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: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

^*Corresponding author for this work

Department of Immunology and Cancer Research

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

169 Scopus citations

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_H2) 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_H2 antiparasitic cytokine; this predisposed the host to parasite infection. Infection of Dicer1^δgut mice with helminths favored a futile T_H1 response with hallmarks of inflammatory bowel disease. Interleukin 13 (IL-13) induced the microRNA miR-375, which regulates the expression of TSLP, a T_H2-facilitating epithelial cytokine; this indicated a T_H2-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.

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

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

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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 (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.",

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",

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doi = "10.1038/ni.1994",

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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

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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

PY - 2011/3

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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 (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.

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

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