title: MicroRNA-146a constrains multiple parameters of intestinal  immunity and increases susceptibility to DSS colitis.
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.
authors.forename: Marah C
authors.initials: MC
authors.lastname: Runtsch
authors.forename: Ruozhen
authors.initials: R
authors.lastname: Hu
authors.forename: Margaret
authors.initials: M
authors.lastname: Alexander
authors.forename: Jared
authors.initials: J
authors.lastname: Wallace
authors.forename: Dominique
authors.initials: D
authors.lastname: Kagele
authors.forename: Charisse
authors.initials: C
authors.lastname: Petersen
authors.forename: John F
authors.initials: JF
authors.lastname: Valentine
authors.forename: Noah C
authors.initials: NC
authors.lastname: Welker
authors.forename: Mary P
authors.initials: MP
authors.lastname: Bronner
authors.forename: Xinjian
authors.initials: X
authors.lastname: Chen
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Smith
authors.forename: Nadim J
authors.initials: NJ
authors.lastname: Ajami
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Petrosino
authors.forename: June L
authors.initials: JL
authors.lastname: Round
authors.forename: Ryan M
authors.initials: RM
authors.lastname: O'Connell
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D000069467:Fecal Microbiota Transplantation; D000069196:Gastrointestinal Microbiome / Q000276:immunology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D054884:Host-Pathogen Interactions; D018928:Immunity, Mucosal; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D018836:Inflammation Mediators; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016264:Dextran Sulfate