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Epithelial microRNAs regulate gut mucosal immunity via epithelium–T cell crosstalk

Nature Immunology volume 12, pages 239–246 (2011)Cite this article

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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 (TH2) responses. Abolishing the induction of microRNA by gut-specific deletion of Dicer1 (Dicer1Δgut), which encodes an enzyme involved in microRNA biogenesis, deprived goblet cells of RELMβ, a key TH2 antiparasitic cytokine; this predisposed the host to parasite infection. Infection of Dicer1Δgut mice with helminths favored a futile TH1 response with hallmarks of inflammatory bowel disease. Interleukin 13 (IL-13) induced the microRNA miR-375, which regulates the expression of TSLP, a TH2-facilitating epithelial cytokine; this indicated a TH2-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 Dicer1Δgut mice to parasites. Our findings indicate that epithelial microRNAs are key regulators of gut homeostasis and mucosal immunity.

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Figure 1: Inducible ablation of Dicer1 specifically in the gut epithelium results in depletion of goblet cells.
Figure 2: The microRNA miR-375 is a key factor in goblet cell differentiation.
Figure 3: Klf5 is a target of miR-375.
Figure 4: Immunological changes after Dicer1 ablation in the gut.
Figure 5: Deletion of Dicer1 in the gut epithelium results in ineffective inflammatory responses to and susceptibility to T. muris.
Figure 6: IL-13 induces miR-375 expression via the PI(3)K pathway.
Figure 7: Regulation of TSLP expression by miR-375.

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Acknowledgements

We thank S. Robine (Institut Curie, Centre National de la Recherche Scientifique) for Villin Cre-ERT2 mice; C.J. Tabin (Harvard Medical School) for Dicer1fl/fl mice; P.P. Pandolfi (Harvard Medical School) for Ptenfl/fl mice; K. Rajewsky (Harvard Medical School) for antibody to Dicer; I. Ben-Porath (Hebrew University) for reagents; H. Clevers for IEC-isolation protocols; Y. Smith for assistance in genomic data analysis; M. Leshets and I. Burstain for handling the confocal microscopy; and R. Goldstein for critical review of the manuscript. Supported by the Israel Science Foundation, Israel Cancer Research Fund, Hadassah Medical Center (A.L.), the German-Israeli Foundation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Crohn's & Colitis Foundation of America.

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  1. Moshe Biton and Avi Levin: These authors contributed equally to this work.

Authors and Affiliations

  1. Lautenberg Center for Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel

    Moshe Biton, Avi Levin, Michal Slyper, Irit Alkalay, Elad Horwitz, Hagar Mor, Gady Cojocaru, Eli Pikarsky & Yinon Ben-Neriah

  2. Department of Gastroenterology, Division of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel

    Avi Levin

  3. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

    Sharon Kredo-Russo & Eran Hornstein

  4. Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel

    Tali Avnit-Sagi & Michael D Walker

  5. Department of Pathology, Hebrew University Hadassah Medical School, Jerusalem, Israel

    Farid Zreik & Eli Pikarsky

  6. Rosetta Genomics, Rehovot, Israel

    Zvi Bentwich

  7. Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

    Matthew N Poy

  8. Department of Microbiology and Institute for Immunology, and Department of Pathobiology, School of Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    David Artis

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Contributions

M.B. and A.L. did experiments, analyzed data, provided ideas and contributed to the writing of the manuscript; M.S. did experiments, analyzed data and contributed ideas; I.A., H.M., F.Z. and E.H. did experiments and analyzed data; G.C. provided bioinformatics assistance; S.K.-R., T.A.-S., M.N.P., D.A., M.D.W. and E.H. provided ideas and experimental reagents; Z.B. and E.H. contributed to preparing the manuscript; and Y.B.-N. and E.P. directed the study, contributed to the writing of the manuscript and supervised the work.

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Correspondence to Eli Pikarsky or Yinon Ben-Neriah.

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Biton, M., Levin, A., Slyper, M. et al. Epithelial microRNAs regulate gut mucosal immunity via epithelium–T cell crosstalk. Nat Immunol 12, 239–246 (2011). https://doi.org/10.1038/ni.1994

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