Emerging Roles for the Immune System in Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) affects an ever-growing population of all ages with long-term consequences on health and cognition. Many of the issues that TBI patients face are thought to be mediated by the immune system. Primary brain damage that occurs at the time of injury can be exacerbated and prolonged for months or even years by chronic inflammatory processes, which can ultimately lead to secondary cell death, neurodegeneration, and long-lasting neurological impairment. Researchers have turned to rodent models of TBI in order to understand how inflammatory cells and immunological signaling regulate the post-injury response and recovery mechanisms. In addition, the development of numerous methods to manipulate genes involved in inflammation has recently expanded the possibilities of investigating the immune response in TBI models. As results from these studies accumulate, scientists have started to link cells and signaling pathways to pro- and anti-inflammatory processes that may contribute beneficial or detrimental effects to the injured brain. Moreover, emerging data suggest that targeting aspects of the immune response may offer promising strategies to treat TBI. This review will cover insights gained from studies that approach TBI research from an immunological perspective and will summarize our current understanding of the involvement of specific immune cell types and cytokines in TBI pathogenesis.

Keywords: cytokine; inflammasome; innate immunology; microglia; neurodegeneration; neuroinflammation; neuroprotection; traumatic brain injury.

Figure 1

Beneficial and detrimental roles for the immune system in TBI. Common consequences of neuroinflammation after TBI include neuronal death and tissue loss, BBB breakdown and edema, upregulation of inflammatory mediators, and gliosis and cell infiltration. Researchers have evaluated these processes in order to understand which inflammatory cells and molecules potentiate (blue arrows) and inhibit (orange bars) the inflammatory environment of the brain. While we are beginning to link certain cells and molecules to their beneficial and detrimental effects in CNS injury, an important takeaway from these findings is that facilitators of inflammation may be involved in multiple processes at different points in time after injury.

Figure 2

Timeline of the immune response to TBI. Upon an impact to the head, cellular damage results in the rapid release of damage-associated molecular patterns (DAMPs) that prompt resident cells to release cytokines and chemokines. These signals quickly call in neutrophils, which aid in the containment of the injury site and promote the removal of debris and damaged cells. As neutrophil numbers begin to decline after a period of days, infiltrating monocytes and activated glia begin to accumulate around the site of injury to perform reparative functions. Depending on the severity of the brain injury, T and B cells can also be recruited to sites of brain pathology at later time points in the response (3–7 days post-injury).

Figure 3

The involvement of TREM2 in post-TBI amyloid beta clearance. (A) Aβ released after TBI quickly forms into plaques and may bind to lipoproteins. TREM2 assists surrounding myeloid cells in sensing Aβ-lipoprotein complexes, engulfing and breaking down the Aβ, and recruiting other phagocytes to the site of injury. (B) In the case of TREM2 mutations or dysfunction, these cells may not be able to properly sense and clear Aβ or recruit other cells, so that more Aβ builds up over time and leads to plaque formation as seen in Alzheimer’s disease. (C) Another possibility is that in the absence of TREM2 signaling, other signaling pathways may predominate in myeloid cells. For example, when a complex of CD36 with a TLR4-TLR6 heterodimer senses Aβ, instead of phagocytosis, it leads to release of pro-inflammatory cytokines and chemokines that can induce upregulation of secretases in other cells, which are known to lead to increased production of Aβ.