TY - JOUR
T1 - Sortilin in Biliary Epithelial Cells Promotes Ductular Reaction and Fibrosis during Cholestatic Injury
AU - Hubel, Einav
AU - Neumann, Anat
AU - Fishman, Sigal
AU - Schaffer, Ortal
AU - Erez, Noam
AU - Shrkihe, Bander Abu
AU - Shteingard, Yuval
AU - Gross, Tamar
AU - Shibolet, Oren
AU - Varol, Chen
AU - Zvibel, Isabel
N1 - Publisher Copyright:
© 2024 American Society for Investigative Pathology
PY - 2024/6
Y1 - 2024/6
N2 - 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 (hGFAPcre.Sort1fl/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, hGFAPcre.Sort1fl/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. hGFAPcre.Sortfl/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.
AB - 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 (hGFAPcre.Sort1fl/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, hGFAPcre.Sort1fl/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. hGFAPcre.Sortfl/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.
UR - http://www.scopus.com/inward/record.url?scp=85189968685&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2024.01.023
DO - 10.1016/j.ajpath.2024.01.023
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C2 - 38493927
AN - SCOPUS:85189968685
SN - 0002-9440
VL - 194
SP - 941
EP - 957
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -