Deletion of Mcpip1 in Mcpip1^fl/flAlb^Cre mice recapitulates the phenotype of human primary biliary cholangitis

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by progressive destruction of the intrahepatic bile ducts. The immunopathology of PBC involves excessive inflammation; therefore, negative regulators of inflammatory response, such as Monocyte Chemoattractant Protein-1-Induced Protein-1 (MCPIP1) may play important roles in the development of PBC. The aim of this work was to verify whether Mcpip1 expression protects against development of PBC. Genetic deletion of Zc3h12a was used to characterize the role of Mcpip1 in the pathogenesis of PBC in 6–52-week-old mice. We found that Mcpip1 deficiency in the liver (Mcpip1fl/flAlbCre) recapitulates most of the features of human PBC, in contrast to mice with Mcpip1 deficiency in myeloid cells (Mcpip1fl/flLysMCre mice), which present with robust myeloid cell-driven systemic inflammation. In Mcpip1fl/flAlbCre livers, intrahepatic bile ducts displayed proliferative changes with inflammatory infiltration, bile duct destruction, and fibrosis leading to cholestasis. In plasma, increased concentrations of IgG, IgM, and AMA autoantibodies (anti-PDC-E2) were detected. Interestingly, the phenotype of Mcpip1fl/flAlbCre mice was robust in 6-week-old, but milder in 12–24-week-old mice. Hepatic transcriptome analysis of 6-week-old and 24-week-old Mcpip1fl/flAlbCre mice showed 812 and 8 differentially expressed genes, respectively, compared with age-matched control mice, and revealed a distinct set of genes compared to those previously associated with development of PBC. In conclusion, Mcpip1fl/flAlbCre mice display early postnatal phenotype that recapitulates most of the features of human PBC.