of various groups of mice, and the extent of neurodegeneration, myelin damage, and inflammation was evaluated within a period of 2 weeks. We used synthetic glucocorticoid (GC), myeloid differentiation factor 88 (MyD88)-deficient mice to suppress nuclear factor kappaB (NF-kappaB) signaling and transgenic mice that express the thymidine kinase (TK) protein under the control of the CD11b promoter to determine the role of proliferating and infiltrating microglia in acute models of brain injury. Neurodegeneration was more extensive in GC-treated and MyD88-deficient mice, suggesting that NF-kappaB signaling and microglia activation are potent neuroprotective mechanisms in the presence of SNP. KA was also highly toxic to neurons of the amygdala in MyD88 knockout mice but not in their WT littermates. Although bone marrow-derived cells are clearly attracted to neurodegenerative areas, preventing their infiltration and differentiation did not affect the extent of SNP-related damage. These data indicate that MyD88/NF-kappaB signaling in resident non-proliferating microglia plays a critical role by restricting damage during acute excitotoxicity.     

经侧脑室注射脂多糖诱导大鼠黑质部位小胶质细胞激活及多巴胺能神经元损伤的研究

目的观察经脑室注射脂多糖(LPS)后大鼠的黑质部小胶质细胞激活及多巴胺(DA)能神经元的变化,探讨脑内炎性反应在黑质DA能神经元慢性变性过程中的作用。方法健康雄性SD大鼠30只,随机分为生理盐水(NS)对照组和LPS组,分别向大鼠右侧脑室注射20μL NS或50μg LPS,40周后用免疫组织化学方法检测大鼠黑质小胶质细胞是否激活、激活的程度(OX-42及OX-6抗体水平),以及酪氨酸羟化酶(TH)阳性神经元的形态和数量。以Fluoro-Jade B(FJB)染色法检测黑质部位神经元变性情况。结果 (1)NS对照组大鼠黑质部位OX-42阳性小胶质细胞呈静息状态,染色浅。LPS组大鼠黑质部OX-42阳性小胶质细胞呈部分激活状态,染色深。两组大鼠黑质部位均未发现OX-6阳性小胶质细胞。(2)NS对照组大鼠黑质部位有大量深染的TH阳性神经元。LPS组大鼠黑质部位TH阳性染色神经元数目(99.11±20.31)比NS对照组(189.52±12.12)减少47.7%(P<0.01)。(3)两组大鼠黑质部位均未见FJB阳性染色神经元。结论经侧脑室单次注射LPS可能造成大鼠黑质部位小胶质细胞长期慢性激活及DA能神经元慢性迟发性功能性损伤。     

Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo

Accumulating evidence suggests that changes in the metabolic signature of microglia underlie their response to inflammation. We sought to increase our knowledge of how pro-inflammatory stimuli induce metabolic changes. Primary microglia exposed to lipopolysaccharide (LPS)-expressed excessive fission leading to more fragmented mitochondria than tubular mitochondria. LPS-mediated Toll-like receptor 4 (TLR4) activation also resulted in metabolic reprogramming from oxidative phosphorylation to glycolysis. Blockade of mitochondrial fission by Mdivi-1, a putative mitochondrial division inhibitor led to the reversal of the metabolic shift. Mdivi-1 treatment also normalized the changes caused by LPS exposure, namely an increase in mitochondrial reactive oxygen species production and mitochondrial membrane potential as well as accumulation of key metabolic intermediate of TCA cycle succinate. Moreover, Mdivi-1 treatment substantially reduced LPS induced cytokine and chemokine production. Finally, we showed that Mdivi-1 treatment attenuated expression of genes related to cytotoxic, repair, and immunomodulatory microglia phenotypes in an in vivo neuroinflammation paradigm. Collectively, our data show that the activation of microglia to a classically pro-inflammatory state is associated with a switch to glycolysis that is mediated by mitochondrial fission, a process which may be a pharmacological target for immunomodulation.     

Neurochemical effects of cocaine following acute and repeated injection

Following repeated injection in the rat, cocaine decreased the concentration of serotonin in the septum-caudate and increased the metabolism of hypothalamic norepinephrine and also striatal dopamine to a lesser extent. Furthermore, cocaine significantly decreased the activity of the rate-limiting enzyme, tryptophan hydroxylase. In a comparative study d-amphetamine and methylphenidate were found to exert an effect opposite to cocaine in the activation of tryptophan hydroxylase. These findings indicate that cocaine may lower central serotonin function by decreasing its availability for neural transmission. This count account for the stimulation of locomotor activity observed after cocaine administration.     

CNS中抗原递呈细胞调节T细胞对CNS抗原的应答

在中枢神经系统 (CNS)炎症或损伤时 ,T细胞对CNS抗原的应答启动于外周免疫系统 ,而作用于CNS。CNS中小胶质细胞、星形胶质细胞和血管周围巨噬细胞可作为抗原递呈细胞 ,通过对Th1和Th2细胞的再刺激 ,分泌可溶性因子调节Th1和Th2细胞应答 ,以及与T细胞间相互作用 ,调控Th1细胞和Th2细胞间的平衡 ,从而促进或抑制T细胞应答 ,影响CNS炎症损伤的结局     

Vulnerability of brain tissue to inflammatory oxidant, hypochlorous acid

CNS inflammation is a sequela of a variety of neuropathological conditions resulting in extensive tissue loss. Inflammation is mediated primarily by phagocytic cells, but the mechanisms of CNS tissue destruction are not fully understood. Hypochlorous acid (HOCl) is by far the most abundant agent generated by phagocytic cells and may be the major mediator of inflammatory tissue damage. However, the effects of HOCl on nervous tissue have not been examined. In this study we used an in vitro model system of rat brain slices to determine neurotoxicity of HOCl. The slices were exposed to HOCl at pathologically relevant doses, and the incorporation of [3H]leucine into proteins and lipids was analyzed in total homogenate, and in particulate fractions obtained by density gradient centrifugation. The results demonstrated that a brief HOCl exposure profoundly suppressed protein biosynthesis in the slices. Also, lipid synthesis was suppressed in nonmyelin particulate fraction. However, lipid synthesis in myelin was significantly stimulated in HOCl-exposed slices indicating that oligodendrocyte response to the oxidant differs from that of other CNS cells. The effects of HOCl could be blocked by coadministration of antioxidants, i.e., N-acetylcystein (NAC), uric acid (UA) and ascorbic acid (AA). The protective potency of the antioxidants was NAC>UA>AA. In conclusion, our study demonstrated that HOCl generated by phagocytic cells during inflammatory episodes has a potential to damage surrounding CNS tissue, and that tissue damage can be prevented by HOCl scavenging with clinically applicable antioxidants.     

The interaction of Schwann cells with CNS axons in regions containing normal astrocytes

Summary On occasions retinal axons can be myelinated elinated by Schwann cells. In the present experiments cultured autologous Schwann cells were injected into the optic disc of adult cats and the extent of Schwann cell myelination determined. Little if any Schwann cell myelination of retinal ganglion cell axons developed. Schwann cells were also injected into lesions in the cerebral cortex induced by ethidium bromide. In this site some Schwann cell remyelination was detected, but it was restricted to areas next to regions of malacia induced by the injection procedure. It was concluded that astrocyte responses, limit Schwann cell myelination and remyelination in normal tissue by excluding Schwann cells from the CNS compartment, and induce changes in chronically demyelinated and amyelinated axons which may affect myelination.Supported by a grant from the Multiple Sclerosis Society     

Attenuation of acute inflammatory response by atorvastatin after spinal cord injury in rats

Spinal cord injury (SCI) is a devastating and complex clinical condition involving proinflammatory cytokines and nitric oxide toxicity that produces a predictable pattern of progressive injury entailing neuronal loss, axonal destruction, and demyelination at the site of impact. The involvement of proinflammatory cytokines and inducible nitric oxide synthase (iNOS) in exacerbation of SCI pathology is well documented. We have reported previously the antiinflammatory properties and immunomodulatory activities of statins (3-hydroxy-3-methylglutaryl [HMG]-CoA reductase inhibitors) in the animal model of multiple sclerosis, experimental allergic encephalitis (EAE). The present study was undertaken to investigate the efficacy of atorvastatin (Lipitor; LP) treatment in attenuating SCI-induced pathology. Immunohistochemical detection and real-time PCR analysis showed increased expression of iNOS, tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) after SCI. In addition, neuronal apoptosis was detected 24 hr after injury followed by a profound increase in ED1-positive inflammatory infiltrates, glial fibrillary acidic protein (GFAP)-positive reactive astrocytes, and oligodendrocyte apoptosis by 1 week after SCI relative to control. LP treatment attenuated the SCI-induced iNOS, TNFalpha, and IL-1beta expression. LP also provided protection against SCI-induced tissue necrosis, neuronal and oligodendrocyte apoptosis, demyelination, and reactive gliosis. Furthermore, rats treated with LP scored much higher on the locomotor rating scale after SCI (19.13 +/- 0.53) than did untreated rats (9.04 +/- 1.22). This study therefore reports the beneficial effect of atorvastatin for the treatment of SCI-related pathology and disability.     

Infectious inflammation of the CNS involves activation of mitogen-activated protein kinase and AKT proteins in CSF in humans

Abstract The mitogen-activated protein kinases (MAPKs) and the AKT are interacting proteins that serve as transmitters of numerous extracellular signals to their intracellular targets, thereby regulating many cellular processes, such as proliferation, differentiation, development or stress responses. Whereas a large amount of information about the MAPKs/AKT participation in biological processes is available, less is known about their role in human diseases. We postulated that the MAPKs/AKT could be involved in inflammatory processes of the central nervous system (CNS) in humans and we investigated the CSF of 12 patients with viral infection of the CNS for the presence of the distinct components of these cascades. The cerebrospinal fluid (CSF) of 18 individuals who underwent a lumbar puncture for diagnostic purposes served as controls. Six patients with inflammatory disease of the CNS revealed the presence of activated ERK. In five patients p38MAPK was detected, in three in its activated form. The activity of AKT could be demonstrated in four patients. JNK was not found. None of the control patients showed the presence of MAPK enzymes. The mean CSF cellularity was higher in MAPK-positive than in MAPKnegative patients. There was no difference in mean age or gender between the patients and controls, or between the MAPK- and AKT-positive or -negative patients. Our work demonstrates that the MAPK and AKT cascades might participate in inflammatory processes of the CNS. As selective inhibitors of the MAPKs are available, their application in the future might reduce an inappropriate inflammatory response and thus limit brain damage in severe cases of meningoencephalitis.     

Dynamics of the inflammatory response after murine spinal cord injury revealed by flow cytometry

Spinal cord injury (SCI) triggers a robust inflammatory response that contributes in part to the secondary degeneration of spared tissue. Here, we use flow cytometry to quantify the inflammatory response after SCI. Besides its objective evaluation, flow cytometry allows for levels of particular markers to be documented that further aid in the identification of cellular subsets. Analyses of blood from SCI mice for CD45 (common leukocyte antigen), CD11b (complement receptor-3), Gr-1 (neutrophil/monocyte marker), and CD3 (T-cell marker) revealed a marked increase in circulating neutrophils (CD45(high):Gr-1(high)) at 12 hr compared with controls. Monocyte density in blood increased at 24 hr, and in contrast, lymphocyte numbers were significantly decreased. Mirroring the early increase in neutrophils within the blood, flow analysis of the spinal cord lesion site revealed a significant (P < 0.01) and maintained increase in blood-derived leukocytes (CD45(high):CD11b(high)) from 12 to 96 hr compared with sham-injured and naive controls. Importantly, this technique clearly distinguishes blood-derived neutrophils (CD45:Gr-1(high):F4/80(negative)) and monocyte/macrophages (CD45(high)) from resident microglia (CD45(low)) and revealed that the majority of the blood-derived infiltrate were neutrophils. Our results highlight an assumed, but previously uncharacterized, marked and transient increase in leukocyte populations in blood early after SCI followed by the orchestrated invasion of neutrophils and monocytes into the injured cord. In contrast to mobilization of neutrophils, SCI induces lymphopenia that may contribute negatively to the overall outcome after spinal cord trauma.     

Review: The long‐term consequences of microglial activation following acute traumatic brain injury

The brain is vulnerable to a number of acute insults, with traumatic brain injury being among the commonest. Neuroinflammation is a common response to acute injury and microglial activation is a key component of the inflammatory response. In the acute and subacute phase it is likely that this response is protective and forms an important part of the normal tissue reaction. However, there is considerable literature demonstrating an association between acute traumatic brain injury to the brain and subsequent cognitive decline. This article will review the epidemiological literature relating to both single and repetitive head injury. It will focus on the neuropathological features associated with long‐term complications of a single blunt force head injury, repetitive head injury and blast head injury, with particular reference to chronic traumatic encephalopathy, including dementia pugilistica. Neuroinflammation has been postulated as a key mechanism linking acute traumatic brain injury with subsequent neurodegenerative disease, and this review will consider the response to injury in the acute phase and how this may be detrimental in the longer term, and discuss potential genetic factors which may influence this cellular response. Finally, this article will consider future directions for research and potential future therapies.