title: The far-reaching scope of neuroinflammation after traumatic brain injury.
abstract: 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.
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, Pennsylvania 15224, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Simon
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, 3500 Terrace Street, BST South, S719, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Mandy J
authors.initials: MJ
authors.lastname: McGeachy
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, Pennsylvania 15224, USA.
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayır
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, Pennsylvania 15224, USA.
authors.forename: Robert S B
authors.initials: RS
authors.lastname: Clark
authors.affiliation: Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, Maryland 21201, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Loane
authors.affiliation: Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, 3434 Fifth Avenue, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology*