Journal Article

MiR-146a alleviates inflammatory bowel disease in mice through systematic regulation of multiple genetic networks

Xia, Wei, Yu, Xin, Xia, Ruilong, Wen, Ting, Qian, Ran, Liu, Jianping, Yang, Taotan, Liu, Yang, Tian, Li, Zheng, Mei, Zhu, Fengting, Peng, Changgeng, Ning, Mengmeng, Fu, Yan, Sun, Minxuan, Zhou, Qian, Li, Yang

2024

Overview

Inflammatory bowel disease (IBD) is a chronic disease involving multiple genes, and the current available targeted drugs for IBD only deliver moderate efficacy. Whether there is a single gene that systematically regulates IBD is not yet known. plays a pivotal role in repression of innate immunity, but its function in the intestinal inflammation is sort of controversy, and the genetic regulatory networks regulated by miR-146a in IBD has not been revealed. RT-qPCR was employed to detect the expression of in IBD patients and in a mouse IBD model induced by dextran sulfate sodium (DSS), and then we generated a knock-out mouse line with C57/Bl6N background. The disease activity index was scored in DSS-treated miR-146a deficiency mice and their wild type ( ) littermates. Bulk RNA-sequencing, RT-qPCR and immunostaining were done to illustrate the downstream genetic regulatory networks of in flamed colon. Finally, the modified mimics were used to treat DSS-induced IBD in knock-out and IBD mice. We showed that the expression of in the colon was elevated in dextran sulfate sodium (DSS)-induced IBD mice and patients with IBD. DSS induced dramatic body weight loss and more significant rectal bleeding, shorter colon length, and colitis in knock-out mice than mice. The miR-146a mimics alleviated DSS-induced symptoms in both and mice. Further RNA sequencing illustrated that the deficiency of de-repressed majority of DSS-induced IBD-related genes that cover multiple genetic regulatory networks in IBD, and supplementation with mimics inhibited the expression of many IBD-related genes. Quantitative RT-PCR or immunostaining confirmed that , MMP3, MMP8, MMP10, IL1A, IL1B, IL6, CXCL2, CXCL3, S100A8, S100A9, TRAF6, P65, p-P65, and IRAK1 were regulated by miR-146a in DSS induced IBD. Among them, , and were involved in the active stage of IBD in humans. Our date demonstrated that miR-146a acts as a top regulator in C57/BL6N mice to systematically repress multiple genetic regulatory networks involved in immune response of intestine to environment factors, and combinatory treatment with and mimics attenuates DSS-induced IBD in mice through down-regulating multiple genetic regulatory networks which were increased in colon tissue from IBD patients. Our findings suggests that is a top inhibitor of IBD, and that and mimics might be potential drug for IBD.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animals / Biopsy / Body weight loss / chemokines / Colitis / Colitis - chemically induced / Colitis - genetics / Colon / Colon - metabolism / Colon - pathology / Dextran / Dextran Sulfate / Disease Models, Animal / Drinking water / Drugs / Ethics / Feces / Female / Gene Expression Regulation / Gene Regulatory Networks / Genes / genetic regulatory networks / Humans / IL-1β / Immune response / Immunosuppressive agents / Inflammation / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory Bowel Diseases - genetics / Inflammatory Bowel Diseases - immunology / Innate immunity / Interleukin 1 / Intestine / IRAK protein / Kinases / Laboratory animals / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / MicroRNAs / MicroRNAs - genetics / miR-146a-3p / miR-146a-5p / MMPs / Neutrophil collagenase / Stromelysin 2 / TRAF6 protein