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

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, M. Kay Washington, Tracy C. Grikscheit, David Warburton, Michael J. Rosen and Mark R. Frey ()
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Michael A. Schumacher: Children’s Hospital Los Angeles
Jonathan J. Hsieh: Children’s Hospital Los Angeles
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
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
David Warburton: Children’s Hospital Los Angeles
Michael J. Rosen: Cincinnati Children’s Hospital Medical Center
Mark R. Frey: Children’s Hospital Los Angeles

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21113-7

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