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 identified IL-22, an inflammation-associated cytokine, as a key regulator that promotes PCM formation in the colonic epithelium through suppression of Notch signaling and induces REG3A expression within metaplastic niches. In vitro, we show that Reg3a directly enhances cell proliferation and promotes wound healing using mouse colonic organoids. In vivo, Reg3aΔIEC 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. Together, these findings support a protective role of PCM-associated REG3A in the colonic epithelium of patients with UC. In ulcerative colitis, Paneth cell metaplasia in the colon correlates with disease duration and histological inflammatory activity. Here the authors report that chronic inflammation induces Paneth cell metaplasia via IL-22, and that metaplastic Paneth cells express REG3A to promote epithelial proliferation and wound healing.