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Leishmaniasis is a neglected tropical disease affecting millions of individuals worldwide. P2X7 receptor has been linked to the elimination of  Leishmania amazonensis . Biological responses evoked by P2X7 receptor activation have been well-documented, including apoptosis, phagocytosis, cytokine release, such as IL-1β. It was demonstrated that NLRP3 inflammasome activation and IL-1β signaling participated in resistance against  L .  amazonensis . Furthermore, our group has shown that  L .  amazonensis  elimination through P2X7 receptor activation depended on leukotriene B 4  (LTB 4 ) production and release. Therefore, we investigated whether  L .  amazonensis  elimination by P2X7 receptor and LTB 4  involved NLRP3 inflammasome activation and IL-1β signaling. We showed that macrophages from NLRP3 -/- , ASC -/- , Casp-1/11 -/- , gp91 phox-/- ,  and IL-1R -/-  mice treated with ATP or LTB 4  did not decrease parasitic load as was observed in WT mice. When ASC -/-  macrophages were treated with exogenous IL-1β, parasite killing was noted, however, we did not see parasitic load reduction in IL-1R -/-  macrophages. Similarly, macrophages from P2X7 receptor-deficient mice treated with IL-1β also showed decreased parasitic load. In addition, when we infected Casp-11 -/-  macrophages, neither ATP nor LTB 4  were able to reduce parasitic load, and Casp-11 -/-  mice were more susceptible to  L .  amazonensis  infection than were WT mice. Furthermore, P2X7 -/-   L .  amazonensis- infected mice locally treated with exogenous LTB 4  showed resistance to infection, characterized by lower parasite load and smaller lesions compared to untreated P2X7 -/-  mice. A similar observation was noted when infected P2X7 -/-  mice were treated with IL-1β, i.e., lower parasite load and smaller lesions compared to P2X7 -/-  mice. These data suggested that  L .  amazonensis  elimination mediated by P2X7 receptor and LTB 4  was dependent on non-canonical NLRP3 inflammasome activation, ROS production, and IL-1β signaling.

Non-canonical NLRP3 inflammasome activation and IL-1β signaling are necessary to L. amazonensis control mediated by P2X7 receptor and leukotriene B4