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

Immunity. 2022 Feb 8;55(2):237-253.e8. doi: 10.1016/j.immuni.2021.12.016. Epub 2022 Jan 25.


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.

Keywords: ATOH1; IL-17A; Lgr5; Th17; intestine; organoids; progenitor cells; secretory cell lineage; stem cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Communication
  • Cell Differentiation / drug effects
  • Cell Lineage / drug effects
  • Colitis / chemically induced
  • Colitis / metabolism
  • Colitis / pathology
  • Dextran Sulfate / adverse effects
  • Humans
  • Interleukin-17 / metabolism
  • Interleukin-17 / pharmacology
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Intestines / metabolism
  • Intestines / pathology
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Interleukin-17 / deficiency
  • Receptors, Interleukin-17 / metabolism*
  • SOX9 Transcription Factor / metabolism
  • Signal Transduction
  • Stem Cells / cytology
  • Stem Cells / metabolism*


  • Atoh1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Il17a protein, mouse
  • Il17ra protein, mouse
  • Interleukin-17
  • Lgr5 protein, mouse
  • NF-kappa B
  • Receptors, G-Protein-Coupled
  • Receptors, Interleukin-17
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Dextran Sulfate