Deletion of Mcpip1 in Mcpip1^AlbKOmice recapitulates the phenotype of human primary biliary cholangitis

Abstract

Background & Aims: 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, alias Regnase1) 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. Methods: Genetic deletion of Zc3h12a was used to characterize the role of Mcpip1 in the pathogenesis of PBC. 6-52-week-old Mcpip1fl/fl and Mcpip1AlbKO mice were used for immunohistochemical, biochemical and molecular tests. Results: We found that Mcpip1 deficiency in the liver recapitulates most of the features of human PBC, in contrast to mice with Mcpip1 deficiency in myeloid cells (Mcpip1LysMKO mice), which present with robust myeloid cell-driven systemic inflammation. In Mcpip1AlbKO 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 Mcpip1AlbKO mice was robust in 6-week-old and 52-week-old mice, but milder in 12-24-week-old mice, suggesting early prenatal origin of the phenotype and age-dependent progression of the disease. Hepatic transcriptome analysis of 6-week-old and 24-week-old Mcpip1AlbKO mice showed 812 and 8 differentially expressed genes (DEGs), respectively, compared with age-matched control mice, and revealed a distinct set of genes compared to those previously associated with development of PBC. Conclusions: The phenotype of Mcpip1AlbKO mice recapitulates most of the features of human PBC, and demonstrates early prenatal origin and age-dependent progression of PBC. Therefore, Mcpip1AlbKO mice provide a unique model for the study of PBC.

When healing turns into killing – the pathophysiology of pancreatic and hepatic fibrosis

“…Monocyte chemoattractant protein-induced protein 1 (MCPIP1, also known as Regnase-1) controls (post)transcriptionally the activation of inflammatory cells, for example by reducing the life of cytokines secreted by these cells. A recent study by Kotlinowski et al has demonstrated that loss of Mcpip1 in the liver (Mcpip1 fl/fl Alb Cre mouse model) increases the extent of inflammation and liver fibrosis and may be important in the pathogenesis of primary biliary cholangitis (Kotlinowski et al, 2021).…”

“…A recent study by Kotlinowski et al. has demonstrated that loss of Mcpip1 in the liver (Mcpip1 fl/fl Alb Cre mouse model) increases the extent of inflammation and liver fibrosis and may be important in the pathogenesis of primary biliary cholangitis (Kotlinowski et al., 2021).…”

Role of Mcpip1 in obesity‐induced hepatic steatosis as determined by myeloid and liver‐specific conditional knockouts

“…Notably, our observations are in accordance with another study, demonstrating that the deletion of Mcpip1 in Mcpip1 fl/fl Alb Cre mice is asymptomatic, in terms of blood morphology, cytokines, and chemokines detected in plasma. Instead, it leads to a massive hyperplasia of cholangiocytes and the development of primary biliary cholangitis [23]. The important role of Mcpip1 in regulation of hepatic homeostasis was recently demonstrated by Sun and coworkers.…”

“…S3B-E). S4 right panel, asterisk) reflecting most of the features of human primary biliary cholangitis (PBC) (presented and discussed in details in [23]).…”

Hepatic MCPIP1 protein levels are reduced in NAFLD patients and are predominantly expressed in cholangiocytes and liver endothelium

“…Mcpip1 acts as an important regulator of liver homeostasis both in mice fed chow and mice fed a high-fat diet [8]. Additionally, its deletion in murine liver epithelial cells recapitulates the features of primary biliary cholangitis, which manifests as excessive proliferation of intrahepatic bile ducts, bile duct destruction, inflammatory infiltration and fibrosis [9]. Sun and coworkers described a protective role of Mcpip1 in liver recovery after ischemia/reperfusion injury.…”