Abstract
Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished Fas mAb-induced FLF through suppression of Vα14iNKT cell activation, IFN-γ signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to Vα14iNKT cells deficiency, induced an anti-inflammatory response in the liver of Jα18−/− mice that inhibited apoptosis, nitrotyrosine formation, IFN-γ signaling and effector functions. In summary, we propose a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating Th1 signaling in Vα14iNKT cells to promote the development of FLF. Therefore, our study provides critical new insights into how NAC, a ROS scavenger, regulates Th1 signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses.
Highlights
Fas (CD95), a 45-kDa type I membrane protein, is expressed on numerous cell types including lymphoid cells (NK cells, T cells, Va14iNKT cells) [1,2,3,4,5] and non-lymphoid cells such as hepatocytes [1,2,3]
We recently demonstrated that Ja182/2 mice, which are deficient in Va14iNKT cells, are highly resistant to agonistic Fas mAb-induced acute fulminant liver failure (FLF) [5]
We provide new data demonstrating that resistance of Ja182/2 mice to FLF was associated with a dramatic decrease in hepatic apoptosis as revealed by reduced expression of active caspase 3 and TUNEL staining in the liver (Figure 1E and 1F)
Summary
Fas (CD95), a 45-kDa type I membrane protein, is expressed on numerous cell types including lymphoid cells (NK cells, T cells, Va14iNKT cells) [1,2,3,4,5] and non-lymphoid cells such as hepatocytes [1,2,3]. Fas-associated protein with death domain and procaspase 8 are recruited to initiate caspase 8 proteolytic autocleavage, leading to activation of the effector caspase, caspase 3, and cell death [1,2]. The fundamental concept that the liver is highly sensitive to Fasmediated apoptosis was first demonstrated in 1993 by Ogasawara and colleagues [1] where systemic administration of agonistic Fas mAb (Jo2) caused acute FLF, and mice mortality within a few hours due to diffuse hemorrhage and massive apoptosis of hepatocytes [1]. Fas activation is widely associated with caspase-mediated cell death, growing evidence have increasingly highlighted an important pro-inflammatory role for Fas in promoting NF-kB/AP-1 activation [6,7,8], chemokine/cytokine production [6,7,9] and leukocyte infiltration [6,7,9] in tissue sites
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