IL-22 receptor signaling in Paneth cells is critical for their maturation, microbiota colonization, Th17-related immune responses, and anti-Salmonella immunity

Gaudino, S. J., Beaupre, M., Lin, X., Joshi, P., Rathi, S., McLaughlin, P. A., Kempen, C., Mehta, N., Eskiocak, O., Yueh, B., Blumberg, R. S., van der Velden, A. W. M., Shroyer, K. R., Bialkowska, A. B., Beyaz, S., Kumar, P. (October 2020) IL-22 receptor signaling in Paneth cells is critical for their maturation, microbiota colonization, Th17-related immune responses, and anti-Salmonella immunity. Mucosal Immunol. ISSN 1933-0219

Abstract

Interleukin-22 (IL-22) signaling in the intestines is critical for promoting tissue-protective functions. However, since a diverse array of cell types (absorptive and secretory epithelium as well as stem cells) express IL-22Ra1, a receptor for IL-22, it has been difficult to determine what cell type(s) specifically respond to IL-22 to mediate intestinal mucosal host defense. Here, we report that IL-22 signaling in the small intestine is positively correlated with Paneth cell differentiation programs. Our Il22Ra1(fl/fl);Lgr5-EGFP-cre(ERT2)-specific knockout mice and, independently, our lineage-tracing findings rule out the involvement of Lgr5(+) intestinal stem cell (ISC)-dependent IL-22Ra1 signaling in regulating the lineage commitment of epithelial cells, including Paneth cells. Using novel Paneth cell-specific IL-22Ra1 knockout mice (Il22Ra1(fl/fl);Defa6-cre), we show that IL-22 signaling in Paneth cells is required for small intestinal host defense. We show that Paneth cell maturation, antimicrobial effector function, expression of specific WNTs, and organoid morphogenesis are dependent on cell-intrinsic IL-22Ra1 signaling. Furthermore, IL-22 signaling in Paneth cells regulates the intestinal commensal bacteria and microbiota-dependent IL-17A immune responses. Finally, we show ISC and, independently, Paneth cell-specific IL-22Ra1 signaling are critical for providing immunity against Salmonella enterica serovar Typhimurium. Collectively, our findings illustrate a previously unknown role of IL-22 in Paneth cell-mediated small intestinal host defense.

Item Type:	Paper
Additional Information:	1935-3456 Gaudino, Stephen J Beaupre, Michael Lin, Xun Joshi, Preet Rathi, Sonika McLaughlin, Patrick A Kempen, Cody Mehta, Neil Eskiocak, Onur Yueh, Brian Blumberg, Richard S van der Velden, Adrianus W M Shroyer, Kenneth R Bialkowska, Agnieszka B Beyaz, Semir Kumar, Pawan Orcid: 0000-0003-3628-452x Journal Article United States Mucosal Immunol. 2020 Oct 15. doi: 10.1038/s41385-020-00348-5.
Subjects:	organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell differentiation organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell signaling organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > differentiation organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction organs, tissues, organelles, cell types and functions > tissues types and functions
CSHL Authors:	Beyaz, Semir Eskiocak, Onur Yueh, Brian
Communities:	CSHL labs > Beyaz lab CSHL Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program
Depositing User:	Matthew Dunn
Date:	15 October 2020
Date Deposited:	19 Feb 2021 20:18
Last Modified:	13 Feb 2024 16:54
PMCID:	PMC7946635
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/39858

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