Onion-skin type of periductular sclerosis in mice with genetic deletion of biliary kindlin-2 as tight junction stabilizer: a pilot experiment indicating a primary sclerosing cholangitis (PSC) phenotype

Abstract

Aim: Primary sclerosing cholangitis (PSC) and ulcerative colitis are often associated. In ulcerative colitis, a tight junction defect can be detected, resulting in impaired secretion of hydrophobic phosphatidylcholine to the intestinal mucus. This defect causes a vulnerable mucus shield, allowing the microbiota to attack and leading to mucosal inflammation. A similar pathomechanism may be present in PSC.

Methods: To study biliary deletion of tight junctions, mice carrying a Cre/loxP system sensitive to tamoxifen were used to delete kindlin-2, a tight junction adapter protein. The Cre-preceded promoter was derived from hepatocyte nuclear factor-1β (Hnf1β), which is specific for biliary and pancreatic epithelium operative in embryonic life until adolescence. Cre-negative kindlin-2^flox/flox mice treated with tamoxifen served as controls.

Results: After tamoxifen induction, alterations in the biliary epithelium were detectable. As a hallmark feature of PSC, an onion-skin type of fibrosis around the bile ducts was present. However, levels of alkaline phosphatase, bilirubin, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in the serum were not yet elevated in these young mice.

Conclusion: Genetic deletion of cholangiocyte kindlin-2 impairs tight junctions, revealing a PSC-like phenotype. This supports the hypothesis that an impaired phosphatidylcholine content of biliary mucus allows luminal bile acids to attack the biliary epithelium, leading to cholangitis.

Keywords

Primary sclerosing cholangitis (PSC) / tight junctions / kindlin-2 / Fermt2 / animal model / phosphatidylcholine

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