Lipopolysaccharide upregulates miR-132/212 in Hirschsprung-associated enterocolitis, facilitating pyroptosis by activating NLRP3 inflammasome via targeting Sirtuin 1 (SIRT1).
Lipopolysaccharide upregulates miR-132/212 in Hirschsprung-associated enterocolitis, facilitating pyroptosis by activating NLRP3 inflammasome via targeting Sirtuin 1 (SIRT1).
复制标题
脂多糖上调先天性巨结肠相关小肠结肠炎中的 miR-132/212，通过靶向 Sirtuin 1 (SIRT1) 激活 NLRP3 炎性体，促进细胞焦亡
DOI：
10.18632/aging.103852
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发表时间：
2020-09-20
期刊：
影响因子：
--
通讯作者：
Tong M
中科院分区：
文献类型：
--
作者：
Li H;Zhou L;Zhi Z;Lv X;Wei Z;Zhang X;Tang W;Tong M
先天性巨结肠是一种神经嵴衍生物沿后肠沿着迁移和/或分化障碍的先天性疾病。先天性巨结肠患者最常见的并发症是先天性巨结肠相关性小肠结肠炎（HAEC）。然而，其发病机制尚未完全了解。本研究旨在探讨HAEC术后患者体内内毒素（LPS）对miRNAs表达的影响及其在小肠结肠炎发病中的作用和机制。miR-132和miR-212在HAEC扩张组织和LPS处理的小鼠肠炎样品中上调。LPS刺激的HT 29细胞显示miR-132和miR-212的高表达。体外QRT-PCR分析、Western blotting、荧光素酶报告基因分析和流式细胞术分析表明，miR-132和miR-212可直接抑制SIRT 1的表达。因此，LPS刺激的HT 29细胞系和LPS处理的小鼠中的SIRT 1缺陷激活NLRP 3炎性体和Caspase-1介导的细胞凋亡。miR-132/212抑制剂或SIRT 1过表达质粒转染可逆转上述炎症激活。总之，LPS上调HAEC中miR-132和miR-212的表达，抑制SIRT 1并促进NLRP 3炎性小体活化，从而诱导细胞凋亡。我们的研究结果阐明了LPS/miR-132/-212/SIRT1/NLRP 3调控网络在HAEC发生发展中的作用，并提出了LPS介导的细胞凋亡的新分子途径。
Hirschsprung disease (HSCR) is a congenital disorder attributed to the failure of the neural crest derivatives migrating and/or differentiating along the hindgut. The most frequent complication in Hirschsprung disease patients is Hirschsprung-associated enterocolitis (HAEC). However, its pathogenesis has not been fully understood. This study investigated miRNAs influenced by Lipopolysaccharide (LPS) in postoperative HAEC patients, their effect on enterocolitis and the underlying mechanism. MiR-132 and miR-212 were up-regulated in HAEC dilated tissues and LPS-treated mice enteritis samples. LPS-stimulated HT29 cells showed a high expression of miR-132 and miR-212. QRT-PCR analysis, western blotting, luciferase reporter assay, and flow cytometric analysis were carried out in vitro, showing that miR-132 and miR-212 could directly inhibit Sirtuin 1 (SIRT1) expression. Consequently, SIRT1 deficiency in LPS-stimulated HT29 cell line and LPS-treated mice activated NLRP3 inflammasome and Caspase-1-mediated pyroptosis. Furthermore, the above inflammation activation was reversed by miR-132/212 inhibitor or SIRT1 overexpression plasmid transfection. In conclusion, LPS upregulated miR-132 and miR-212 expression in HAEC, suppressing SIRT1 and facilitating NLRP3 inflammasome activation, which induced pyroptosis. Our findings illustrated the role of LPS/miR-132/-212/SIRT1/NLRP3 regulatory network in the occurrence and progression of HAEC and proposed a new molecular pathway for LPS-mediated cell pyroptosis.
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影响因子：
3.7
作者：
Frykman PK;Nordenskjöld A;Kawaguchi A;Hui TT;Granström AL;Cheng Z;Tang J;Underhill DM;Iliev I;Funari VA;Wester T;HAEC Collaborative Research Group (HCRG)
通讯作者：
HAEC Collaborative Research Group (HCRG)
影响因子：
4.6
作者：
Gao K;Liu L;Dou X;Wang C;Liu J;Zhang W;Wang H
通讯作者：
Wang H
影响因子：
1.4
作者：
Guillaume, Alexander W. D.;Miller, Andrew C.;Nguyen, Michael C.
通讯作者：
Nguyen, Michael C.
DOI：
10.1126/science.1240988
发表时间：
2013-09-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hagar JA;Powell DA;Aachoui Y;Ernst RK;Miao EA
通讯作者：
Miao EA
影响因子：
1.8
作者：
Cheng Z;Zhao L;Dhall D;Ruegger PM;Borneman J;Frykman PK
通讯作者：
Frykman PK