Sortilin in Biliary Epithelial Cells Promotes Ductular Reaction and Fibrosis during Cholestatic Injury

Abstract

Cholestatic injuries are accompanied by a ductular reaction, initiated by proliferation and activation of biliary epithelial cells (BEC), leading to fibrosis. Sortilin (Sort1) facilitates IL-6 secretion and leukemia inhibitory factor (LIF) signaling. This study investigated the interplay between sortilin, IL-6 and LIF in cholestatic injury-induced ductular reaction, morphogenesis of new ducts and fibrosis. Cholestatic injury was induced by bile duct ligation (BDL) in WT and Sort1-/- mice, with or without augmentation of IL-6 or LIF. Mice with BEC sortilin deletion (HgfapcreSort1fl/fl) and controls were subjected to BDL and 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine diet (DDC)-induced cholestatic injury. Sort1-/- mice displayed reduced BEC proliferation and expression of BEC reactive markers. Administration of LIF or IL-6 restored BEC proliferation in Sort1-/- mice, without affecting BEC reactive or inflammatory markers. Sort1-/- mice also displayed impaired morphogenesis, which was corrected by LIF treatment. Similarly, HgfapcreSort1fl/f mice exhibited reduced BEC proliferation, but similar expression of reactive and inflammatory markers. Serum IL-6 and LIF levels were comparable, yet liver pSTAT3 was reduced, indicating that sortilin is essential for co-activation of LIFR/gp130 signaling in BEC, but not for IL-6 secretion. Notably, HgfapcreSortfl/fl mice displayed impaired morphogenesis and diminished fibrosis following BDL and DDC. In conclusion, sortilin-governed engagement of LIF signaling in BEC promotes ductular reaction and morphogenesis during cholestatic injury. Moreover, BEC sortilin is pivotal for the development of fibrosis.