Caspase-1-deficient mice are more resistant to severe sepsis

Abstract

The establishment of a local inflammatory response with production of cytokines/chemokines and the consequent neutrophil recruitment are critical to control an infection. In this context, our group had demonstrated an impairment of neutrophil migration toward the infectious focus in severe sepsis. The failure of neutro-phil migration is markedly associated with increased systemic cytokines levels and high mortality of the severe sepsis, either in experimental models or in patients. Recently, the participation of Toll-like receptors (TLRs) in the failure of neutrophil migration was described. Caspase-1 seems to be important in the activation of TLR signaling pathways. Moreover, it is also critical to the activation of inflammatory cytokines IL-1β, IL-18 and IL-33. The aim of the present study was to evaluate the participation of caspase-1 during severe sepsis. The caspase-1-deficient mice presented increased resistance to severe sepsis induced by CLP. However, IL-18 and ST2 (receptor of IL-33)-deficient mice did not present a reduction of mortality after sepsis. The treatment with antagonist of IL-1 receptor was also unable to modify the survival rate of wild-type mice that underwent severe sepsis. These data indicate that the reduction in levels of these cytokines is not critical for reduction of mortality observed in caspase-1-deficient mice. The reduction in mortality of caspase-1-deficient mice was associated with decreased systemic levels of TNFα and IL-6. Despite the unaltered local levels of cytokines and chemokines, caspase-1-deficient mice that underwent severe sepsis presented a marked increase in neutrophil migration to the peritoneal cavity, which was supported by an increased rolling and adhesion of leukocytes in these mice. As consequence, a reduced bacterial growth in peritoneal exudates and blood was observed in these animals, although neutrophils from caspase-1-deficient and wild-type mice presented similar killing and cellular viability. Thus, in the absence of caspase-1, neutrophil migration to the peritoneal cavity is increased and culminates in a reduction of mortality because of efficient control of the infection.