4.8 Article

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

期刊

IMMUNITY
卷 55, 期 2, 页码 237-+

出版社

CELL PRESS
DOI: 10.1016/j.immuni.2021.12.016

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资金

  1. National Cancer Institute [P30 CA016087]
  2. Crohn's and Colitis Foundation [476637, DK121798, AI149257]
  3. SUNY Research Foundation [DE022550, DK103788, AI121244, HL123340, DK093668, AI130945, HL125816, DK124336, AI140754]
  4. NYU CTSA [UL1TR001445]
  5. NYU Cancer Center [P30CA016087]
  6. NYU Colton Center for Autoimmunity
  7. Howard Hughes Medical Institute
  8. Crohn's & Colitis Foundation
  9. Burroughs Wellcome Fund PATH award
  10. Kenneth Rainin Foundation
  11. Abbvie
  12. Pfizer
  13. National Science Foundation Graduate Research Fellowship
  14. NRSA [T32AI007539, DK088199, R35 HL139930, R01 AI120033, DK052230]

向作者/读者索取更多资源

IL-17A plays a crucial role in the differentiation of secretory epithelial cells in the gut, maintaining the integrity and health of the mucosa by regulating the cross talk between intestinal cells.
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.

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