Multiple cell-type interactions drive invariant NKT cell hepatitis.

Abstract

Background: α-Galactosylceramide (α-Galcer), a specific ligand for invariant natural killer T (NKT) cell activation, has been actively investigated in clinical trials such as antitumor therapy; however, treatment with α-Galcer is well known to induce acute hepatitis due to enriched NKT cells in the liver. The molecular mechanisms underlying NKT-mediated hepatitis still remain obscure. The object of this study was to investigate whether and how myeloid cells affect NKT-mediated hepatitis.

Methods: α-Galcer-induced NKT hepatitis was used in this study. microRNA-223 (miR-223) and neutrophil cytosolic factor 1 (Ncf1)-deficent mice were generated and subjected to α-Galcer-induced NKT hepatitis.

Results: In this study, we demonstrated that α-Galcer-induced NKT cell activation resulted in neutrophil and monocyte-derived macrophage accumulation in the liver. Importantly, serum levels of several hepatic myeloid cell infiltration-related cytokines and chemokines were significantly elevated after α-Galcer administration. Among these myeloid cells, blockade of neutrophil or macrophage migration through using different inhibitors of (C-X-C Motif) receptor 2, (C-C motif) receptor 2, and (C-C motif) receptor 5 signaling ameliorated α-Galcer-induced liver injury, mainly due to the decrease of reactive oxygen species production and inflammation. Depletion of neutrophils reduced α-Galcer-induced liver injury and hepatitis. Interestingly, genetic deletion of neutrophil-specific miR-223 markedly enhanced while Ncf1 deficiency significantly ameliorated liver inflammation and oxidative damage caused by α-Galcer.

Conclusions: Neutrophil and macrophage infiltration through multiple inflammatory mediators is required for NKT cell activation-induced hepatitis, which sheds light on the myeloid cell infiltration-related molecular mechanisms of NKT cell-mediated liver injury. Our study may provide a novel therapeutical strategy for the treatment of NKT cell hepatitis.