Research Papers: Immunology:
MicroRNA-146a constrains multiple parameters of intestinal immunity and increases susceptibility to DSS colitis
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Marah C. Runtsch1, Ruozhen Hu1, Margaret Alexander1, Jared Wallace1, Dominique Kagele1, Charisse Petersen1, John F. Valentine4, Noah C. Welker2, Mary P. Bronner2, Xinjian Chen1, Daniel P. Smith3, Nadim J. Ajami3, Joseph F. Petrosino3, June L. Round1 and Ryan M. O’Connell1
1 Department of Pathology, University of Utah, Salt Lake City, UT, USA
2 Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, UT, USA
3 The Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
4 Department of Medicine, Division of Gastroenterology, University of Utah, Salt Lake City, UT, USA
Ryan M. O’Connell, email:
Keywords: miRNA, miR-146a, intestine, microbiota, colitis
Received: August 14, 2015 Accepted: August 22, 2015 Published: September 10, 2015
Host-microbial interactions within the mammalian intestines must be properly regulated in order to promote host health and limit disease. Because the microbiota provide constant immunological signals to intestinal tissues, a variety of regulatory mechanisms have evolved to ensure proper immune responses to maintain homeostasis. However, many of the genes that comprise these regulatory pathways, including immune-modulating microRNAs (miRNAs), have not yet been identified or studied in the context of intestinal homeostasis. Here, we investigated the role of microRNA-146a (miR-146a) in regulating intestinal immunity and barrier function and found that this miRNA is expressed in a variety of gut tissues in adult mice. By comparing intestinal gene expression in WT and miR-146a-/- mice, we demonstrate that miR-146a represses a subset of gut barrier and inflammatory genes all within a network of immune-related signaling pathways. We also found that miR-146a restricts the expansion of intestinal T cell populations, including Th17, Tregs, and Tfh cells. GC B cells, Tfh ICOS expression, and the production of luminal IgA were also reduced by miR-146a in the gut. Consistent with an enhanced intestinal barrier, we found that miR-146a-/- mice are resistant to DSS-induced colitis, a model of Ulcerative Colitis (UC), and this correlated with elevated colonic miR-146a expression in human UC patients. Taken together, our data describe a role for miR-146a in constraining intestinal barrier function, a process that alters gut homeostasis and enhances at least some forms of intestinal disease in mice.
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