Macrophage polarization is involved in liver fibrosis induced by β ₁-adrenoceptor autoantibody

Accumulating evidence suggests that liver injury can be induced by the over-expression of β ₁-adrenergic receptors (β ₁-ARs). High titers of autoantibodies specific to β ₁-adrenergic receptors (β ₁-AA) are detected in the sera of heart failure patients, potentially playing agonist-like roles. However, the role of β ₁-AA in liver function has not been characterized. In this study, we collect the sera of primary biliary cholangitis (PBC) patients, a condition which easily develops into liver fibrosis, and analyze the relationship between PBC and β ₁-AA. A passive immunization model is established to assess the effect of β ₁-AA on the liver. Subsequently, the effect of β ₁-AA on macrophages is investigated in vitro. Results show that PBC patients have a high titer and ratio of β ₁-AA, compared to controls. Liver injury and fibrosis are induced by β ₁-AA. In vitro experiments with ROS probe demonstrate that β ₁-AA induces macrophages to produce ROS and secrete TNFα. These effects can be partially reversed by metoprolol, a blocker for β ₁-AR. Results from the transwell and phagocytosis assays show that β ₁-AA promotes macrophage migration and phagocytosis. FCM tests suggest that β ₁-AA induces the alteration of M1 rather than M2 markers in macrophages. Finally, the Annexin V/PI assay indicates that macrophage culture supernatants stimulated by β ₁-AA cause hepatocyte apoptosis. Overall, these results suggest that β ₁-AA is involved in PBC. The β ₁-AA-induced activation, phagocytosis and phenotypic modification of macrophages may play an important role in the development of hepatic fibrosis and injury.