IGFBP4 is a Metric for Primary Biliary Cholangitis and Attenuates Biliary Epithelial Cell Injury

Background and Aims: Immune-mediated bile duct injury is the primary histological feature of autoimmune cholestatic liver diseases. Macrophages, the most abundant immune cell population in the liver, have been postulated to play a critical role in biliary repair. However, it is unclear whether activated macrophages interact with injured biliary epithelial cells. Methods: We evaluated the expression of insulin-like growth factor-binding protein 4 (IGFBP4) in primary monocytes, MDMΦ, serum, and liver tissue sections from a total of 292 samples from PBC, PSC, and healthy controls using RNA-sequencing, ELISA, and immunohistochemistry analysis. The signal pathways involved in the effect of IGFBP4 in human intrahepatic biliary epithelial cells were examined by phospho-kinase arrays. Results: Herein we demonstrate a role for insulin-like growth factor binding protein 4 (IGFBP4) in the interaction of macrophages and biliary cells. Importantly, the serum levels of IGFBP4 are significantly increased in PBC and negatively correlate with bilirubin levels. Furthermore, immunohistochemistry revealed an increase in IGFBP4 positive cells located not only in the periductal area but also around the portal tract in the PBC liver. In vitro study indicated that IGFBP4 protected biliary cells from bile salt-induced cell injury and promoted biliary cell proliferation, which was associated with reduced expression of the bile acid receptor TGR5, bile acid efflux transporter SLCO3A1, and activation of the GSK-3β/β-catenin signalling pathway. Conclusions: These data highlight that IGFBP4 not only serves as a potential biomarker for PBC but also plays a protective role against bile duct injury.