Th2 signals induce epithelial injury in mice and are compatible with the biliary atresia phenotype
Jun Li, … , Gilda Porta, Jorge A. Bezerra
Jun Li, … , Gilda Porta, Jorge A. Bezerra
Published October 17, 2011
Citation Information: J Clin Invest. 2011;121(11):4244-4256. https://doi.org/10.1172/JCI57728.
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Research Article Gastroenterology

Th2 signals induce epithelial injury in mice and are compatible with the biliary atresia phenotype

Abstract

Biliary atresia (BA) is a destructive cholangiopathy of childhood in which Th1 immunity has been mechanistically linked to the bile duct inflammation and obstruction that culminate in liver injury. Based on reports of decreased Th1 cytokines in some patients and the development of BA in mice lacking CD4+ T cells, we hypothesized that Th1-independent mechanisms can also activate effector cells and induce BA. Here, we tested this hypothesis using Stat1–/– mice, which lack the ability to mount Th1 immune responses. Infection of Stat1–/– mice with rhesus rotavirus type A (RRV) on postnatal day 1 induced a prominent Th2 response, duct epithelial injury and obstruction within 7 days, and atresia shortly thereafter. A high degree of phosphorylation of the Th2 transcription factor Stat6 was observed; however, concurrent inactivation of Stat1 and Stat6 in mice did not prevent BA after RRV infection. In contrast, depletion of macrophages or combined loss of Il13 and Stat1 reduced tissue infiltration by lymphocytes and myeloid cells, maintained epithelial integrity, and prevented duct obstruction. In concordance with our mouse model, humans at the time of BA diagnosis exhibited differential hepatic expression of Th2 genes and serum Th2 cytokines. These findings demonstrate compatibility between Th2 commitment and the pathogenesis of BA, and suggest that patient subgrouping in future clinical trials should account for differences in Th2 status.

Authors

Jun Li, Kazuhiko Bessho, Pranavkumar Shivakumar, Reena Mourya, Sujit Kumar Mohanty, Jorge L. dos Santos, Irene K. Miura, Gilda Porta, Jorge A. Bezerra

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Figure 5

Myeloid cells infiltrate livers and bile ducts of Stat1–/– mice after RRV challenge.

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Myeloid cells infiltrate livers and bile ducts of Stat1–/– mice after RR...
H&E staining of liver sections shows mild infiltration of portal tracts by neutrophils 3 days after RRV in WT and Stat1–/– mice (A). The degree of infiltration increases in both mouse lines at 7 and 10 days, primarily with lymphocytes in WT mice and persistent neutrophilic infiltration in Stat1–/– mice. (B) Similar staining of longitudinal sections of extrahepatic bile ducts shows mild submucosal inflammation at day 3, formation of an inflammatory plug obstructing the lumen at day 7, and the ongoing obstruction at day 10. Notably, inflammatory cells in WT bile ducts are predominantly lymphocytes at day 10, while they are primarily neutrophils in Stat1–/– ducts. (C) Section in the distal end of a Stat1–/– duct shows a cystic dilatation, which is lined by largely intact epithelium but also displays neutrophils and macrophages in the lumen and within the wall. Scale bars: 200 μm; original magnification, ×1000 (insets). (D–F) Mean ± SEM percentage of hepatic mononuclear cells that are stained for CD3, CD19, and CD11b by flow cytometry at days 3, 7, 10 after RRV challenge. *P < 0.05; ***P < 0.001. n = 4–10 mice in each group.