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: Natália Ketelut-Carneiro, Grace Kelly Silva, Fernanda Agostini Rocha, Cristiane Maria Milanezi, Florêncio Figueiredo Cavalcanti-Neto, Dario Simões Zamboni, João Santana Silva
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 9 Pg. 4507-17 (May 01 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25825440 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Carrier Proteins
• Inflammasomes
• Interleukin-18
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Caspase 1

Topics

• Animals
• Carrier Proteins (metabolism)
• Caspase 1 (metabolism)
• Disease Models, Animal
• Disease Resistance (genetics, immunology)
• Granuloma (genetics, immunology, metabolism)
• Immunity, Innate
• Inflammasomes (genetics, metabolism)
• Interleukin-18 (genetics, metabolism)
• Interleukin-1beta (biosynthesis)
• Lung Diseases, Fungal (immunology, metabolism, mortality)
• Macrophages (immunology, metabolism, microbiology)
• Male
• Mice
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein
• Paracoccidioides (immunology)