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Inhibition of type I natural killer T cells by retinoids or following sulfatide‐mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice
Author(s) -
Maricic Igor,
Sheng Huiming,
Marrero Idania,
Seki Ekihiro,
Kisseleva Tatiana,
Chaturvedi Som,
Molle Natasha,
Mathews Stephanie A.,
Gao Bin,
Kumar Vipin
Publication year - 2015
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27632
Subject(s) - natural killer t cell , alcoholic liver disease , immunology , biology , chemistry , medicine , immune system , t cell , cirrhosis
Innate immune mechanisms leading to liver injury subsequent to chronic alcohol ingestion are poorly understood. Natural killer T (NKT) cells, enriched in the liver and comprised of at least two distinct subsets, type I and II, recognize different lipid antigens presented by CD1d molecules. We have investigated whether differential activation of NKT cell subsets orchestrates inflammatory events leading to alcoholic liver disease (ALD). We found that after chronic plus binge feeding of Lieber‐DeCarli liquid diet in male C57BL/6 mice, type I, but not type II, NKT cells are activated, leading to recruitment of inflammatory Gr‐1 high CD11b + cells into the liver. A central finding is that liver injury after alcohol feeding is dependent upon type I NKT cells. Thus, liver injury is significantly inhibited in Jα18 −/− mice deficient in type I NKT cells as well as after their inactivation by sulfatide‐mediated activation of type II NKT cells. Furthermore, we have identified a novel pathway involving all‐trans retinoic acid (ATRA) and its receptor (RARγ) signaling that inhibits type I NKT cells and, consequently, ALD. A semiquantitative polymerase chain reaction analysis of hepatic gene expression of some of the key proinflammatory molecules shared in human disease indicated that their up‐regulation in ALD is dependent upon type I NKT cells. Conclusions : Type I, but not type II, NKT cells become activated after alcohol feeding. Type I NKT cell‐induced inflammation and neutrophil recruitment results in liver tissue damage whereas type II NKT cells protect from injury in ALD. Inhibition of type I NKT cells by retinoids or by sulfatide prevents ALD. Given that the CD1d pathway is highly conserved between mice and humans, NKT cell subsets might be targeted for potential therapeutic intervention in ALD. (H epatology 2015;61:1357–1369)