A concerted effort to tackle the global health problem posed by traumatic brain injury (TBI) is long overdue. TBI is a public health challenge of vast, but insufficiently recognised, proportions. Worldwide, more than 50 million people have a TBI each year, and it is estimated that about half the world's population will have one or more TBIs over their lifetime. TBI is the leading cause of mortality in young adults and a major cause of death and disability across all ages in all countries, with a disproportionate burden of disability and death occurring in low-income and middle-income countries (LMICs). It has been estimated that TBI costs the global economy approximately $US400 billion annually. Deficiencies in prevention, care, and research urgently need to be addressed to reduce the huge burden and societal costs of TBI. This Commission highlights priorities and provides expert recommendations for all stakeholders—policy makers, funders, health-care professionals, researchers, and patient representatives—on clinical and research strategies to reduce this growing public health problem and improve the lives of people with TBI.Additional co-authors: Endre Czeiter, Marek Czosnyka, Ramon Diaz-Arrastia, Jens P Dreier, Ann-Christine Duhaime, Ari Ercole, Thomas A van Essen, Valery L Feigin, Guoyi Gao, Joseph Giacino, Laura E Gonzalez-Lara, Russell L Gruen, Deepak Gupta, Jed A Hartings, Sean Hill, Ji-yao Jiang, Naomi Ketharanathan, Erwin J O Kompanje, Linda Lanyon, Steven Laureys, Fiona Lecky, Harvey Levin, Hester F Lingsma, Marc Maegele, Marek Majdan, Geoffrey Manley, Jill Marsteller, Luciana Mascia, Charles McFadyen, Stefania Mondello, Virginia Newcombe, Aarno Palotie, Paul M Parizel, Wilco Peul, James Piercy, Suzanne Polinder, Louis Puybasset, Todd E Rasmussen, Rolf Rossaint, Peter Smielewski, Jeannette Söderberg, Simon J Stanworth, Murray B Stein, Nicole von Steinbüchel, William Stewart, Ewout W Steyerberg, Nino Stocchetti, Anneliese Synnot, Braden Te Ao, Olli Tenovuo, Alice Theadom, Dick Tibboel, Walter Videtta, Kevin K W Wang, W Huw Williams, Kristine Yaffe for the InTBIR Participants and Investigator

Within minutes of a traumatic impact, a robust inflammatory response is elicited in the injured brain. The complexity of this post-traumatic squeal involves a cellular component, comprising the activation of resident glial cells, microglia, and astrocytes, and the infiltration of blood leukocytes. The second component regards the secretion immune mediators, which can be divided into the following sub-groups: the archetypal pro-inflammatory cytokines (Interleukin-1, Tumor Necrosis Factor, Interleukin-6), the anti-inflammatory cytokines (IL-4, Interleukin-10, and TGF-beta), and the chemotactic cytokines or chemokines, which specifically drive the accumulation of parenchymal and peripheral immune cells in the injured brain region. Such mechanisms have been demonstrated in animal models, mostly in rodents, as well as in human brain. Whilst the humoral immune response is particularly pronounced in the acute phase following Traumatic brain injury (TBI), the activation of glial cells seems to be a rather prolonged effect lasting for several months. The complex interaction of cytokines and cell types installs a network of events, which subsequently intersect with adjacent pathological cascades including oxidative stress, excitotoxicity, or reparative events including angiogenesis, scarring, and neurogenesis. It is well accepted that neuroinflammation is responsible of beneficial and detrimental effects, contributing to secondary brain damage but also facilitating neurorepair. Although such mediators are clear markers of immune activation, to what extent cytokines can be defined as diagnostic factors reflecting brain injury or as predictors of long term outcome needs to be further substantiated. In clinical studies some groups reported a proportional cytokine production in either the cerebrospinal fluid or intraparenchymal tissue with initial brain damage, mortality, or poor outcome scores. However, the validity of cytokines as biomarkers is not broadly accepted. This review article will discuss the evidence from both clinical and laboratory studies exploring the validity of immune markers as a correlate to classification and outcome following TBI.

Summary:Despite dramatic improvements in the management of traumatic brain injury (TBI), to date there is no effective treatment available to patients, and morbidity and mortality remain high. The damage to the brain occurs in two phases, the initial primary phase being the injury itself, which is irreversible and amenable only to preventive measures to minimize the extent of damage, followed by an ongoing secondary phase, which begins at the time of injury and continues in the ensuing days to weeks. This delayed phase leads to a variety of physiological, cellular, and molecular responses aimed at restoring the homeostasis of the damaged tissue, which, if not controlled, will lead to secondary insults. The development of secondary brain injury represents a window of opportunity in which pharmaceutical compounds with neuroprotective properties could be administered. To establish effective treatments for TBI victims, it is imperative that the complex molecular cascades contributing to secondary injury be fully elucidated. One pathway known to be activated in response to TBI is cellular and humoral inflammation. Neuroinflammation within the injured brain has long been considered to intensify the damage sustained following TBI. However, the accumulated findings from years of clinical and experimental research support the notion that the action of inflammation may differ in the acute and delayed phase after TBI, and that maintaining limited inflammation is essential for repair. This review addresses the role of several cytokines and chemokines following focal and diffuse TBI, as well as the controversies around the use of therapeutic anti-inflammatory treatments versus genetic deletion of cytokine expression.