The changing phenotype of microglia from homeostasis to disease

Luo, Xiao-Guang; Chen, Sheng-Di

In the two situations of neurogenesis and neuronal survival, similar factors are shared, leading microglia to take supportive or detrimental roles. Among these factors, the most prominent is the microglial activation phenotype that is associated with different cytokine profiles. When acutely activated by either LPS or injury, microglia that release the pro-inflammatory cytokines IL-6, TNF-α or IL-1β usually down-regulate the differentiation or proliferation of neural stem cells or induce the aberrant migration of newborn neurons [178] . This group of inflammatory cytokines has been proven to inhibit neurogenesis [176, 177, 179] ; conversely, blocking antibodies to these pro-inflammatory cytokines (such as IL-6 [177] ) or the use of monocycline to mitigate the microglial activation simply restores neurogenesis [176] . In contrast, microglia that are activated by anti-inflammatory cytokines such as IL-4 or TGF-β increase neurogenesis in vitro or the differentiation of neural stem cells (NSCs) in vivo [180, 181] . Neurotrophins, such as IGF-1, were identified [181] in anti-inflammatory cytokineactivated microglia and were proposed to be one of the mechanisms underlying this pro-neurogenic activity of microglia [182, 183] . However, just like the dual roles in neuroprotection, whether a specific cytokine-activated microglial cell will take a pro-or anti-neurogenic role is also context-dependent. For example, microglial cells activated by IFN-γ, a pro-inflammatory cytokine can be neurotoxic or supportive of neurogenesis, depending on the concentration of IFN-γ [184] . TGF-β, which is considered to be beneficial to neurogenesis, can actually exert a negative influence on neurogenesis when it is chronically produced in the aged brain [185] . Additionally, if other cytokines exist in the same niche simultaneously, the outcome will be determined by the balance among the various cytokines; some authors have concluded that activated microglia are not pro-or anti-neurogenic per se, but the balance between pro-and anti-inflammatory secreted molecules influences the final effect of microglial activation [172, 180] . However, in which situations the microglia will release pro-or anti-inflammatory cytokines is complicated and is affected by multiple factors such as the injury type, the phase of disease or inflammation, and crosstalk with other regulating components, including neural precursors; this is similar to the question of whether microglia will be neuroprotective or neurotoxic. Most likely the same inflammatory scenario that induces neurodegeneration would also inhibit neurogenesis, while a situation that favors neuronal survival would also support neurogenesis. Interestingly, even in a high-inflammation environment, such as two days after a Trimethyltin-induced acute injury in the hippocampus, significant neurogenesis can be detected [186, 187] , suggesting a complicated system of neurogenesis regulation beyond the inflammation scenario.