Suppression of autophagy through TLR4/PI3K/FoxO3 signaling impairs phagocytic degradation of microglia

Abstract

Autophagy is an essential intracellular degradation process for turnover of proteins and organelles. Recently autophagy also plays important roles in immune system. Deficits of au-tophagy in innate immune systems are related with many inflammatory diseases including neurodegenerative disorders. Various immune triggers activate autophagy in innate immune cells including macrophages. Microglia are the resident macrophages in the central nervous system. However, the detailed mechanisms of autophagy regulation by immune triggers in microglia are not well understood. Here, we found that autophagy in microglia is suppressed by lipopolysaccharide (LPS), a prototypical inflammation inducer and toll-like receptor 4 activator. The expression levels of major autophagy related genes were significantly sup-pressed in LPS-treated microglia in dose- and time- dependent manner, which is contrary to the reports in macrophages. LPS-induced suppression of microglial autophagy was mainly through the activation of PI3K/AKT pathway and following inactivation of FoxO3 transcrip-tion factor, while mTOR or MAPK pathways did not play major roles. Suppression of au-tophagy was related to impaired phagocytic degradation as shown in LC3-associated phago-cytosis (LAP) and amyloid β (Aβ) clearance in LPS-treated microglia, which were reversed by inhibition of PI3K. Taken together, our novel findings indicate the unique signaling mech-anism for regulation of microglia autophagy, and point to TLR4/PI3K/FoxO3 pathway as potential therapeutic target for microglia in brain disorders. ⓒ 2017 DGIST