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Small heterodimer partner deficiency exacerbates binge drinking?induced liver injury via modulation of natural killer T cell and neutrophil infiltration.

ABSTRACT: 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?? 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.

SUBMITTER: Go MJ

PROVIDER: S-EPMC5865959 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Small heterodimer partner deficiency exacerbates binge drinking‑induced liver injury via modulation of natural killer T cell and neutrophil infiltration.

Go Min-Jeong MJ Noh Jung-Ran JR Hwang Jung Hwan JH Kim Kyoung-Shim KS Choi Dong-Hee DH Lee Jong-Soo JS Kim Yong-Hoon YH Lee Chul-Ho CH

Molecular medicine reports 20180126 4

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) ...[more]

PMID: 29393499

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Project description:Background and purposeThe immune system plays an important role in driving the acute inflammatory response following myocardial ischaemia/reperfusion injury (MIRI). IL-21 is a pleiotropic cytokine with multiple immunomodulatory effects, but its role in MIRI is not known.Experimental approachMyocardial injury, neutrophil infiltration and the expression of neutrophil chemokines KC (CXCL1) and MIP-2 (CXCL2) were studied in a mouse model of MIRI. Effects of IL-21 on the expression of KC and MIP-2 in neonatal mouse cardiomyocytes (CMs) and cardiac fibroblasts (CFs) were determined by real-time PCR and ELISA. The signalling mechanisms underlying these effects were explored by western blot analysis.Key resultsIL-21 was elevated within the acute phase of murine MIRI. Neutralization of IL-21 attenuated myocardial injury, as illustrated by reduced infarct size, decreased cardiac troponin T levels and improved cardiac function, whereas exogenous IL-21 administration exerted opposite effects. IL-21 increased the infiltration of neutrophils and increased the expression of KC and MIP-2 in myocardial tissue following MIRI. Moreover, neutrophil depletion attenuated the IL-21-induced myocardial injury. Mechanistically, IL-21 increased the production of KC and MIP-2 in neonatal CMs and CFs, and enhanced neutrophil migration, as revealed by the migration assay. Furthermore, we demonstrated that this IL-21-mediated increase in chemokine expression involved the activation of Akt/NF-κB signalling in CMs and p38 MAPK/NF-κB signalling in CFs.Conclusions and implicationsOur data provide novel evidence that IL-21 plays a pathogenic role in MIRI, most likely by promoting cardiac neutrophil infiltration. Therefore, targeting IL-21 may have therapeutic potential as a treatment for MIRI.Linked articlesThis article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Dataset Information

Small heterodimer partner deficiency exacerbates binge drinking?induced liver injury via modulation of natural killer T cell and neutrophil infiltration.

Publications

Small heterodimer partner deficiency exacerbates binge drinking‑induced liver injury via modulation of natural killer T cell and neutrophil infiltration.

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