Ceci, LudovicaFrancis, HeatherZhou, TianhaoGiang, ThaoYang, ZhihongMeng, FanyinWu, NanKennedy, LindseyKyritsi, KonstantinaMeadows, VikWu, ChaodongLiangpunsakul, SuthatFranchitto, AntonioSybenga, AmeliaEkser, BurcinMancinelli, RominaOnori, PaoloGaudio, EugenioGlaser, ShannonAlpini, Gianfranco2023-03-312023-03-312020-11Ceci L, Francis H, Zhou T, et al. Knockout of the Tachykinin Receptor 1 in the Mdr2-/- (Abcb4-/-) Mouse Model of Primary Sclerosing Cholangitis Reduces Biliary Damage and Liver Fibrosis. Am J Pathol. 2020;190(11):2251-2266. doi:10.1016/j.ajpath.2020.07.007https://hdl.handle.net/1805/32167Activation 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.en-USPublisher PolicyBile ductsSclerosing cholangitisLiver cirrhosisNeurokinin-1 receptorsArticle