Biliary repair and carcinogenesis are mediated by IL-33–dependent cholangiocyte proliferation

TLDR

Injury to the biliary epithelium initiates inflammation and fibrosis that can progress to severe liver disease and malignancy, yet the interplay between inflammatory drivers, epithelial repair, and carcinogenesis—particularly the role of Th2 cytokines—is poorly understood. IL‑33 drives cholangiocyte proliferation by expanding type‑2 innate lymphoid cells that secrete IL‑13, which in turn induces cholangiocyte hyperplasia. Elevated IL‑33 in biliary atresia patients and experimental models promotes rapid bile‑duct enlargement and repair, but activation of the IL‑33/ILC2/IL‑13 axis in mice with constitutive AKT/YAP signaling leads to cholangiocarcinoma with liver metastases, indicating that this pathway can both aid repair and, if dysregulated, drive carcinogenesis.

Abstract

Injury to the biliary epithelium triggers inflammation and fibrosis, which can result in severe liver diseases and may progress to malignancy. Development of a type 1 immune response has been linked to biliary injury pathogenesis; however, a subset of patients with biliary atresia, the most common childhood cholangiopathy, exhibit increased levels of Th2-promoting cytokines. The relationship among different inflammatory drivers, epithelial repair, and carcinogenesis remains unclear. Here, we determined that the Th2-activating cytokine IL-33 is elevated in biliary atresia patient serum and in the livers and bile ducts of mice with experimental biliary atresia. Administration of IL-33 to WT mice markedly increased cholangiocyte proliferation and promoted sustained cell growth, resulting in dramatic and rapid enlargement of extrahepatic bile ducts. The IL-33-dependent proliferative response was mediated by an increase in the number of type 2 innate lymphoid cells (ILC2s), which released high levels of IL-13 that in turn promoted cholangiocyte hyperplasia. Induction of the IL-33/ILC2/IL-13 circuit in a murine biliary injury model promoted epithelial repair; however, induction of this circuit in mice with constitutive activation of AKT and YAP in bile ducts induced cholangiocarcinoma with liver metastases. These findings reveal that IL-33 mediates epithelial proliferation and suggest that activation of IL-33/ILC2/IL-13 may improve biliary repair and disruption of the circuit may block progression of carcinogenesis.