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

Moshe Biton; Avi Levin; Michal Slyper; Irit Alkalay; Elad Horwitz; Hagar Mor; Sharon Kredo-Russo; Tali Avnit-Sagi; Gady Cojocaru; Farid Zreik; Zvi Bentwich; Matthew N. Poy; David Artis; Michael D. Walker; Eran Hornstein; Eli Pikarsky; Yinon Ben-Neriah

doi:https://doi.org/10.1038/ni.1994

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

Moshe Biton, Avi Levin, Michal Slyper, Irit Alkalay, Elad Horwitz, Hagar Mor, Sharon Kredo-Russo, Tali Avnit-Sagi, Gady Cojocaru, Farid Zreik, Zvi Bentwich, Matthew N. Poy, David Artis, Michael D. Walker, Eran Hornstein, Eli Pikarsky, Yinon Ben-Neriah

Weizmann Institute of Science, The Hebrew University of Jerusalem

Research output: Contribution to journal › Article › peer-review

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(Delta gut)), which encodes an enzyme involved in microRNA biogenesis, deprived goblet cells of RELM beta, a key T(H)2 antiparasitic cytokine; this predisposed the host to parasite infection. Infection of Dicer1(Delta gut) 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 RELM beta expression in vivo; miR-375-deficient mice had significantly less intestinal RELM beta, which possibly explains the greater susceptibility of Dicer1(Delta gut) mice to parasites. Our findings indicate that epithelial microRNAs are key regulators of gut homeostasis and mucosal immunity.

Original language	English
Pages (from-to)	239-246
Number of pages	8
Journal	Nature Immunology
Volume	12
Issue number	3
Early online date	30 Jan 2011
DOIs	https://doi.org/10.1038/ni.1994
State	Published - 1 Mar 2011

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

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Biton, M., Levin, A., Slyper, M., Alkalay, I., Horwitz, E., Mor, H., Kredo-Russo, S., Avnit-Sagi, T., Cojocaru, G., Zreik, F., Bentwich, Z., Poy, M. N., Artis, D., Walker, M. D., Hornstein, E., Pikarsky, E., & Ben-Neriah, Y. (2011). Epithelial microRNAs regulate gut mucosal immunity via epithelium-T cell crosstalk. Nature Immunology, 12(3), 239-246. Advance online publication. https://doi.org/10.1038/ni.1994

@article{92a7ef0b7eb04bbd95df46f08fe527ea,

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(Delta gut)), which encodes an enzyme involved in microRNA biogenesis, deprived goblet cells of RELM beta, a key T(H)2 antiparasitic cytokine; this predisposed the host to parasite infection. Infection of Dicer1(Delta gut) 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 RELM beta expression in vivo; miR-375-deficient mice had significantly less intestinal RELM beta, which possibly explains the greater susceptibility of Dicer1(Delta gut) mice to parasites. Our findings indicate that epithelial microRNAs are key regulators of gut homeostasis and mucosal immunity.",

author = "Moshe Biton and Avi Levin and Michal Slyper and Irit Alkalay and Elad Horwitz and Hagar Mor and Sharon Kredo-Russo and Tali Avnit-Sagi and Gady Cojocaru and Farid Zreik and Zvi Bentwich and Poy, {Matthew N.} and David Artis and Walker, {Michael D.} and Eran Hornstein and Eli Pikarsky and Yinon Ben-Neriah",

note = "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. Moshe Biton and Avi Levin: These authors contributed equally to this work.",

year = "2011",

month = mar,

day = "1",

doi = "https://doi.org/10.1038/ni.1994",

language = "الإنجليزيّة",

volume = "12",

pages = "239--246",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

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Biton, M, Levin, A, Slyper, M, Alkalay, I, Horwitz, E, Mor, H, Kredo-Russo, S, Avnit-Sagi, T, Cojocaru, G, Zreik, F, Bentwich, Z, Poy, MN, Artis, D, Walker, MD, Hornstein, E , Pikarsky, E & Ben-Neriah, Y 2011, 'Epithelial microRNAs regulate gut mucosal immunity via epithelium-T cell crosstalk', Nature Immunology, vol. 12, no. 3, pp. 239-246. https://doi.org/10.1038/ni.1994

TY - JOUR

T1 - Epithelial microRNAs regulate gut mucosal immunity via epithelium-T cell crosstalk

AU - Biton, Moshe

AU - Levin, Avi

AU - Slyper, Michal

AU - Alkalay, Irit

AU - Horwitz, Elad

AU - Mor, Hagar

AU - Kredo-Russo, Sharon

AU - Avnit-Sagi, Tali

AU - Cojocaru, Gady

AU - Zreik, Farid

AU - Bentwich, Zvi

AU - Poy, Matthew N.

AU - Artis, David

AU - Walker, Michael D.

AU - Hornstein, Eran

AU - Pikarsky, Eli

AU - Ben-Neriah, Yinon

N1 - 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. Moshe Biton and Avi Levin: These authors contributed equally to this work.

PY - 2011/3/1

Y1 - 2011/3/1

N2 - 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(Delta gut)), which encodes an enzyme involved in microRNA biogenesis, deprived goblet cells of RELM beta, a key T(H)2 antiparasitic cytokine; this predisposed the host to parasite infection. Infection of Dicer1(Delta gut) 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 RELM beta expression in vivo; miR-375-deficient mice had significantly less intestinal RELM beta, which possibly explains the greater susceptibility of Dicer1(Delta gut) mice to parasites. Our findings indicate that epithelial microRNAs are key regulators of gut homeostasis and mucosal immunity.

AB - 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(Delta gut)), which encodes an enzyme involved in microRNA biogenesis, deprived goblet cells of RELM beta, a key T(H)2 antiparasitic cytokine; this predisposed the host to parasite infection. Infection of Dicer1(Delta gut) 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 RELM beta expression in vivo; miR-375-deficient mice had significantly less intestinal RELM beta, which possibly explains the greater susceptibility of Dicer1(Delta gut) mice to parasites. Our findings indicate that epithelial microRNAs are key regulators of gut homeostasis and mucosal immunity.

UR - http://www.scopus.com/inward/record.url?scp=79951598704&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/ni.1994

DO - https://doi.org/10.1038/ni.1994

M3 - مقالة

C2 - 21278735

SN - 1529-2908

VL - 12

SP - 239

EP - 246

JO - Nature Immunology

JF - Nature Immunology

IS - 3

ER -

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

Abstract

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