Guilty molecules, guilty minds? The conflicting roles of the innate immune response to traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a complex disease in the most complex organ of the body, whose victims endure lifelong debilitating physical, emotional, and psychosocial consequences. Despite advances in clinical care, there is no effective neuroprotective therapy for TBI, with almost every compound showing promise experimentally having disappointing results in the clinic. The complex and highly interrelated innate immune responses govern both the beneficial and deleterious molecular consequences of TBI and are present as an attractive therapeutic target. This paper discusses the positive, negative, and often conflicting roles of the innate immune response to TBI in both an experimental and clinical settings and highlights recent advances in the search for therapeutic candidates for the treatment of TBI.

Figure 1

Passage of innate immune components through the blood brain barrier (BBB) after TBI. Injury to the brain results in transient opening of the BBB, in which complement proteins and neutrophils are able to directly enter the parenchyma. Peripheral monocytes enter the brain through a process of extravasation, in which several adhesion molecules are upregulated in turn on both the monocyte and endothelial cell to first tether, then provide passage for the cell through the BBB. First, constitutively expressed L-selectin binds to upregulated P/E-selectin on the endothelial cell surface. Once tethered to the endothelium, monocytes are exposed to chemokines that bind to their cognate receptors on the cell, inducing conformational change and upregulation of β2 integrins, which bind to ICAMs expressed on endothelial cells. This final interaction between adhesion molecules signals the cell to migrate across the endothelium into the parenchyma, where it begins to differentiate and take on the morphology of an activated macrophage. Under the influence of chemokines, the cell continues the transition to an activated macrophage state migrates to the site of injury. Figure adapted from [51].