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

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]

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

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF IMMUNOLOGY; v. 194, n. 9, p. 4507-4517, MAY 1 2015.
• Citações Web of Science: 31

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: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• 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
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 12/14524-9 - Modulação da diferenciação de linfócitos T em infecções por protozoários, fungos e bactérias
• Beneficiário: João Santana da Silva
• Modalidade de apoio: Auxílio à Pesquisa - Temático