Invariant natural killer T‐cell‐deficient mice display increased CCl 4 ‐induced hepatitis associated with CXCL1 over‐expression and neutrophil infiltration

Invariant natural killer T (iNKT) cells are involved in the intrahepatic immune response and in hepatitis. In particular, iNKT lymphocytes are responsible for hepatocyte death in concanavalin A‐induced hepatitis in mice. We examined the role of iNKT cells in acute hepatitis induced by a hepatotoxic agent, carbon tetrachloride (CCl 4 ). WT and iNKT cell‐deficient (Jα18 −/− ) mice were challenged with a single dose of 2.4 g/kg CCl 4 and both hepatic physiopathology and immune responses were studied. Plasma alanine and aspartate amino‐transferase levels were significantly higher in Jα18 −/− mice than in WT mice two days after CCl 4 administration. Chemokine CXCL1/keratinocyte‐derived chemokine (KC) and MMP‐8 were significantly higher in iNKT cell‐deficient mice than in control mice. The more severe liver injury in Jα18 −/− mice was associated with greater leukocyte infiltrate, which was enriched in neutrophils (CD11b + CD11c − Gr‐1 + cells), in agreement with CXCL1/KC and MMP‐8 levels. Complementary experiments with NK‐depleted animals indicate a minor role for NK cells in the liver damage found in iNKT‐deficient mice. Thus, unlike for ConA‐induced hepatitis, we report that iNKT cells protect the liver against acute hepatitis induced by CCl 4 and limit neutrophil infiltration.