title: Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration.
abstract: Neutrophil infiltration is a hallmark of alcoholic steatohepatitis; however, the underlying mechanisms remain unclear. We previously reported that chronic-plus-binge ethanol feeding synergistically induces hepatic recruitment of neutrophils, which contributes to liver injury. In this paper, we investigated the roles of invariant natural killer T (iNKT) cells in chronic-plus-binge ethanol feeding-induced hepatic neutrophil infiltration and liver injury. Wild-type and two strains of iNKT cell-deficient mice (CD1d- and Jα18-deficient mice) were subjected to chronic-plus-binge ethanol feeding. Liver injury and inflammation were examined. Chronic-plus-binge ethanol feeding synergistically increased the number of hepatic iNKT cells and induced their activation, compared with chronic feeding or binge alone. iNKT cell-deficient mice were protected from chronic-plus-binge ethanol-induced hepatic neutrophil infiltration and liver injury. Moreover, chronic-plus-binge ethanol feeding markedly upregulated the hepatic expression of several genes associated with inflammation and neutrophil recruitment in wild-type mice, but induction of these genes was abrogated in iNKT cell-deficient mice. Importantly, several cytokines and chemokines (e.g., MIP-2, MIP-1, IL-4, IL-6 and osteopontin) involved in neutrophil infiltration were upregulated in hepatic NKT cells isolated from chronic-plus-binge ethanol-fed mice compared to pair-fed mice. Finally, treatment with CD1d blocking antibody, which blocks iNKT cell activation, partially prevented chronic-plus-binge ethanol-induced liver injury and inflammation. Chronic-plus-binge ethanol feeding activates hepatic iNKT cells, which play a critical role in the development of early alcoholic liver injury, in part by releasing mediators that recruit neutrophils to the liver, and thus, iNKT cells represent a potential therapeutic target for the treatment of alcoholic liver disease.
authors: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors: Stephanie
authors: S
authors: Mathews
authors: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors: Dechun
authors: D
authors: Feng
authors: Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, CA, USA.
authors: Igor
authors: I
authors: Maricic
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences and Integrated Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors: Cynthia
authors: C
authors: Ju
authors: Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, CA, USA.
authors: Vipin
authors: V
authors: Kumar
authors: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors: Bin
authors: B
authors: Gao
mesh_terms: D000818:Animals; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000431:Ethanol / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology
chemical_list: D000431:Ethanol