title: Programming of Intestinal Epithelial Differentiation by IL-33 Derived from Pericryptal Fibroblasts in Response to Systemic Infection.
abstract: 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.
authors.affiliation: Medical Clinic 1, Friedrich-Alexander-University, Erlangen 91054, Germany.
authors.forename: Mousumi
authors.initials: M
authors.lastname: Mahapatro
authors.affiliation: Medical Clinic 1, Friedrich-Alexander-University, Erlangen 91054, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Foersch
authors.affiliation: Medical Clinic 1, Friedrich-Alexander-University, Erlangen 91054, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Hefele
authors.affiliation: Medical Clinic 1, Friedrich-Alexander-University, Erlangen 91054, Germany.
authors.forename: Gui-Wei
authors.initials: GW
authors.lastname: He
authors.affiliation: Department of Pharmacology, University of Valencia, Burjassot, Valencia 46100, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giner-Ventura
authors.affiliation: Medical Clinic 1, Friedrich-Alexander-University, Erlangen 91054, Germany.
authors.forename: Tamar
authors.initials: T
authors.lastname: Mchedlidze
authors.affiliation: Medical Clinic 1, Friedrich-Alexander-University, Erlangen 91054, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kindermann
authors.affiliation: Humanitas Clinical and Research Center, Milan 20089, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Vetrano
authors.affiliation: Humanitas Clinical and Research Center, Milan 20089, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.affiliation: Medical Clinic 1, Friedrich-Alexander-University, Erlangen 91054, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Günther
authors.affiliation: Medical Clinic 1, Friedrich-Alexander-University, Erlangen 91054, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.affiliation: Medical Clinic 1, Friedrich-Alexander-University, Erlangen 91054, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.affiliation: Medical Clinic 1, Friedrich-Alexander-University, Erlangen 91054, Germany. Electronic address: christoph.becker@uk-erlangen.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000378:metabolism; D000067596:Interleukin-33 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000473:pathology*; D007421:Intestine, Small / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D051880:Receptors, Notch / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000382:microbiology / Q000473:pathology*; D012486:Salmonella typhimurium / Q000502:physiology; D015398:Signal Transduction
chemical_list: C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D051880:Receptors, Notch