한빛사 논문
Ji-Won Lee*,a, Hyeri Nam*,a, Leah Eunjung Kim*,a, Yoonjeong Jeona,b, Hyunjung Minc, Shinwon Haa, Younghwan Leea, Seon-Young Kimd, Sung Joong Leec, Eun-Kyoung Kima,b, and Seong-Woon Yua,b,*
aDepartment of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea; bNeurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea; cDepartment of Neuroscience and Physiology,
Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea; dGene Editing Research Center, KRIBB, Daejeon, Republic of Korea
*These authors contributed equally to this work.
Correspondence to Seong-Woon Yu
Abstract
Macroautophagy/autophagy is a lysosome-dependent catabolic process for the turnover of proteins and organelles in eukaryotes. Autophagy plays an important role in immunity and inflammation as well as metabolism and cell survival. Diverse immune and inflammatory signals induce autophagy in macrophages through pattern recognition receptors, such as toll-like receptors (TLRs). However, the physiological role of autophagy and its signaling mechanisms in microglia remain poorly understood. Microglia are phagocytic immune cells that are resident in the central nervous system and share many characteristics with macrophages. Here, we show that autophagy flux and expression of autophagy-related (Atg) genes in microglia are significantly suppressed upon TLR4 activation by lipopolysaccharide (LPS), in contrast to their stimulation by LPS in macrophages. Metabolomics analysis of the levels of phosphatidylinositol (PtdIns) and its 3-phosphorylated form, PtdIns3P, in combination with bioinformatics prediction, revealed an LPS-induced reduction in the synthesis of PtdIns and PtdIns3P in microglia but not macrophages. Interestingly, inhibition of PI3K, but not MTOR or MAPK1/3, restored autophagy flux with concomitant dephosphorylation and nuclear translocation of FOXO3. A constitutively active form of FOXO3 also induced autophagy, suggesting FOXO3 as a downstream target of the PI3K pathway for autophagy inhibition. LPS treatment impaired phagocytic capacity of microglia, including MAP1LC3B/LC3-associated phagocytosis (LAP) and amyloid β (Aβ) clearance. PI3K inhibition restored LAP and degradation capacity of microglia against Aβ. These findings suggest a unique mechanism for the regulation of microglial autophagy and point to the PI3K-FOXO3 pathway as a potential therapeutic target to regulate microglial function in brain disorders.
Key words: amyloidβ, FOXO3, LC3-associated phagocytosis, microglia, PI3K, PtdIns3K
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