NKT cells enhance C5a generation by CD11b+Gr-1+ peritoneal cells via IL-10 and IFN-gamma mediated cross-talk, thereby promoting sepsis in mice (45.9)

Abstract

Abstract Both NKT cells and complement protein C5a have been implicated in the pathogenesis of sepsis, but the issue of whether NKT cells regulate C5a generation during sepsis has been unclear. To investigate this issue, we examined immune responses in WT and NKT cell-deficient mice during cecal ligation and puncture (CLP)-induced sepsis. The levels of C5a, IFN-gamma, and IL-10 during sepsis were higher in the serum and peritoneal fluid of WT mice than in those of CD1d-/- mice. Furthermore, the mortality rate was lower in CD1d-/- mice than in WT mice. Adoptive transfer of liver mononuclear cells (LMCs) of WT mice increased mortality and C5a generation during sepsis in CD1d-/- mice, whereas transfer of IL-10- or IFN-gamma-deficient LMCs did not. In co-culture experiments, IL-10 and IFN-gamma produced by NKT cells enhanced C5a generation by CD11b+Gr-1+ peritoneal cells. Furthermore, treatment with anti-C5a antibody during sepsis decreased CD4+ T-cell apoptosis, serum D-dimer levels, and numbers of bacterial colony-forming units, but increased responsiveness against lipopolysaccharide in WT and WT-LMC-treated CD1d-/- mice, increasing survival rates. Taken together, these results suggest that CD1d-restricted NKT cells enhance C5a generation through IL-10- and IFN-gamma- mediated cross-talk with CD11b+Gr-1+ peritoneal cells, thereby aggravating CLP-induced sepsis.