Fig. 3

Graphical representation of the cellular response and brain damage post-TBI, including the proposed microglia (M1 and M2) and astrocytes (A1 and A2) dynamics over time. a Injury to the brain may cause cell membrane disruption, vascular rupture and BBB damage. This leads to the release of DAMPs, cytokines, chemokines immediately after injury and peaks within minutes to hours and continue to release by the damaged tissue and infiltrating cells. This causes the activation of microglia and astrocytes and recruitment of circulating immune cells. These immune responses are largely overlapped (Fig. 1). The inflammatory response is the key to debris clearance, repair and regeneration post-TBI. But skewed inflammation might lead to secondary brain injury. The role of microglial activation is increasingly recognised as both a critical pathological mechanism and therapeutic target. Specifically, there is a shift from a dominance of M2 (neuroprotective) microglia into a preponderance of M1 (neurotoxic) microglia [141]. M1:M2 microglia population ratio shifts from 1:5 (day 1) to 7.5:1 (day 7) following injury [142]. Also, Wang et al. [143] whilst working with CCI mice model discovered that the phenotypic ratio of M1 and M2 at 48 h (day 2) is 1:3 and the M2-like microglia/macrophages peaked at day 5 but decreased rapidly thereafter. b Both microglia and astrocytes are highly sensitive to their environment. Unlike other inflammatory cells, astrocytes and microglia are in a constant dynamic mode. Their subtypes will shift with time and space, and with other unknown variables. Microglia and astrocytes so far have been shown to exist in two distinct reactive states (Microglia, M1-neurotoxic and M2-neuroprotective; Astrocytes, A1-neurotoxic and A2-neuroprotective). Considering these two states, it is possible that they exist as a continuum, with a heterogeneous mixed population in the middle. It should be noted that this classification is somewhat limited because microglia/macrophages can exhibit more than two canonical polarisation states [144]. In much a similar way, reactive astrocytes might have more than two polarised states. The heterogeneity of reactive microglia and astrocytes need to be investigated thoroughly