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

• Published in: PLoS pathogens Vol. 15; no. 6; p. e1007887
• Main Authors: Chaves, Mariana M., Sinflorio, Debora A., Thorstenberg, Maria Luiza, Martins, Monique Daiane Andrade, Moreira-Souza, Aline Cristina Abreu, Rangel, Thuany Prado, Silva, Claudia L. M., Bellio, Maria, Canetti, Claudio, Coutinho-Silva, Robson
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2019; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; ATP; Biology and Life Sciences; Biophysics; Cell activation; Disease control; IL-1β; Immune system; Infections; Inflammasomes; Inflammasomes - genetics; Inflammasomes - immunology; Interleukin 1 receptors; Interleukin-1beta - genetics; Interleukin-1beta - immunology; Leishmania - immunology; Leishmaniasis; Leishmaniasis - genetics; Leishmaniasis - immunology; Leishmaniasis - pathology; Lesions; Leukotriene B4 - genetics; Leukotriene B4 - immunology; Leukotriene B4 receptors; Macrophages; Macrophages - immunology; Macrophages - parasitology; Medicine and Health Sciences; Mice; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - immunology; Parasites; Parasitic diseases; Participation; Phagocytosis; Receptor mechanisms; Receptors, Purinergic P2X7 - genetics; Receptors, Purinergic P2X7 - immunology; Signal Transduction - genetics; Signal Transduction - immunology; Signaling; Vector-borne diseases; Brazil; Rio de Janeiro Brazil
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007887

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 B4 (LTB4) production and release. Therefore, we investigated whether L. amazonensis elimination by P2X7 receptor and LTB4 involved NLRP3 inflammasome activation and IL-1β signaling. We showed that macrophages from NLRP3-/-, ASC-/-, Casp-1/11-/-, gp91phox-/- , and IL-1R-/- mice treated with ATP or LTB4 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 LTB4 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 LTB4 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 LTB4 was dependent on non-canonical NLRP3 inflammasome activation, ROS production, and IL-1β signaling.