Biliary repair and carcinogenesis are mediated by IL-33–dependent cholangiocyte proliferation
Jun Li, Nataliya Razumilava, Gregory J. Gores, Stephanie Walters, Tatsuki Mizuochi, Reena Mourya, Kazuhiko Bessho, Yui-Hsi Wang, Shannon S. Glaser, Pranavkumar Shivakumar, Jorge A. Bezerra
Jun Li, Nataliya Razumilava, Gregory J. Gores, Stephanie Walters, Tatsuki Mizuochi, Reena Mourya, Kazuhiko Bessho, Yui-Hsi Wang, Shannon S. Glaser, Pranavkumar Shivakumar, Jorge A. Bezerra
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Research Article Oncology

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

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.

Authors

Jun Li, Nataliya Razumilava, Gregory J. Gores, Stephanie Walters, Tatsuki Mizuochi, Reena Mourya, Kazuhiko Bessho, Yui-Hsi Wang, Shannon S. Glaser, Pranavkumar Shivakumar, Jorge A. Bezerra

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Figure 5

Hepatic ILC2s increase after IL-33 treatment.

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Hepatic ILC2s increase after IL-33 treatment. Representative dot plots (...
Representative dot plots (A) and quantification from 3 independent experiments (B and C) of flow cytometric assays show that hepatic ILC2s increase after 4 and 7 days of IL-33 injection. (D) By gating on Lin–ST2+ cells, plots show that IL-33 upregulates the expression of Sca1, ICOS, CD127, CD25, and CD44, but not that of CD45, cKit, or Flt3 (Flt3–). (E and F) Intracellular staining shows ILC2 cells harvested from livers at the specified time points after daily injections of IL-33 produce high levels of IL-13 and minimal amounts of IFN-γ after restimulation with phorbol 12-myristate 13-acetate and ionomycin in vitro for 4 hours. Data in C are absolute cell count at specified time points, E contains representative dot plots, and F shows percent of ILC2s expressing IL-13 from 3 independent experiments. Mean ± SD, 4–5 replicates. *P < 0.05; **P < 0.01; ***P < 0.001.