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

Suppression of autophagy through TLR4/PI3K/FoxO3 signaling impairs phagocytic degradation of microglia
Alternative Title
미세아교세포에서 TLR4/PI3K/FoxO3 기전을 통한 자가포식작용 억제와 식작용을 통한 분해 능력 저해
Nam, Hyeri
Seong-Woon Yu
Lee, Byung Hoon
Issued Date
Awarded Date
2018. 2
autophagymicrogliaPI3KFoxO3phagocytic degradation미세아교세포자가포식작용신경염증반응
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
Table Of Contents
1. Introduction 5--

2. Material and methods 9--

2.1 Cell culture 8--

2.2 Acute isolation of primary microglia and peritoneal macrophages 9--

2.3 Reagents and antibodies 10--

2.4 Plasmids and transfection 10--

2.5 Immunocytochemistry 11--

2.6 LAP assay with zymosan 11--

2.7 Proximity ligation assay (PLA) 12--

2.8 Western blotting 12--

2.9 Quantitative real-time polymerase chain reaction (qRT-PCR) 13--

2.10 Statistical analysis 16--

3. Results 18--

3.1 Autophagy is suppressed by LPS in microglia 18--

3.2 LPS decreased the mRNA expression of autophagy-related gene (Atg) in microglia 22--

3.3 LPS-induced autophagic suppression was mediated by TLR4-dependent signaling 24--

3.4 LPS down-regulates autophagy via PI3K/Akt signaling pathway 26--

3.5 Phosphorylation of FoxO3 by PI3K/Akt suppresses autophagy in microglia 29--

3.6 LPS suppresses LC3-associated phagocytosis (LAP) and Aβ degradation 34--

4. Discussion 38--

Reference 42--

Abstract in Korean 45
Brain and Cognitive Sciences
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Department of Brain Sciences Theses Master


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