Endogenous ROS Regulates Vα14iNKT Cells Signaling during Agonistic Fas mAb-dependent Fulminant Liver Failure (176.3)

Abstract

Abstract Current theories recognize uncontrolled systemic activation of the immune system as an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In the present study, we identify a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating signaling in IFN-γ-expressing Vα14iNKT cells in a pSTAT-1/T-bet dependent manner to promote the development of FLF. Specifically, we show that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished IFN-γ signaling and nitrosative stress in Vα14iNKT cells. Conversely, fortification of the antioxidant, GSH, in the liver due to Vα14iNKT cells deficiency, induces anti-inflammatory responses to prevent/limit the development of FLF and hepatic apoptosis in Jα18−/− mice through suppression of IFN-γ signaling and effector functions. This study provides critical new insights into how ROS regulates IFN-γ signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses.