Knockout of the Tachykinin Receptor 1 in the Mdr2^-/- (Abcb4^-/-) Mouse Model of Primary Sclerosing Cholangitis Reduces Biliary Damage and Liver Fibrosis.

Activation of the substance P (SP)/neurokinin 1 receptor (NK1R) axis triggers biliary damage/senescence and liver fibrosis in bile duct ligated and Mdr2^-/- (alias Abcb4^-/-) mice through enhanced transforming growth factor-β1 (TGF-β1) biliary secretion. Recent evidence indicates a role for miR-31 (MIR31) in TGF-β1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-β1/miR-31 axis in regulating biliary proliferation and liver fibrosis during cholestasis. Thus, we generated a novel model with double knockout of Mdr2^-/- and NK1R^-/ (alias Tacr1^-/-) to further address the role of the SP/NK1R axis during chronic cholestasis. In vivo studies were performed in the following 12-week-old male mice: (i) NK1R^-/-; (ii) Mdr2^-/-; and (iii) NK1R^-/-/Mdr2^-/- (Tacr1^-/-/Abcb4^-/-) and their corresponding wild-type controls. Liver tissues and cholangiocytes were collected, and liver damage, changes in biliary mass/senescence, and inflammation as well as liver fibrosis were evaluated by both immunohistochemistry in liver sections and real-time PCR. miR-31 expression was measured by real-time PCR in isolated cholangiocytes. Decreased ductular reaction, liver fibrosis, biliary senescence, and biliary inflammation were observed in NK1R^-/-/Mdr2^-/- mice compared with Mdr2^-/- mice. Elevated expression of miR-31 was observed in Mdr2^-/- mice, which was reduced in NK1R^-/-/Mdr2^-/- mice. Targeting the SP/NK1R and/or miR-31 may be a potential approach in treating human cholangiopathies, including primary sclerosing cholangitis. Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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