Journal Article

The far-reaching scope of neuroinflammation after traumatic brain injury

Bayır, Hülya, Kochanek, Patrick M., McGeachy, Mandy J., Clark, Robert S. B., Loane, David J., Simon, Dennis W.

2017

Overview

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 Neuroinflammation can cause acute secondary injury after traumatic brain injury (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, the authors propose a new framework for targeted immunomodulation after TBI. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/420/256 / 692/617/375/1345 / 692/699/578 / Anesthesiology / Animals / Brain Injuries, Traumatic - immunology / Brain Injuries, Traumatic - pathology / Brain research / Chronic traumatic encephalopathy / Cytokines / Humans / Inflammation / Inflammation - immunology / Inflammation - pathology / Kinases / Medicine / Medicine & Public Health / Neurodegeneration / Neurological disorders / Neurology / Proteins / review-article / Traumatic brain injury / Tumor necrosis factor-TNF