Lipopolysaccharide-Induced Exosomal miR-146a Is Involved in Altered Expression of Alzheimer's Risk Genes Via Suppression of TLR4 Signaling.
Lipopolysaccharide-Induced Exosomal miR-146a Is Involved in Altered Expression of Alzheimer's Risk Genes Via Suppression of TLR4 Signaling.
复制标题
脂多糖诱导的外泌体miR-146 a通过抑制TLR 4信号转导参与阿尔茨海默病风险基因的表达改变
DOI：
10.1007/s12031-020-01750-1
复制
发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Fukuchi KI
中科院分区：
文献类型：
--
作者：
Yang J;Malone F;Go M;Kou J;Lim JE;Caughey RC;Fukuchi KI
重复暴露于toll样受体4（TLR 4）配体，如脂多糖（LPS），降低单核细胞/巨噬细胞对LPS的应答（LPS/内毒素耐受性）。小胶质细胞暴露于Aβ沉积物（一种TLR 4配体）可能导致“Aβ/LPS耐受”，导致Aβ清除率降低。我们证明，与非AD小鼠和无Aβ沉积的2月龄AD小鼠相比，LPS对12月龄AD模型小鼠小胶质细胞的激活作用减弱。由于miR-146 a在诱导巨噬细胞TLR耐受中起主要作用，并且由于炎性巨噬细胞脱落的细胞外囊泡（EV）中的miR-146 a在循环中增加，我们研究了miR-146 a和炎性EV在诱导小胶质细胞TLR耐受和改变炎性AD风险基因表达中的潜在作用。我们发现miR-146 a上调诱导TLR耐受并改变炎症性AD风险基因在BV 2小胶质细胞中对LPS处理的响应。LPS脑注射改变了12月龄AD小鼠中AD风险基因的表达，但在非AD同窝出生的小鼠中没有改变。来自炎性巨噬细胞的EV将BV 2小胶质细胞转化为M1表型并诱导TLR耐受。暴露于脑中的Aβ的小胶质细胞显示对由于外周LPS注射引起的全身性炎症的细胞因子应答降低，表明小胶质细胞中的TLR/Aβ耐受。我们的研究结果表明，增加的miR-146 a诱导小胶质细胞Aβ/LPS耐受，并且由炎性巨噬细胞释放的循环EV有助于小胶质细胞Aβ/LPS耐受，导致Aβ清除减少。我们的研究还表明，炎症性AD风险基因的表达改变可能有助于AD的发展，通过相同的分子机制LPS耐受。
Repeated exposure to toll-like receptor 4 (TLR4) ligands, such as lipopolysaccharide (LPS), reduces responses of monocytes/macrophages to LPS (LPS/endotoxin tolerance). Microglial exposure to Aβ deposits, a TLR4 ligand, may cause “Aβ/LPS tolerance”, leading to decreased Aβ clearance. We demonstrated that microglial activation by LPS is diminished in Aβ deposit-bearing 12-month-old model mice of Alzheimer’s disease (AD), compared with non-AD mice and Aβ deposit-free 2-month-old AD mice. Because miR-146a plays a predominant role in inducing TLR tolerance in macrophages and because miR-146a in extracellular vesicles (EVs) shed by inflammatory macrophages increases in circulation, we investigated potential roles of miR-146a and inflammatory EVs in inducing TLR tolerance in microglia and in altering expression of inflammatory AD risk genes. We found that miR-146a upregulation induces TLR tolerance and alters expression of inflammatory AD risk genes in response to LPS treatment in BV2 microglia. LPS brain injection altered expression of the AD risk genes in 12-month-old AD mice but not in non-AD littermates. EVs from inflammatory macrophages polarize BV2 microglia to M1 phenotype and induce TLR tolerance. Microglia exposed to Aβ in the brain show reduced cytokine responses to systemic inflammation due to peripheral LPS injection, indicating TLR/Aβ tolerance in microglia. Our results suggest that increased miR-146a induces microglial Aβ/LPS tolerance and that circulating EVs shed by inflammatory macrophages contribute to microglial Aβ/LPS tolerance, leading to reduced Aβ clearance. Our study also suggests that altered expression of inflammatory AD risk genes may contribute to AD development via the same molecular mechanism underlying LPS tolerance.
登录
查看更多内容
影响因子：
2.5
作者：
Li YY;Cui JG;Hill JM;Bhattacharjee S;Zhao Y;Lukiw WJ
通讯作者：
Lukiw WJ
影响因子：
2.1
作者：
Arena, A.;Iyer, A. M.;Aronica, E.
通讯作者：
Aronica, E.
影响因子：
27.4
作者：
Chan EK;Ceribelli A;Satoh M
通讯作者：
Satoh M
影响因子：
3.7
作者：
Fülöp T;Itzhaki RF;Balin BJ;Miklossy J;Barron AE
通讯作者：
Barron AE
影响因子：
2.7
作者：
Fernández-Messina L;Gutiérrez-Vázquez C;Rivas-García E;Sánchez-Madrid F;de la Fuente H
通讯作者：
de la Fuente H