The far-reaching scope of neuroinflammation after traumatic brain injury

  • An Erratum to this article was published on 04 August 2017

Key Points

  • Traumatic brain injury (TBI) is an important public health issue: the global incidence of TBI is on the rise, and mild, repetitive and blast injuries, in particular, are increasingly recognized in the popular press

  • Neuroinflammation, triggered by release of endogenous danger signals and innate immune activation, is crucial to recovery after TBI; however, a dysregulated immune response can result in secondary injury

  • After TBI, the activity of microglia and infiltrating macrophages and adaptive immune cells is driven by extracellular injury signals and intracellular molecular pathways that might represent novel therapeutic targets

  • Trials assessing immunomodulatory interventions should account for changes in neuroinflammation that occur over time, between injury type and severity, and across patient characteristics such as age, sex and genetic variability

  • Some individuals with TBI develop chronic neuroinflammation, which can last for years after the injury, and is being investigated as a link to accelerated neurodegeneration and chronic traumatic encephalopathy


The 'silent epidemic' of traumatic brain injury (TBI) has been placed in the spotlight as a result of clinical investigations and popular press coverage of athletes and veterans with single or repetitive head injuries. Neuroinflammation can cause acute secondary injury after TBI, and has been linked to chronic neurodegenerative diseases; however, anti-inflammatory agents have failed to improve TBI outcomes in clinical trials. In this Review, we therefore propose a new framework of targeted immunomodulation after TBI for future exploration. Our framework incorporates factors such as the time from injury, mechanism of injury, and secondary insults in considering potential treatment options. Structuring our discussion around the dynamics of the immune response to TBI — from initial triggers to chronic neuroinflammation — we consider the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration. We summarize both animal model and human studies, with clinical data explicitly defined throughout this Review. Recent advances in neuroimmunology and TBI-responsive neuroinflammation are incorporated, including concepts of inflammasomes, mechanisms of microglial polarization, and glymphatic clearance. Moreover, we highlight findings that could offer novel therapeutic targets for translational and clinical research, assimilate evidence from other brain injury models, and identify outstanding questions in the field.

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Figure 1: Neuroinflammation after traumatic brain injury.
Figure 2: Polarization of microglia and macrophages following TBI.
Figure 3: Novel TBI therapies targeting inflammation at different time points.
Figure 4: Effects of chronic neuroinflammation.

Change history

  • 04 August 2017

    In the initially published version of this article, reference 194 was incorrectly cited as reference 193 in the Conclusions section. This error has been corrected in the HTML and PDF versions of the article.


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The authors acknowledge the following funding sources: NIH grants T32 HD40686 (D.W.S.) and R01 NS082308 (D.J.L.); National Institute of Child Health and Human Development grants R01 NS087978 (P.M.K.), NS061817 and NS076511 (H.B.); National Institute of Allergy and Infectious Diseases grant R01 AI110822-01 (M.J.M.); Department of Defense Grants W81XWH-10-1-0623 and W81XWH-14-2-0018 (P.M.K.); NIA Claude D. Pepper Older Americans Independence Center grant P30-AG028747 (D.J.L.); and Children's Hospital of Pittsburgh — Children's Trust (D.W.S.).

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The authors contributed equally to all aspects of the manuscript.

Correspondence to Patrick M. Kochanek.

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Chronic traumatic encephalopathy

A progressive neurodegenerative disease associated with head trauma and characterized histologically by formation of neurofibrillary tangles, accumulation of phosphorylated TAR DNA-binding protein 43 (TDP-43) accumulation, and deposition of amyloid-β.

Damage-associated molecular patterns

Host-derived molecules that trigger and/or exacarbate the inflammatory response. Prominent examples include DNA and RNA, high mobility group protein B1 (HMGB1), S100 proteins, ATP, uric acid, lysophospholipids, and lipid peroxidation-derived carbonyl adducts of proteins.

CD11d/CD18 integrin

A pattern recognition receptor that is located on the surface of neutrophils and monocytes and is functionally important in recognition of complement, as well as cell–cell interactions and cellular adhesion.

Chemokine gradients

Concentration gradients of chemotactic cytokines with the ability to influence inflammatory cell migration and function. For example, C–C motif chemokine 2 (CCL2), a chemokine for monocytes, macrophages and microglia, and its receptor CCR2 interact to recruit these immune cells to injured tissue after traumatic brain injury.

Autoimmune T cells

Also called autoreactive T cells, these T lymphocytes react to self antigens and may cause autoimmune disease, but are also critical for normal brain function and repair.

TH17 cells

A subset of effector T-helper cells that produce IL-17 and other proinflammatory cytokines.

Glymphatic system

Astrocyte-regulated convective bulk flow of the cerebrospinal fluid from the paravascular space through interstitial fluid in an arterial–venous direction.

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Simon, D., McGeachy, M., Bayır, H. et al. The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol 13, 171–191 (2017) doi:10.1038/nrneurol.2017.13

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