Autophagy Plays an Important Role in Anti-inflammatory Mechanisms Stimulated by Alpha7 Nicotinic Acetylcholine Receptor

文献类型： 外文期刊

第一作者： Shao, Bo-Zong

作者： Shao, Bo-Zong;Ke, Ping;Xu, Zhe-Qi;Cheng, Ming-He;Han, Bin-Ze;Su, Ding-Feng;Liu, Chong;Wei, Wei;Chen, Xiong-Wen

作者机构：

关键词： alpha7 nicotinic acetylcholine receptor;autophagy;neuroinflammation;experimental autoimmune encephalomyelitis;microglia

期刊名称：FRONTIERS IN IMMUNOLOGY （ 影响因子：7.561； 五年影响因子：7.624 ）

ISSN： 1664-3224

年卷期： 2017 年 8 卷

页码：

收录情况： SCI

摘要： Alpha7 nicotinic acetylcholine receptor (alpha 7nAChR) has been reported to alleviate neuroinflammation. Here, we aimed to determine the role of autophagy in alpha 7nAChR-mediated inhibition of neuroinflammation and its underlying mechanism. Experimental autoimmune encephalomyelitis (EAE) mice and lipopolysaccharide-stimulated BV2 microglia were used as in vivo and in vitro models of neuroinflammation, respectively. The severity of EAE was evaluated with neurological scoring. Autophagy-related proteins (Beclin 1, LC3-II/I, p62/SQSTM1) were detected by immunoblot. Autophagosomes were observed using transmission electron microscopy and tandem fluorescent mRFP-GFP- LC3 plasmid was applied to test autophagy flux. The mRNA levels of interleukin-6 (IL-6), IL-1 beta, IL-18, and tumor necrosis factor-alpha (TNF-alpha) were detected by real-time PCR. We used 3-methyladenine (3-MA) and autophagy-related gene 5 small interfering RNA (Atg5 siRNA) to block autophagy in vivo and in vitro, respectively. Activating a7nAChR with PNU282987 ameliorates EAE severity and spinal inflammatory infiltration in EAE mice. PNU282987 treatment also enhanced monocyte/microglia autophagy (Beclin 1, LC3-II/I ratio, p62/SQSTM1, colocalization of CD45- or CD68-positive cells with LC3) both in spinal cord and spleen from EAE mice. The beneficial effects of PNU282987 on EAE mice were partly abolished by 3-MA, an autophagy inhibitor. In vitro, PNU282987 treatment increased autophagy and promoted autophagy flux. Blockade of autophagy by Atg5 siRNA or bafilomycin A1 attenuated the inhibitory effect of PNU282987 on IL-6, IL-1 beta, IL-18, and TNF-alpha mRNA. Our results demonstrate for the first time that activating a7nAChR enhances monocyte/microglia autophagy, which suppresses neuroinflammation and thus plays an alleviative role in EAE.

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