Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 190, Issue 11, Pages 2251-2266Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2020.07.007
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Funding
- Hickam Endowed Chair, Gastroenterology, Medicine, Indiana University
- Indiana University HealtheIndiana University School of Medicine Strategic Research Initiative
- US Department of Veteran's Affairs, Biomedical Laboratory Research and Development Service VA Merit awards [5I01BX000574, 1I01BX003031, 1I01BX001724]
- NIH [DK108959, DK119421, DK054811, DK115184, DK076898, DK107310, DK110035, DK062975, AA025997, AA025157]
- PSC Partners Seeking a Cure
- Sapienza University [RM1181642BEF570E]
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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-beta 1 (TGF-beta 1) biliary secretion. Recent evidence indicates a role for miR-31 (MIR31) in TGF-beta 1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-beta 1/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.
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