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Updated: May 21, 2026
Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
The ROS scavenger, NAC, regulates hepatic Vα14iNKT cells signaling during Fas mAb-dependent fulminant liver failure
Isaac Downs1, Jianfeng Liu, Tak Yee Aw
1Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America.
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.
Insights
N-acetylcysteine (NAC) prevents acute liver failure by suppressing immune cell activation and inflammation. This antioxidant therapy offers a novel approach to managing liver injury by targeting reactive oxygen species (ROS) and Th1 signaling.
Area of Science:
- Immunology
- Hepatology
- Oxidative Stress Biology
Background:
- Acute fulminant liver failure (FLF) can result from uncontrolled immune system activation.
- Fas agonistic monoclonal antibody (mAb) treatment in mice triggers FLF via systemic immune activation.
Purpose of the Study:
- To investigate the protective effects of N-acetylcysteine (NAC) against Fas mAb-induced FLF in mice.
- To elucidate the mechanisms by which NAC and glutathione (GSH) modulate immune responses and liver pathology.
Main Methods:
- Treatment of mice with Fas mAb and N-acetylcysteine (NAC).
- Assessment of liver injury markers, including apoptosis and nitrotyrosine formation.
- Analysis of Vα14iNKT cell activation, IFN-γ signaling, and Th1 responses.
- Studies in Jα18(-/-) mice with Vα14iNKT cell deficiency.
Main Results:
- NAC treatment significantly abolished Fas mAb-induced FLF.
- NAC suppressed Vα14iNKT cell activation, IFN-γ signaling, apoptosis, and nitrotyrosine formation.
- Vα14iNKT cell deficiency led to GSH enrichment in the liver, inducing an anti-inflammatory response that inhibited apoptosis and effector functions.
Conclusions:
- Endogenous reactive oxygen species (ROS) play a pro-inflammatory and pro-apoptotic role by stimulating Th1 signaling in Vα14iNKT cells, promoting FLF.
- NAC, as a ROS scavenger, regulates Th1 signaling in intrahepatic Vα14iNKT cells, offering a therapeutic strategy for FLF.
