Traumatic Brain Injury and Peripheral Immune Suppression: Primer and Prospectus

Abstract

Nosocomial infections are a common occurrence in patients following traumatic brain injury (TBI) and are associated with an increased risk of mortality, longer length of hospital stay, and poor neurological outcome. Systemic immune suppression arising as a direct result of injury to the central nervous system (CNS) is considered to be primarily responsible for this increased incidence of infection, a view strengthened by recent studies that have reported novel changes in the composition and function of the innate and adaptive arms of the immune system post-TBI. However, our knowledge of the mechanisms that underlie TBI-induced immune suppression is equivocal at best. Here, after summarizing our current understanding of the impact of TBI on peripheral immunity and discussing CNS-mediated regulation of immune function, we propose roles for a series of novel mechanisms in driving the immune suppression that is observed post-TBI. These mechanisms, which have never been considered before in the context of TBI-induced immune paresis, include the CNS-driven emergence into the circulation of myeloid-derived suppressor cells and suppressive neutrophil subsets, and the release from injured tissue of nuclear and mitochondria-derived damage associated molecular patterns. Moreover, in an effort to further our understanding of the mechanisms that underlie TBI-induced changes in immunity, we pose throughout the review a series of questions, which if answered would address a number of key issues, such as establishing whether manipulating peripheral immune function has potential as a future therapeutic strategy by which to treat and/or prevent infections in the hospitalized TBI patient.

Keywords: immune suppression; immune system; infection; traumatic brain injury.

Figure 1

Proposed mechanisms underlying TBI-induced changes in peripheral innate and adaptive immunities. Applying the findings of studies performed on patients with general trauma (111, 113–115, 118, 122, 127) and CNS injury (131) to the hospitalized TBI patient, we propose three novel mechanisms contribute in part to the peripheral immune suppression that is observed post-TBI. Mechanism 1: secondary complications arising from TBI such as raised intracranial pressure (ICP) and cerebral ischemia result in elevated serum levels of glucocorticoids (GCs) and catecholamines (CAs) through activation of the HPA axis and SNS, respectively. GCs and CAs drive the proliferation and accumulation of myeloid derived suppressor cells (MDSC) in the circulation that subsequently inhibit T-cell function via depletion of arginine from the local environment and the production of reactive oxygen species (ROS). Mechanism 2: TBI triggers emergency granulopoiesis, which results in the emergence into the circulation of immature granulocytes (IGs) and the generation of a heterogeneous pool of neutrophils that contains CD16^BRIGHT CD16^DIM-suppressive neutrophils. Through ROS generation, CD16^BRIGHT CD16^DIM neutrophils would suppress T-cell proliferation, while via direct cytotoxicity IGs would induce T-cell apoptosis and thus lymphocytopenia. Mechanism 3: neuronal cell death combined with disruption of the blood–brain barrier (BBB) would lead to the emergence into the circulation of both nuclear- and mitochondrial-derived damage-associated molecular patterns (DAMPs). The nuclear-derived DAMP high mobility group box 1 (HMGB1) would promote the expansion of MDSCs, monocyte hyporesponsiveness, and lymphocytopenia, while the presence of mtDAMPs would induce a state of systemic immune cell tolerance. More specifically, as a consequence of exposure to N-formyl peptides, circulating neutrophils would exhibit reduced antimicrobial activity upon secondary stimulation, while mitochondrial DNA (mtDNA) would promote a state of endotoxin tolerance in circulating monocytes. The consequence of all three of these proposed mechanisms is profound suppression of the peripheral immune system, resulting in an increased susceptibility to infection and an increased risk of poor outcome.