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Cell Rep. 2016 May 24;15(8):1743-56. doi: 10.1016/j.celrep.2016.04.049. Epub 2016 May 12.

Programming of Intestinal Epithelial Differentiation by IL-33 Derived from Pericryptal Fibroblasts in Response to Systemic Infection.

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Medical Clinic 1, Friedrich-Alexander-University, Erlangen 91054, Germany.
Department of Pharmacology, University of Valencia, Burjassot, Valencia 46100, Spain.
Humanitas Clinical and Research Center, Milan 20089, Italy.
Medical Clinic 1, Friedrich-Alexander-University, Erlangen 91054, Germany. Electronic address:


The intestinal epithelium constitutes an efficient barrier against the microbial flora. Here, we demonstrate an unexpected function of IL-33 as a regulator of epithelial barrier functions. Mice lacking IL-33 showed decreased Paneth cell numbers and lethal systemic infection in response to Salmonella typhimurium. IL-33 was produced upon microbial challenge by a distinct population of pericryptal fibroblasts neighboring the intestinal stem cell niche. IL-33 programmed the differentiation of epithelial progenitors toward secretory IEC including Paneth and goblet cells. Finally, IL-33 suppressed Notch signaling in epithelial cells and induced expression of transcription factors governing differentiation into secretory IEC. In summary, we demonstrate that gut pericryptal fibroblasts release IL-33 to translate bacterial infection into an epithelial response to promote antimicrobial defense.

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