The changing phenotype of microglia from homeostasis to disease

Luo, Xiao-Guang; Chen, Sheng-Di

Two distinct phenotypes of macrophages have long been known to play different roles in the inflammatory context. Classically-activated macrophages, characterized by the involvement of T Helper type 1 (Th-1) cytokines such as interferon-γ, promote the release of various proinflammatory cytokines and thus exacerbate the inflammation. Alternatively, activated macrophages predominate in the T Helper type 2 (Th-2) microenvironment and tend to soothe the inflammation. Thus, the behavior of macrophages is dictated by their phenotype, which may eventually affect the beneficial or detrimental roles of macrophages during inflammation. Similarly, research over the past few years has established that microglia do not constitute a single, uniform cell population, but rather comprise a family of cells with diverse phenotypes; some are neuroprotective while others are destructive [92] . So far, three distinct functions have been proposed for microglia. The first is the classical activation state of microglia, which, accompanied by the induction of receptors that participate in the innate immune response [159] , is responsible for the pro-inflammatory milieu, and has been linked to neurotoxic effects in the brain. The second is alternatively activated microglia, which are associated with the production of anti-inflammatory cytokines in the resolution phase of the inflammatory response. Recently, the third activation state of microglia has been identified: it overlaps with and is complementary to the alternative activation and is called acquired deactivation [160, 161] . This is another activation state that promotes immunosuppression and is associated with the anti-inflammatory and functional repair phenotype .Both alternative activation and acquired deactivation down-regulate innate immune responses and have similar gene profiles; the most prominent difference is that acquired deactivation is induced by the exposure of microglia to apoptotic cells or to TGF-β or IL-10, while IL-4 and IL-13 induce alternative activation [160, 161] . It has been observed that multiple activation states of microglia coexist in certain chronic inflammations due to parasitic disease [162] , in which the balance between classical activation and alternative activation/acquired deactivation states is of "benefit" to both host and parasite: the host benefits from reduced self-damage, and the parasite eventually survives within the host. Neurodegenerative disorders are also associated with chronic inflammation and the coexistence of various activation states. For example, in AD, some levels of classical activation may be required to limit the brain levels of Aβ despite the risk of self-damage [163] , while alternative activation of microglia in AD may foster the protection of the surrounding tissue from immune damage even though it may facilitate Aβ deposits. Similar studies [164] [165] [166] have shown that the immune cells in the vicinity of amyloid deposits in AD express mRNA and proteins for pro-inflammatory cytokines, leading to the hypothesis that microglia demonstrate classical activation in AD, while Colton et al. found increased mRNA expression of alternative activation-associated gene profiles in microglia in both the AD brain and an AD mouse model [167] , suggesting the presence of multiple activation states of microglia during neurodegeneration. However, the recognition of heterogeneous phenotypes of microglia only raises more questions: what instructs microglia to