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Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

Author

Listed:
  • Michael A. Schumacher

    (Children’s Hospital Los Angeles
    University of Southern California Keck School of Medicine)

  • Jonathan J. Hsieh

    (Children’s Hospital Los Angeles
    University of Southern California Keck School of Medicine)

  • Cambrian Y. Liu

    (Children’s Hospital Los Angeles)

  • Keren L. Appel

    (Children’s Hospital Los Angeles)

  • Amanda Waddell

    (Cincinnati Children’s Hospital Medical Center)

  • Dana Almohazey

    (Imam Abdulrahman Bin Faisal University)

  • Kay Katada

    (Children’s Hospital Los Angeles)

  • Jessica K. Bernard

    (Children’s Hospital Los Angeles)

  • Edie B. Bucar

    (Children’s Hospital Los Angeles
    University of Southern California Keck School of Medicine)

  • Safina Gadeock

    (Children’s Hospital Los Angeles)

  • Kathryn M. Maselli

    (Children’s Hospital Los Angeles)

  • M. Kay Washington

    (Vanderbilt University Medical Center)

  • Tracy C. Grikscheit

    (Children’s Hospital Los Angeles
    University of Southern California)

  • David Warburton

    (Children’s Hospital Los Angeles)

  • Michael J. Rosen

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Mark R. Frey

    (Children’s Hospital Los Angeles
    University of Southern California Keck School of Medicine)

Abstract

Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we ask whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion leads to expanded tuft and goblet cell populations. Sprouty2 loss induces PI3K/Akt signaling, leading to GSK3β inhibition and epithelial interleukin (IL)-33 expression. In vivo, this results in increased stromal IL-13+ cells. IL-13 in turn induces tuft and goblet cell expansion in vitro and in vivo. Sprouty2 is downregulated by acute inflammation; this appears to be a protective response, as VillinCre;Sprouty2F/F mice are resistant to DSS colitis. In contrast, Sprouty2 is elevated in chronic colitis and in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.

Suggested Citation

  • Michael A. Schumacher & Jonathan J. Hsieh & Cambrian Y. Liu & Keren L. Appel & Amanda Waddell & Dana Almohazey & Kay Katada & Jessica K. Bernard & Edie B. Bucar & Safina Gadeock & Kathryn M. Maselli &, 2021. "Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21113-7
    DOI: 10.1038/s41467-021-21113-7
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