Microglial Activation in Traumatic Brain Injury

Abstract

Microglia have a variety of functions in the brain, including synaptic pruning, CNS repair and mediating the immune response against peripheral infection. Microglia rapidly become activated in response to CNS damage. Depending on the nature of the stimulus, microglia can take a number of activation states, which correspond to altered microglia morphology, gene expression and function. It has been reported that early microglia activation following traumatic brain injury (TBI) may contribute to the restoration of homeostasis in the brain. On the other hand, if they remain chronically activated, such cells display a classically activated phenotype, releasing pro-inflammatory molecules, resulting in further tissue damage and contributing potentially to neurodegeneration. However, new evidence suggests that this classification is over-simplistic and the balance of activation states can vary at different points. In this article, we review the role of microglia in TBI, analyzing their distribution, morphology and functional phenotype over time in animal models and in humans. Animal studies have allowed genetic and pharmacological manipulations of microglia activation, in order to define their role. In addition, we describe investigations on the in vivo imaging of microglia using translocator protein (TSPO) PET and autoradiography, showing that microglial activation can occur in regions far remote from sites of focal injuries, in humans and animal models of TBI. Finally, we outline some novel potential therapeutic approaches that prime microglia/macrophages toward the beneficial restorative microglial phenotype after TBI.

Keywords: CCI; TSPO; microglia; neuroinflammation; polarization states; traumatic brain injury.

Figure 1

Iba-1 staining illustrating the ramified microglial morphology associated with normal surveillance activity (A) compared to that seen in patients where there has been damage to the vasculature and the microglia take on a more rounded phagocytic appearance (B). Scale bar corresponds to 50 μM.

Figure 2

Imaging of chronic microglial activation after TBI. Images of [11C]PK11195 PET images are shown superimposed on the T1 MRI scan at the level of the thalamus for 10 TBI patients, 11 months to 17 years after injury, and a representative control participant. Numbers indicate time since injury (months). R right. The figure has been reproduced with permission of the copyright holder (Ramlackhansingh et al., 2011).

Figure 3

How chronic microglial activation and axonal injury may be linked after TBI. Microglial activation (green cells) and traumatic axonal injury in thalamo-cortical white matter tracts (red areas) have been demonstrated after TBI. Sites of chronic microglial activation can co-localize with axonal abnormality (A) as well as along the entire axonal tract affected by injury. Remote from sites of primary axonal injury, microglia may be observed both in retrograde projection areas, toward the cell bodies of damaged neurons (B), and in anterograde areas (C,D). The thalamus is a highly-connected structure. Thalamic microglial activation may be observed after TBI because of the high density of connections to damaged axons. The number of cortico-thalamic projections far exceeds thalamo-cortical projections. If microglial activation preferentially favors anterograde involvement, then relatively increased activation would be expected in the thalamus (C) compared to corresponding cortical areas (B).