IL-22 induces Paneth cell metaplasia in the colonic epithelium of ulcerative colitis, promoting wound healing via REG3A

Paneth cell metaplasia (PCM) is a phenomenon in which Paneth cells, typically found in the small intestine, appear in the colonic epithelium of patients with ulcerative colitis (UC). Our study demonstrates that the PCM occurrence correlates with disease duration and active inflammation. Furthermore, we reveal that the inflammation-induced cytokine IL-22 suppresses Notch signaling, thereby promoting PCM formation in the colonic epithelium while simultaneously inducing REG3A expression in metaplastic niches. In vitro, we show that Reg3a directly enhances cell proliferation and promotes wound healing using mouse colonic organoids. In vivo, Reg3a?IEC mice in both acute and chronic DSS-induced colitis models exhibit delayed wound healing. Additionally, studies conducted with patient-derived human colonic organoids revealed that REG3A administration stimulates cell proliferation and accelerates wound healing. These findings underscore a novel protective role of PCM-mediated REG3A in the colonic epithelium of patients with UC. Overall design: RNA-seq analysis comparing Reg3afl/fl and Reg3a?IEC colonic organoids. Treated or not with IL22.