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

Ludovica Ceci; Heather Francis; Tianhao Zhou; Thao Giang; Zhihong Yang; Fanyin Meng; Nan Wu; Lindsey Kennedy; Konstantina Kyritsi; Vik Meadows; Chaodong Wu; Suthat Liangpunsakul; Antonio Franchitto; Amelia Sybenga; Burcin Ekser; Romina Mancinelli; Paolo Onori; Eugenio Gaudio; Shannon Glaser; Gianfranco Alpini

doi:10.1016/j.ajpath.2020.07.007

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 Nov;190(11):2251-2266. doi: 10.1016/j.ajpath.2020.07.007. Epub 2020 Jul 23.

Authors

Ludovica Ceci¹, Heather Francis², Tianhao Zhou³, Thao Giang³, Zhihong Yang¹, Fanyin Meng², Nan Wu¹, Lindsey Kennedy¹, Konstantina Kyritsi¹, Vik Meadows¹, Chaodong Wu⁴, Suthat Liangpunsakul², Antonio Franchitto⁵, Amelia Sybenga⁶, Burcin Ekser⁷, Romina Mancinelli⁸, Paolo Onori⁸, Eugenio Gaudio⁸, Shannon Glaser³, Gianfranco Alpini⁹

Affiliations

¹ Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana.
² Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana.
³ Department of Medical Physiology, Texas A&M University, Bryan, Texas.
⁴ Department of Nutrition, Texas A&M University, College Station, Texas.
⁵ Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy.
⁶ Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, Burlington, Vermont.
⁷ Division of Transplant Surgery, Department of Surgery, Indiana University, Indianapolis, Indiana.
⁸ Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
⁹ Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana. Electronic address: galpini@iu.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / deficiency*
ATP Binding Cassette Transporter, Subfamily B / metabolism
ATP-Binding Cassette Sub-Family B Member 4
Animals
Bile Ducts* / injuries
Bile Ducts* / metabolism
Bile Ducts* / pathology
Cholangitis, Sclerosing* / genetics
Cholangitis, Sclerosing* / metabolism
Cholangitis, Sclerosing* / pathology
Disease Models, Animal
Gene Knockdown Techniques
Liver Cirrhosis* / genetics
Liver Cirrhosis* / metabolism
Liver Cirrhosis* / pathology
Mice, Knockout
Receptors, Neurokinin-1 / deficiency*
Receptors, Neurokinin-1 / metabolism

Substances

ATP Binding Cassette Transporter, Subfamily B
Receptors, Neurokinin-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding