Invariant natural killer T-cell-deficient mice display increased CCl4-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 (CCl4). WT and iNKT cell-deficient (J alpha 18(-/-)) mice were challenged with a single dose of 2.4 g/kg CCl4 and both hepatic physiopathology and immune responses were studied. Plasma alanine and aspartate amino-transferase levels were significantly higher in J alpha 18 (/) mice than in WT mice two days after CCl4 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 Ja18(-/-) 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 CCl4 and limit neutrophil infiltration.