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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 J?18-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.

SUBMITTER: Mathews S

PROVIDER: S-EPMC4786627 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration.

Mathews Stephanie S Feng Dechun D Maricic Igor I Ju Cynthia C Kumar Vipin V Gao Bin B

Cellular & molecular immunology 20150209 2

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-defi ...[more]

PMID: 25661730

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Project description:Binge drinking among alcohol consumers is a common occurrence, and may result in the development of numerous diseases, including liver disorders. It has previously been reported that natural killer T (NKT) cells induce alcohol‑associated liver injury by promoting neutrophil infiltration. In the present study, the role of the orphan nuclear receptor small heterodimer partner (SHP), which is encoded by the NR0B2 gene, in acute binge drinking‑induced liver injury was investigated. SHP‑knockout (KO) and wild‑type (WT) control mice were intragastrically administered single doses of alcohol. The plasma concentrations of alanine aminotransferase and aspartate aminotransferase in SHP‑KO mice following alcohol treatment were significantly increased compared with WT mice. However, results of oil red O staining and 2',7'‑dichlorodihydrofluorescein diacetate staining indicated that levels of acute binge drinking‑associated hepatic lipid accumulation and oxidative stress were not significantly different between WT and SHP‑KO alcohol‑treated mice. Notably, tumor necrosis factor‑α mRNA expression in the liver of SHP‑KO mice was significantly increased following alcohol administration, compared with WT mice. Furthermore, the mRNA expression levels of C‑C motif chemokine ligand 2, C‑X‑C motif chemokine ligand 2 and interleukin‑4, which are all potent chemoattractants of NKT cells, as well as neutrophil expression levels, were significantly increased in the livers of SHP‑KO mice compared with WT mice following alcohol administration, as determined by reverse transcription‑quantitative polymerase chain reaction and flow cytometry. Enhanced infiltration of NKT cells, determined by flow cytometry, was also demonstrated in the livers of SHP‑KO mice following alcohol administration, compared with WT mice. The results of the present study indicate that SHP may be involved in liver‑associated protective mechanisms, with regards to the attenuation of damage caused by acute binge drinking, via regulation of NKT cell and neutrophil migration to the liver. The modulation of SHP may be a novel therapeutic strategy for the treatment of acute binge drinking‑induced liver injury.

Project description:BACKGROUND & AIMS:Neutrophil extracellular traps (NETs) are an important strategy utilized by neutrophils to immobilize and kill invading microorganisms. Herein, we studied NET formation and the process of neutrophil cell death (NETosis), as well as the clearance of NETs by macrophages (M?) (efferocytosis) in acute sepsis following binge drinking. METHODS:Healthy volunteers consumed 2?ml of vodka/kg body weight, before blood endotoxin and 16?s rDNA were measured. Peripheral neutrophils were isolated and exposed to alcohol followed by phorbol 12-myristate 13-acetate (PMA) stimulation. Mice were treated with three alcohol binges and intraperitoneal lipopolysaccharide (LPS) to assess the dynamics of NET formation and efferocytosis. In vivo, anti-Ly6G antibody (IA8) was used for neutrophil depletion. RESULTS:Inducers of NETs (endotoxin and bacterial DNA) significantly increased in the circulation after binge alcohol drinking in humans. Ex vivo, alcohol alone increased NET formation, but upon PMA stimulation alcohol attenuated NET formation. Binge alcohol in mice resulted in a biphasic response to LPS. Initially, binge alcohol reduced LPS-induced NET formation and resulted in a diffuse distribution of neutrophils in the liver compared to alcohol-naïve mice. Moreover, indicators of NET formation including citrullinated histone H3, neutrophil elastase, and neutrophil myeloperoxidase were decreased at an early time point after LPS challenge in mice receiving binge alcohol, suggesting decreased NET formation. However, in the efferocytosis phase (15?h after LPS) citrullinated histone-H3 was increased in the liver in alcohol binge mice, suggesting decreased clearance of NETs. In vitro alcohol treatment reduced efferocytosis and phagocytosis of NETotic neutrophils and promoted expression of CD206 on M?. Finally, depletion of neutrophils prior to binge alcohol ameliorated LPS-induced systemic inflammation and liver injury in mice. CONCLUSIONS:Dysfunctional NETosis and efferocytosis following binge drinking exacerbate liver injury associated with sepsis. LAY SUMMARY:Disease severity in alcoholic liver disease (ALD) is associated with a significant presence of neutrophils (a type of immune cell) in the liver. It remains unknown how alcohol affects the capacity of neutrophils to control infection, a major hallmark of ALD. We found that binge alcohol drinking impaired important strategies used by neutrophils to contain and resolve infection, resulting in increased liver injury during ALD.

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Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration.

Publications

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration.

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