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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

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Autor(es):
Ketelut-Carneiro, Natalia [1] ; Silva, Grace Kelly [1] ; Rocha, Fernanda Agostini [1] ; Milanezi, Cristiane Maria [1] ; Cavalcanti-Neto, Florencio Figueiredo [2] ; Zamboni, Dario Simoes [3] ; Silva, Joao Santana [1]
Número total de Autores: 7
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Ribeira Preto Med Sch, Dept Biochem & Immunol, BR-14049900 Sao Paulo - Brazil
[2] Univ Brasilia, Dept Pathol, BR-70910900 Brasilia, DF - Brazil
[3] Univ Sao Paulo, Ribeira Preto Med Sch, Dept Cell Biol, BR-14049900 Sao Paulo - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: JOURNAL OF IMMUNOLOGY; v. 194, n. 9, p. 4507-4517, MAY 1 2015.
Citações Web of Science: 32
Resumo

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-1 beta). 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-1 beta 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. (AU)

Processo FAPESP: 13/21295-9 - Papel do inflamassoma canônico e não canônico na modulação da resposta imune inata durante a infecção por Paracoccidioides brasiliensis
Beneficiário:Natália Ketelut Carneiro
Linha de fomento: Bolsas no Brasil - Doutorado Direto
Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
Beneficiário:Fernando de Queiroz Cunha
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 12/14524-9 - Modulação da diferenciação de linfócitos T em infecções por protozoários, fungos e bactérias
Beneficiário:João Santana da Silva
Linha de fomento: Auxílio à Pesquisa - Temático