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.

Innate immune responses to trauma

“…Circulating monocytes are also increased but, on balance, indicate a transition toward an anti-inflammatory response. In contrast, the number of cytotoxic CD56 dim natural killer cells seems to decrease in patients early after TBI 151 . ILCs have been detected within the meningeal space and lungs.…”

“…Even low concentrations of brain-derived cytokines in blood are capable of inducing leukocytosis and suppressing key functions of peripheral lymphocytes 103,150 , actions attributed mainly to enhanced intracranial pressure, vagal tone and release of catecholamines and glucocorticoids 103,151 . Presumably through increased C5a 131 , peripheral neutrophils react to TBI with enhanced numbers, release of ROS, decreased phagocytotic capacity and a considerably delayed apoptosis, all of which enhance an aggressive immune reaction that probably induces bystander injury 151 . Circulating monocytes are also increased but, on balance, indicate a transition toward an anti-inflammatory response.…”

The Role of Substance P in Pulmonary Clearance of Bacteria in Comparative Injury Models

“…In severe traumatic brain injury (TBI) patients, it has been proposed that hyperactivity of the vagus depresses immune responses through strong dampening of proinflammatory mediator production. 3 In contrast to these studies showing that the neuroimmune axis decreases immune responses, our previous work documented that head trauma patients showed significantly reduced rates of pneumonia compared with blunt trauma patients. 4 A murine model of mild traumatic brain injury (mTBI) was able to reproduce these findings with enhanced resistance to bacterial pneumonia compared with sham injury mice.…”

Age-Dependent Responses Following Traumatic Brain Injury

“…Injection of IL-1β into the P21 rat brain exacerbates rapid neutrophil recruitment, CXC chemokine production, and BBB disruption compared to adult rats [94][95][96]. While the juvenile immune system may display increased sensitivity to neutrophil chemoattractants (CXCL1, CXCL2, CXC8) [97], extension of neutrophil life span may also translate into increased numbers [98,99]. Indeed, adult neutrophil depletion studies appear to reduce edema, cell death, and macrophage/microglia activation while having no effect on BBB and functional outcome suggesting that neutrophils may negatively impact TBI outcome and their long-lived nature may cause progressive injury and contribute to other age-related responses [100,101].…”