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

Cholestatic injuries are accompanied by ductular reaction, initiated by proliferation and activation of biliary epithelial cells (BECs), leading to fibrosis. Sortilin (encoded by Sort1) facilitates IL-6 secretion and leukemia inhibitory factor (LIF) signaling. This study investigated the interplay between sortilin and 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 wild-type and Sort1^-/- mice, with or without augmentation of IL-6 or LIF. Mice with BEC sortilin deficiency (hGFAP^cre.Sort1^fl/fl) and control mice 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, hGFAP^cre.Sort1^fl/fl mice exhibited reduced BEC proliferation, but similar reactive and inflammatory marker expression. Serum IL-6 and LIF were comparable, yet liver pSTAT3 was reduced, indicating that sortilin is essential for co-activation of LIF receptor/gp130 signaling in BECs, but not for IL-6 secretion. hGFAP^cre.Sort^fl/fl mice displayed impaired morphogenesis and diminished fibrosis after BDL and DDC. In conclusion, sortilin-mediated engagement of LIF signaling in BECs promoted ductular reaction and morphogenesis during cholestatic injury. This study indicates that BEC sortilin is pivotal for the development of fibrosis.