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

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.
Xun Lin 1,  Stephen J Gaudino 1,  Kyung Ku Jang 2,  Tej Bahadur 1,  Ankita Singh 1,  Anirban Banerjee 1,  Michael Beaupre 1,  Timothy Chu 1,  Hoi Tong Wong 1,  Chang-Kyung Kim 3,  Cody Kempen 1,  Jordan Axelrad 4,  Huakang Huang 1,  Saba Khalid 1,  Vyom Shah 5,  Onur Eskiocak 5,  Olivia B Parks 6,  Artan Berisha 1,  Jeremy P McAleer 7,  Misty Good 8,  Miko Hoshino 9,  Richard Blumberg 10,  Agnieszka B Bialkowska 3,  Sarah L Gaffen 11,  Jay K Kolls 12,  Vincent W Yang 3,  Semir Beyaz 5,  Ken Cadwell 13,  Pawan Kumar 14
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, USA.
  • 2 Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, NY, USA.
  • 3 Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
  • 4 Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 5 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • 6 University of Pittsburgh School of Medicine, Medical Scientist Training Program, Pittsburgh, PA 15213, USA.
  • 7 Department of Pharmaceutical Science, Marshall University School of Pharmacy, Huntington, WV 25701, USA.
  • 8 Washington University School of Medicine, Department of Pediatrics, Division of Newborn Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA.
  • 9 Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.
  • 10 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 11 Division of Rheumatology and Clinical Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 12 Center for Translational Research in Infection and Inflammation, Tulane School of Medicine, New Orleans, LA 70112, USA.
  • 13 Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, NY, USA; Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA; Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA. Electronic address: ken.cadwell@med.nyu.edu.
  • 14 Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, USA. Electronic address: pawan.kumar@stonybrook.edu.
PMID: 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.

Keywords

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

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