IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment

Lin, Xun, Gaudino, Stephen J, Jang, Kyung Ku, Bahadur, Tej, Singh, Ankita, Banerjee, Anirban, Beaupre, Michael, Chu, Timothy, Wong, Hoi Tong, Kim, Chang-Kyung, Kempen, Cody, Axelrad, Jordan, Huang, Huakang, Khalid, Saba, Shah, Vyom, Eskiocak, Onur, Parks, Olivia B, Berisha, Artan, McAleer, Jeremy P, Good, Misty, Hoshino, Miko, Blumberg, Richard, Bialkowska, Agnieszka B, Gaffen, Sarah L, Kolls, Jay K, Yang, Vincent W, Beyaz, Semir, Cadwell, Ken, Kumar, Pawan (January 2022) IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment. Immunity. ISSN 1074-7613

URL: https://www.ncbi.nlm.nih.gov/pubmed/35081371
DOI: 10.1016/j.immuni.2021.12.016

Abstract

The Th17 cell-lineage-defining cytokine IL-17A contributes to host defense and inflammatory disease by coordinating multicellular immune responses. The IL-17 receptor (IL-17RA) is expressed by diverse intestinal cell types, and therapies targeting IL-17A induce adverse intestinal events, suggesting additional tissue-specific functions. Here, we used multiple conditional deletion models to identify a role for IL-17A in secretory epithelial cell differentiation in the gut. Paneth, tuft, goblet, and enteroendocrine cell numbers were dependent on IL-17A-mediated induction of the transcription factor ATOH1 in Lgr5+ intestinal epithelial stem cells. Although dispensable at steady state, IL-17RA signaling in ATOH1+ cells was required to regenerate secretory cells following injury. Finally, IL-17A stimulation of human-derived intestinal organoids that were locked into a cystic immature state induced ATOH1 expression and rescued secretory cell differentiation. Our data suggest that the cross talk between immune cells and stem cells regulates secretory cell lineage commitment and the integrity of the mucosa.

Item Type: Paper
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cells
organs, tissues, organelles, cell types and functions > tissues types and functions > epithelium
diseases & disorders > inflammation
CSHL Authors:
Communities: CSHL labs > Beyaz lab
CSHL labs > Meyer Lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 20 January 2022
Date Deposited: 03 Feb 2022 16:44
Last Modified: 07 Mar 2022 14:30
PMCID: PMC8895883
URI: https://repository.cshl.edu/id/eprint/40508

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