The changing phenotype of microglia from homeostasis to disease

Luo, Xiao-Guang; Chen, Sheng-Di

Although less obvious than the crosstalk with neurons, the interactions between microglia and astrocytes are far from simple and are also crucial for our understanding of how microglia respond to their environment and exert influence on neuronal degeneration or regeneration. Several studies have demonstrated the substantial influence of astrocytes on microglial activation [110] . The induction of microglia by Trimethyltin or Borna disease virus-infected neurons is dependent on the presence of astrocytes [111, 112] . Astrocytes play neuroprotective roles by modulating microglial cell activity and decreasing their cytotoxicity [113, 114] . The expression of IL-12 and the production of inducible nitric oxide synthase (iNOS) in activated microglia have been reported to be suppressed by astrocytes or conditioned media from astrocytes [82, 111, [115] [116] [117] , delineating the signals from astrocytes that affect the activities of microglia. Furthermore, the communication between these two types of cells is two-way; microglia both receive and give signals, as proinflammatory cytokines released from microglia inhibit gap junctions and down-regulate connexin 43 expression in astrocytes [118] [119] [120] , which enhances astrocyte survival. In another study, comparative proteome analysis was performed on astrocytes that were treated with conditioned media from quiescent or activated microglia. Following culture in activated-microglial media, the anti-oxidative enzymes expressed in astrocytes were up-regulated, and these astrocytes were protected against oxidative stress. This result gave insight into the complex intercellular events that take place during neurological disorders [121] . Alzheimer's Disease Internalize and degrade amyloid beta [87] Multiple sclerosis Secrete soluble mediators that trigger neural repair and usually contribute to the creation of an environment conductive for regeneration [48] As in many pathological conditions in the central nervous system such as in neurodegeneration [122] , microglia, activated earlier than astrocytes, promote astrocytic activation through IL-1which is mostly from microglia [123] . On the other hand, activated astrocytes not only facilitate activation of distant microglia via calcium wave [124, 125] , but also inhibit microglial activities [126] . Additionally, it was observed that activated-microglial-conditioned media increased astroglial proliferation [127] , down-regulated the astroglial metabotropic glutamate receptor [128] and induced astroglial brain-derived neurotrophic factor (BDNF) and IL-6 gene expression [129] . Taken together, the importance of microglial activities lies in that they not only exert direct effects on neuronal survival, but they also affect the responses of other supporting cells in the same environment.