MicroRNA-146a constrains multiple parameters of intestinal immunity and increases susceptibility to DSS colitis

// Marah C. Runtsch 1 , Ruozhen Hu 1 , Margaret Alexander 1 , Jared Wallace 1 , Dominique Kagele 1 , Charisse Petersen 1 , John F. Valentine 4 , Noah C. Welker 2 , Mary P. Bronner 2 , Xinjian Chen 1 , Daniel P. Smith 3 , Nadim J. Ajami 3 , Joseph F. Petrosino 3 , June L. Round 1 and Ryan M. O’Connell 1 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 Correspondence to: Ryan M. O’Connell, email: // Keywords : miRNA, miR-146a, intestine, microbiota, colitis Received : August 14, 2015 Accepted : August 22, 2015 Published : September 10, 2015 Abstract 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.