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  1. Philip J Smith
  1. Department of Gastroenterology, Royal Liverpool Hospital, Liverpool University Hospitals Foundation NHS Trust, Liverpool, UK
  1. Correspondence to Dr Philip J Smith, Department of Gastroenterology, Royal Liverpool Hospital, Liverpool University Hospitals Foundation NHS Trust, Liverpool, L7 8XP, UK; Philip.Smith{at}

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Basic science

IL-17RA signaling in intestinal stem cells induces the expression of transcription factor ATOH1

Lin X, Gaudino S, Jang K, et al. IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment. Immunity 2022;55:237–53.e8. doi:10.1016/j.immuni.2021.12.016

Interleukin 17A (IL-17A) defines the Th17 (T helper 17) immune cell lineage responsible for the induction of immune responses to microbes. Targeting IL-17A has been shown to treat psoriasis; however, some patients develop Crohn’s-like disease following treatment and anti-IL-17A therapy for IBD inflammation has been shown to worsen inflammation. Lin et al seek to establish the role of IL-17A in intestinal homeostasis. Exposure of intestinal organoids to IL-17A resulted in increased gene expression associated with secretory cell function and an increased number of Paneth cells. This effect appeared lost after organoids become differentiated suggesting that IL-17A has a role in initiating differentiation but not in maintaining a differentiated state. Mice rendered IL-17 receptor A deficient (IL-17RAfl/fl) also showed a loss of Paneth and Goblet cells. The absorptive lineages appeared unaffected. The role of IL-17A in the commitment of secretory lineages was confirmed through the observed loss of Atoh1 (atonal bHLH transcription factor 1, a known secretory lineage transcription factor) in IL-17RAfl/fl mice. Specific loss of IL-17RA in Atoh1+ cells (IL-17RAfl/fl Atoh1-cre mice) appeared however to have no effect on secretory cell gene expression; however, when these mice were subjected to dextran sulfate sodium (DSS) they exhibited exacerbated inflammation suggesting the IL-17RA signalling through Atoh1 is responsible for homeostasis. Paneth cells however appeared to be redundant in this type of damage. Finally, the authors demonstrated that these mice displayed reduced Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5) expression post-DSS treatment. Overall, this study demonstrates a clear role for epithelial (IL-17RA+)-T-cell (IL-17A+) immune interactions in maintaining homeostasis and its breakdown may lead to increased susceptibility to IBD.

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  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.