Wnt/β-catenin maintains epithelial IL-33 in the colonic stem and progenitor cell niche and drives its induction in colitis

Michael A Schumacher; Megan H Thai; Jonathan J Hsieh; Alexa Gramajo; Cambrian Y Liu; Mark R Frey

doi:10.1016/j.mucimm.2024.11.007

Wnt/β-catenin maintains epithelial IL-33 in the colonic stem and progenitor cell niche and drives its induction in colitis

Mucosal Immunol. 2024 Nov 24:S1933-0219(24)00115-6. doi: 10.1016/j.mucimm.2024.11.007. Online ahead of print.

Authors

Michael A Schumacher¹, Megan H Thai², Jonathan J Hsieh², Alexa Gramajo³, Cambrian Y Liu⁴, Mark R Frey⁵

Affiliations

¹ Department of Pediatrics, University of Southern California Keck School of Medicine. Los Angeles, CA, 90089; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027. Electronic address: mschumacher@chla.usc.edu.
² The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027.
³ Department of Pediatrics, University of Southern California Keck School of Medicine. Los Angeles, CA, 90089; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027.
⁴ Department of Medicine, The University of Chicago, Chicago, IL, 60637.
⁵ Department of Pediatrics, University of Southern California Keck School of Medicine. Los Angeles, CA, 90089; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027; Department of Biochemistry and Molecular Medicine, University of Southern California Keck School of Medicine. Los Angeles, CA, 90089.

PMID: 39592069
DOI: 10.1016/j.mucimm.2024.11.007

Abstract

Interleukin (IL)-33 is a key responder to intestinal injury and inflammation. In the colon, it is expressed by several cell populations, with the specific cellular source likely determining its role. The colonic epithelium expresses IL-33; however, the factors controlling its production and the specific epithelial lineage(s) expressing IL-33 are poorly understood. We recently reported that colonic epithelial IL-33 is induced by inhibition of glycogen synthase kinase-3β (GSK3β), but the signaling pathway mediating this induction is unknown. Here we tested the role of Wnt/β-catenin signaling in regulating colonic epithelial IL-33 at homeostasis and in injury-induced colitis. Transcriptomic analysis shows that epithelial IL-33 localizes to stem and progenitor cells. Ligand activation of Wnt/β-catenin signaling induced IL-33 in colonic organoid and cell cultures. Furthermore, small-molecule disruption of β-catenin interaction with cyclic AMP response element binding protein (CBP) prevented epithelial IL-33 induction. Antagonism of CBP/β-catenin signaling also prevented rapid epithelial IL-33 induction in dextran sodium sulfate (DSS)-mediated colitis, and was associated with maintenance of crypt-expressed host defense peptides. Together, these findings show β-catenin-driven production of epithelial IL-33 is an early response to colonic injury that shapes the crypt base defense response and suggest an immunoregulatory role for the stem cell niche in tissue injury.

Keywords: CBP/β-catenin; Colon; Epithelium; IL-33; Wnt.