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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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]
Total Authors: 7
Affiliation:
[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
Total Affiliations: 3
Document type: Journal article
Source: JOURNAL OF IMMUNOLOGY; v. 194, n. 9, p. 4507-4517, MAY 1 2015.
Web of Science Citations: 31
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-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)

FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 13/21295-9 - Role of canonical and non-canonical inflammasome in modulating the innate immune response during infection with Paracoccidioides brasiliensis
Grantee:Natália Ketelut Carneiro
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 12/14524-9 - Modulation of T lymphocytes differentiation in infections by Protozoa, Fungi and Bacteria
Grantee:João Santana da Silva
Support Opportunities: Research Projects - Thematic Grants