Ando, T., Takazawa, I., Spencer, Z.T., Ito, R., Tomimori, Y., Mikulski, Z., Matsumoto, K., Ishitani, T., Denson, L.A., Kawakami, Y., Kawakami, Y., Kitaura, J., Ahmed, Y., Kawakami, T. (2024). Ileal Crohn's Disease Exhibits Reduced Activity of Phospholipase C-β3-Dependent Wnt/β-Catenin Signaling Pathway.  Cells 13(11): 986.

FBrf0259783

Research paper

Crohn's disease is a chronic, debilitating, inflammatory bowel disease. Here, we report a critical role of phospholipase C-β3 (PLC-β3) in intestinal homeostasis. In PLC-β3-deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-β3 deficiency in multiple non-hematopoietic cell types. PLC-β3 deficiency resulted in reduced Wnt/β-catenin signaling, which is essential for homeostasis and the regeneration of the intestinal epithelium. PLC-β3 regulated the Wnt/β-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and, potentially, protein-protein interaction levels. PLC-β3-deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/β-catenin signaling. Reduced expression of PLC-β3 and its signature genes was found in biopsies of patients with ileal Crohn's disease. PLC-β regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that a reduction in PLC-β3-mediated Wnt/β-catenin signaling contributes to the pathogenesis of ileal Crohn's disease.

PMC11171731 (PMC) (EuropePMC)