Macrophage polarization is involved in liver fibrosis induced by β (1)-adrenoceptor autoantibody : β (1)-Adrenoceptor autoantibody and liver fibrosis

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.