Schumacher Michael A, Thai Megan H, Hsieh Jonathan J, Gramajo Alexa, Liu Cambrian Y, Frey Mark R
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.
The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027.
Mucosal Immunol. 2025 Feb;18(1):248-256. doi: 10.1016/j.mucimm.2024.11.007. Epub 2024 Nov 24.
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.
白细胞介素（IL）-33是肠道损伤和炎症的关键应答因子。在结肠中，它由多种细胞群体表达，其具体细胞来源可能决定其作用。结肠上皮表达IL-33；然而，控制其产生的因素以及表达IL-33的特定上皮谱系尚不清楚。我们最近报道，结肠上皮IL-33是由糖原合酶激酶-3β（GSK3β）的抑制诱导产生的，但介导这种诱导的信号通路尚不清楚。在这里，我们测试了Wnt/β-连环蛋白信号在稳态和损伤诱导的结肠炎中调节结肠上皮IL-33的作用。转录组分析表明，上皮IL-33定位于干细胞和祖细胞。Wnt/β-连环蛋白信号的配体激活在结肠类器官和细胞培养物中诱导IL-33。此外，β-连环蛋白与环磷酸腺苷反应元件结合蛋白（CBP）相互作用的小分子破坏阻止了上皮IL-33的诱导。CBP/β-连环蛋白信号的拮抗作用也阻止了右旋糖酐硫酸钠（DSS）介导的结肠炎中上皮IL-33的快速诱导，并与隐窝表达的宿主防御肽的维持有关。总之，这些发现表明β-连环蛋白驱动的上皮IL-33产生是对结肠损伤的早期反应，它塑造了隐窝底部的防御反应，并提示干细胞微环境在组织损伤中具有免疫调节作用。
