Pathogenesis of Hepatic Deposited IgG-induced Liver Inflammation in SLE

Abstract

Abstract Hepatic disorders are frequent in patients with systemic lupus erythematosus ( SLE), yet the etiology and pathogenesis of liver injury in SLE remain unclear. We used lupus-prone mice and established an animal model of intrahepatic deposited lupus IgG to investigate the pathogenesis of liver damage in SLE. We found that liver damage spontaneously developed in lupus-prone mice and that there were a large number of inflammatory cell infiltrates around the portal areas of the liver, apoptosis of hepatocytes, and IgG deposition in the liver. Liver inflammation developed in mice with intrahepatic injection of immune complexes (ICs) from SLE patients. We found that ICs stimulated Kupffer cells (KCs) to secrete TNF-α and mediated hepatic apoptosis. Moreover, IL-12 secreted by KCs induced the accumulation and activation of natural killer cells (NKs) in the liver. Further, IFN-γ produced by activated NKs directly mediated liver damage and also enhanced the TNF-α-mediated apoptotic pathway. The depletion of KCs and NKs abolished apoptosis induced by ICs in vivo, suggesting that KCs and NKs have a synergic effect on liver injury. Lupus IgG induced Syk activation, and inhibitor of sky suppressed skin inflammation triggered by lupus IgG. Taken together, our findings confirmed that the hepatic disease was mediated by SLE, which may provide insight into the cellular and molecular mechanisms of lupus hepatitis; further, our results may aid in future investigations of potential therapeutic strategies for the treatment and control of lupus-mediated injury in disease settings.