Anti-endoglin monoclonal antibody TRC105 prevents the increase of liver inflammatory biomarkers in a mouse model of cholestasis.

Cholestatic liver diseases are characterized by impaired bile flow, leading to inflammation and progression to cirrhosis and liver failure. Endoglin (ENG), a TGF-β co-receptor, regulates SMAD-dependent signalling and endothelial function. Carotuximab (TRC105) is an anti-ENG monoclonal antibody that binds to ENG. We hypothesized that treatment with TRC105 could prevent the upregulation of inflammatory biomarkers reflecting the activation of liver sinusoidal endothelial cells (LSECs) and hepatic inflammation during the progression of intrahepatic cholestasis (IC) in vivo by modulating the ENG and SMAD signaling pathways. IC was induced in male C57BL/6J mice by feeding with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 4 weeks. 18 mice were divided into three groups: a control group (chow diet), an IC group (DDC diet), and a rescue group (DDC diet + TRC105). The rescue group received TRC105 (15 mg/kg) twice weekly throughout the 4 weeks. We observed an inflammation in LSECs and the liver in IC animals characterized by overexpression of p65 NF-κB, ICAM-1, VCAM-1, endothelin-1, Galectin-3, CD11b, Ccl2, Ly6c, Il-1β, and Tnf-α, together with reduced expression of ENG and p-eNOS. TRC105 treatment prevented the downregulation of ENG and p-eNOS, the overexpression of inflammatory biomarkers, and the imbalance of SMAD signalling. We demonstrate for the first time that TRC105 prevents the upregulation of inflammatory biomarkers reflecting LSECs activation and hepatic inflammation, modulates ENG expression, and prevents the imbalance of the SMADs signalling during IC. These findings position ENG as a promising pharmacological target for alleviating inflammation in cholestatic liver disease, thereby opening a new avenue for translational research.