The contribution of astrocytes and microglia to traumatic brain injury

Abstract

Traumatic brain injury (TBI) represents a major cause of death and disability in developed countries. Brain injuries are highly heterogeneous and can also trigger other neurological complications, including epilepsy, depression and dementia. The initial injury often leads to the development of secondary sequelae; cellular hyperexcitability, vasogenic and cytotoxic oedema, hypoxia-ischaemia, oxidative stress and inflammation, all of which influence expansion of the primary lesion. It is widely known that inflammatory events in the brain following TBI contribute to the widespread cell death and chronic tissue degeneration. Neuroinflammation is a multifaceted response involving a number of cell types, both within the CNS and in the peripheral circulation. Astrocytes and microglia, cells of the CNS, are considered key players in initiating an inflammatory response after injury. These cells are capable of secreting various cytokines, chemokines and growth factors, and following injury to the CNS, undergo changes in morphology. Ultimately, these changes can influence the local microenvironment and thus determine the extent of damage and subsequent repair. This review will focus on the roles of microglia and astrocytes following TBI, highlighting some of the key processes, pathways and mediators involved in this response. Additionally, both the beneficial and the detrimental aspects of these cellular responses will be examined using evidence from animal models and human post-mortem TBI studies.

Figure 1

Diagrammatic representation of M1/M2 polarization in microglia. For simplicity, M2 microglia have been represented as just the one phenotype, as opposed to illustrating the various classes. Cellular debris and other mediators released by dying neurons after injury prime microglia. An environment rich with the classical pro‐inflammatory stimuli, such as IFN‐γ and LPS, promotes the polarization of resting microglia into an M1 phenotype. M1 microglia release pro‐inflammatory cytokines, chemokines and iNOS. An M1 environment is neurotoxic, facilitating white matter injury and cell death. In contrast, a neuroinflammatory environment rich in anti‐inflammatory IL‐4 or IL‐13 drives the development of an M2 phenotype. M2 microglia release IL‐10 and TGF‐β, while promoting repair and inflammation resolution. In addition to microglia, peripherally infiltrating macrophages can also undergo polarization into M1 and M2 phenotypes, and recently, this has shown to be true of neutrophils in a murine ischaemic stroke model (Cuartero et al., 2013).