title: Epithelial microRNAs regulate gut mucosal immunity via epithelium-T cell crosstalk.
abstract: Colonic homeostasis entails epithelium-lymphocyte cooperation, yet many participants in this process are unknown. We show here that epithelial microRNAs mediate the mucosa-immune system crosstalk necessary for mounting protective T helper type 2 (T(H)2) responses. Abolishing the induction of microRNA by gut-specific deletion of Dicer1 (Dicer1(Δgut)), which encodes an enzyme involved in microRNA biogenesis, deprived goblet cells of RELMβ, a key T(H)2 antiparasitic cytokine; this predisposed the host to parasite infection. Infection of Dicer1(Δgut) mice with helminths favored a futile T(H)1 response with hallmarks of inflammatory bowel disease. Interleukin 13 (IL-13) induced the microRNA miR-375, which regulates the expression of TSLP, a T(H)2-facilitating epithelial cytokine; this indicated a T(H)2-amplification loop. We found that miR-375 was required for RELMβ expression in vivo; miR-375-deficient mice had significantly less intestinal RELMβ, which possibly explains the greater susceptibility of Dicer1(Δgut) mice to parasites. Our findings indicate that epithelial microRNAs are key regulators of gut homeostasis and mucosal immunity.
authors.affiliation: Lautenberg Center for Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Biton
authors.forename: Avi
authors.initials: A
authors.lastname: Levin
authors.forename: Michal
authors.initials: M
authors.lastname: Slyper
authors.forename: Irit
authors.initials: I
authors.lastname: Alkalay
authors.forename: Elad
authors.initials: E
authors.lastname: Horwitz
authors.forename: Hagar
authors.initials: H
authors.lastname: Mor
authors.forename: Sharon
authors.initials: S
authors.lastname: Kredo-Russo
authors.forename: Tali
authors.initials: T
authors.lastname: Avnit-Sagi
authors.forename: Gady
authors.initials: G
authors.lastname: Cojocaru
authors.forename: Farid
authors.initials: F
authors.lastname: Zreik
authors.forename: Zvi
authors.initials: Z
authors.lastname: Bentwich
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Poy
authors.forename: David
authors.initials: D
authors.lastname: Artis
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walker
authors.forename: Eran
authors.initials: E
authors.lastname: Hornstein
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.forename: Yinon
authors.initials: Y
authors.lastname: Ben-Neriah
mesh_terms: D000818:Animals; D002450:Cell Communication; D004848:Epithelium / Q000276:immunology; D041981:Gastrointestinal Tract / Q000276:immunology; D019073:HT29 Cells; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology*; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018793:Interleukin-13; D035683:MicroRNAs