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J Immunol. 2018 Nov 15;201(10):3017-3035. doi: 10.4049/jimmunol.1800614. Epub 2018 Oct 15.

Differential Activation of Hepatic Invariant NKT Cell Subsets Plays a Key Role in Progression of Nonalcoholic Steatohepatitis.

Author information

1
Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093.
2
Department of Pediatrics, University of California San Diego, La Jolla, CA 92093.
3
Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093.
4
Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA 92093; and.
5
Nonalcoholic Fatty Liver Disease Research Center, University of California San Diego, La Jolla, CA 92093.
6
Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093; vckumar@ucsd.edu.

Abstract

Innate immune mechanisms play an important role in inflammatory chronic liver diseases. In this study, we investigated the role of type I or invariant NKT (iNKT) cell subsets in the progression of nonalcoholic steatohepatitis (NASH). We used α-galactosylceramide/CD1d tetramers and clonotypic mAb together with intracytoplasmic cytokine staining to analyze iNKT cells in choline-deficient l-amino acid-defined (CDAA)-induced murine NASH model and in human PBMCs, respectively. Cytokine secretion of hepatic iNKT cells in CDAA-fed C57BL/6 mice altered from predominantly IL-17+ to IFN-γ+ and IL-4+ during NASH progression along with the downmodulation of TCR and NK1.1 expression. Importantly, steatosis, steatohepatitis, and fibrosis were dependent upon the presence of iNKT cells. Hepatic stellate cell activation and infiltration of neutrophils, Kupffer cells, and CD8+ T cells as well as expression of key proinflammatory and fibrogenic genes were significantly blunted in Jα18-/- mice and in C57BL/6 mice treated with an iNKT-inhibitory RAR-γ agonist. Gut microbial diversity was significantly impacted in Jα18-/- and in CDAA diet-fed mice. An increased frequency of CXCR3+IFN-γ+T-bet+ and IL-17A+ iNKT cells was found in PBMC from NASH patients in comparison with nonalcoholic fatty liver patients or healthy controls. Consistent with their in vivo activation, iNKT cells from NASH patients remained hyporesponsive to ex-vivo stimulation with α-galactosylceramide. Accumulation of plasmacytoid dendritic cells in both mice and NASH patients suggest their role in activation of iNKT cells. In summary, our findings indicate that the differential activation of iNKT cells play a key role in mediating diet-induced hepatic steatosis and fibrosis in mice and its potential involvement in NASH progression in humans.

PMID:
30322964
PMCID:
PMC6219905
[Available on 2019-11-15]
DOI:
10.4049/jimmunol.1800614

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