title: IL-18 triggered by the Nlrp3 inflammasome induces host innate resistance in a pulmonary model of fungal infection.
abstract: Pathogens are sensed by innate immune receptors that initiate an efficient adaptive immune response upon activation. The elements of the innate immune recognition process for Paracoccidioides brasiliensis include TLR-2, TLR-4, and dectin-1. However, there are additional receptors necessary for the host immune responses to P. brasiliensis. The nucleotide-binding oligomerization domain-like receptor (NLRs), which activate inflammasomes, are candidate receptors that deserve renewed investigation. After pathogen infection, the NLRs form large signaling platforms called inflammasomes, which lead to caspase-1 activation and maturation of proinflammatory cytokines (IL-18 and IL-1β). In this study, we showed that NLR family pyrin domain-containing 3 (Nlrp3) is required to induce caspase-1 activation and further secretion of IL-1β and IL-18 by P. brasiliensis-infected macrophages. Additionally, potassium efflux and lysosomal acidification induced by the fungus were important steps in the caspase-1 activation mechanism. Notably, Nlrp3 and caspase-1 knockout mice were more susceptible to infection than were the wild-type animals, suggesting that the Nlrp3-dependent inflammasomes contribute to host protection against P. brasiliensis. This protective effect occurred owing to the inflammatory response mediated by IL-18, as shown by an augmented fungus burden in IL-18 knockout mice. Taken together, our results show that the Nlrp3 inflammasome is essential for resistance against P. brasiliensis because it orchestrates robust caspase-1 activation and triggers an IL-18-dependent proinflammatory response.
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil;
authors.forename: Natália
authors.initials: N
authors.lastname: Ketelut-Carneiro
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil;
authors.forename: Grace Kelly
authors.initials: GK
authors.lastname: Silva
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil;
authors.forename: Fernanda Agostini
authors.initials: FA
authors.lastname: Rocha
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil;
authors.forename: Cristiane Maria
authors.initials: CM
authors.lastname: Milanezi
authors.affiliation: Department of Pathology, University of Brasília, 70910-900 Brasília, Federal District, Brazil; and.
authors.forename: Florêncio Figueiredo
authors.initials: FF
authors.lastname: Cavalcanti-Neto
authors.affiliation: Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil.
authors.forename: Dario Simões
authors.initials: DS
authors.lastname: Zamboni
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil; jsdsilva@fmrp.usp.br.
authors.forename: João Santana
authors.initials: JS
authors.lastname: Silva
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D006099:Granuloma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010228:Paracoccidioides / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020170:Caspase 1