于政权+刘占举等:MIR31可减轻小鼠结肠炎
  • 微RNA31(MIR31)在溃疡性肠炎和克罗恩病患者及小鼠结肠炎的肠组织中表达上调,TNF和IL-6通过激活NF-κB和STAT3上调MIR31的转录;
  • MIR31通过结合到炎症细胞因子受体IL7R、IL17RA和信号蛋白IL6ST的mRNA的3‘-UTR区域,抑制其在结肠上皮细胞中的表达,缓解炎症反应;
  • MIR31调控WNT和Hippo信号通路,促进上皮细胞损伤后再生;
  • MIR31类似物微球定位于小鼠结肠上皮,缓解结肠炎症状、促肠上皮细胞增殖,或可用于治疗炎症性肠病。
主编推荐语
mildbreeze
MIR31是一种microRNA,其表达水平在炎症性肠病(IBD)患者的肠道组织中升高,《Gastroenterology》近期发表了中国农业大学于政权与上海市第十人民医院刘占举与团队的研究,揭示了MIR31对肠道炎症的抑制和缓解作用及其背后的分子机制,并表明MIR31类似物微球或是治疗IBD的潜在策略。
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Gastroenterology [IF:17.373]

MicroRNA-31 Reduces Inflammatory Signaling and Promotes Regeneration in Colon Epithelium, and Delivery of Mimics in Microspheres Reduces Colitis in Mice

微RNA-31降低炎症信号并促进结肠上皮再生,用微球递送其类似物可减少小鼠结肠炎

10.1053/j.gastro.2019.02.023

2019-02-16, Article

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BACKGROUND & AIMS: Levels of microRNA 31 (MIR31) are increased in intestinal tissues from patients with inflammatory bowel diseases and colitis-associated neoplasias. We investigated the effects of this microRNA on intestinal inflammation by studying mice with colitis.
METHODS: We obtained colon biopsy samples from 82 patients with ulcerative colitis (UC), 79 patients with Crohn's disease (CD), and 34 healthy individuals (controls) at Shanghai Tenth People's Hospital. MIR31- knockout mice and mice with conditional disruption of Mir31 specifically in the intestinal epithelium (MIR31 conditional knockouts) were given dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. We performed chromatin immunoprecipitation (ChIP) and luciferase assays to study proteins that regulate expression of MIR31, including STAT3 and p65, in LOVO colorectal cancer cells and organoids derived from mouse colon cells. Partially hydrolyzed alpha-lactalbumin (alpha-La) was used to generate peptosome nanoparticles, and MIR31 mimics were loaded onto their surface using electrostatic adsorption. Peptosome-MIR31 mimic particles were encapsulated into oxidized konjac glucomannan (OKGM) microspheres, which were administered by enema into the large intestines of mice with DSS-induced colitis. Intestinal tissues were collected and analyzed by histology and immunohistochemistry.
RESULTS: Levels of MIR31 were increased in inflamed mucosa from patients with CD or UC, and from mice with colitis, compared with controls. STAT3 and NF-κB activated transcription of MIR31 in colorectal cancer cells and organoids in response to TNF and IL6. MIR31-knockout and conditional-knockout mice developed more severe colitis in response to DSS and TNBS, with increased immune responses, compared to control mice. MIR31 bound to 3' untranslated regions of Il17ra and Il7r mRNAs (which encode receptors for the inflammatory cytokine IL17) and Il16st mRNA (which encodes GP130, a cytokine signaling protein). These mRNAs and proteins were greater in MIR31-knockout mice with colitis, compared with control mice; MIR31 and MIR31 mimics inhibited their expression. MIR31 also promoted epithelial regeneration by regulating the WNT and Hippo signaling pathways. OKGM peptosome-MIR31 mimic microspheres localized to colonic epithelial cells in mice with colitis; they reduced the inflammatory response, increased body weight and colon length, and promoted epithelial cell proliferation.
CONCLUSIONS: MIR31, increased in colon tissues from patients with CD or UC, reduces the inflammatory response in colon epithelium of mice by preventing expression of inflammatory cytokine receptors (Il7R and Il17RA) and signaling proteins (IL6ST). MIR31 also regulates the WNT and Hippo signaling pathways to promote epithelial regeneration following injury. OKGM peptosome-MIR31 microspheres localize to the colon epithelium of mice to reduce features of colitis.

First Authors:
Yuhua Tian,Jiuzhi Xu,Yuan Li

Correspondence Authors:
Zhanju Liu,Zhengquan Yu

All Authors:
Yuhua Tian,Jiuzhi Xu,Yuan Li,Ran Zhao,Sujuan Du,Cong Lv,Wei Wu,Ruiqi Liu,Xiaole Sheng,Yongli Song,Xueyun Bi,Guilin Li,Mengzhen Li,Xi Wu,Pengbo Lou,Huiwen You,Wei Cui,Jinyue Sun,Jianwei Shuai,Fazheng Ren,Bing Zhang,Mingzhou Guo,Xiaohua Hou,Kaichun Wu,Lixiang Xue,Hongquan Zhang,Maksim V Plikus,Yingzi Cong,Christopher J Lengner,Zhanju Liu,Zhengquan Yu

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