Trypanosoma cruzi (T. cruzi) is an intracellular protozoan parasite and the etiological agent of Chagas disease, a chronic infectious illness that affects millions of people worldwide. Although the role of TLR and Nod1 in the control of T. cruzi infection is well-established, the involvement of inflammasomes remains to be elucidated. Herein, we demonstrate for the first time that T. cruzi infection induces IL-1β production in an NLRP3- and caspase-1-dependent manner. Cathepsin B appears to be required for NLRP3 activation in response to infection with T. cruzi, as pharmacological inhibition of cathepsin B abrogates IL-1β secretion. NLRP3−/− and caspase1−/− mice exhibited high numbers of T. cruzi parasites, with a magnitude of peak parasitemia comparable to MyD88−/− and iNOS−/− mice (which are susceptible models for T. cruzi infection), indicating the involvement of NLRP3 inflammasome in the control of the acute phase of T. cruzi infection. Although the inflammatory cytokines IL-6 and IFN-γ were found in spleen cells from NLRP3−/− and caspase1−/− mice infected with T. cruzi, these mice exhibited severe defects in nitric oxide (NO) production and an impairment in macrophage-mediated parasite killing. Interestingly, neutralization of IL-1β and IL-18, and IL-1R genetic deficiency demonstrate that these cytokines have a minor effect on NO secretion and the capacity of macrophages to control T. cruzi infection. In contrast, inhibition of caspase-1 with z-YVAD-fmk abrogated NO production by WT and MyD88−/− macrophages and rendered them as susceptible to T. cruzi infection as NLRP3−/− and caspase-1−/− macrophages. Taken together, our results demonstrate a role for the NLRP3 inflammasome in the control of T. cruzi infection and identify NLRP3-mediated, caspase-1-dependent and IL-1R-independent NO production as a novel effector mechanism for these innate receptors.
Inflammasomes are cytosolic innate receptors that are emerging as central effectors in the control of infections and inflammatory pathologies. NLRP3 is the most studied member of inflammasomes with established role in the control of bacterial and viral infections. This manuscript describes original studies on the involvement of NLRP3 inflammasome in the control of Trypanosoma cruzi, the etiological agent of Chagas disease, a chronic infectious illness that affects millions of people in the world. T. cruzi activates NLRP3 inflammasome by a mechanism involving cathepsin B. NLRP3−/− and caspase1−/− mice display high parasitemia during acute phase of T. cruzi infection, which could be explained by a severe defect in the production of nitric oxide (NO) and in the impairment of their macrophages to control intracellular parasites. Interestingly, inhibition of caspase-1, but not the neutralization of IL-1β and IL-18, the best-studied caspase-1 substrates, abrogated NO production by WT and MyD88−/− macrophages and rendered them as susceptible to T. cruzi infection as NLRP3−/− macrophages. Together, our results indicate a caspase-1-dependent and IL-1β and IL-18-independent pathway for NO production as a new effector mechanism played by NLRP3 to control T. cruzi infection.