The ROS scavenger, NAC, regulates hepatic Vα14iNKT cells signaling during Fas mAb-dependent fulminant liver failure.
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.
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America.
Isaac
I
Downs
Jianfeng
J
Liu
Tak Yee
TY
Aw
Patrick A
PA
Adegboyega
Maureen N
MN
Ajuebor
D000111:Acetylcysteine / Q000494:pharmacology* / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000276:immunology; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D053222:Fas Ligand Protein / Q000276:immunology; D005434:Flow Cytometry; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D000911:Antibodies, Monoclonal; D053222:Fas Ligand Protein; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D007371:Interferon-gamma; D005978:Glutathione; D000111:Acetylcysteine