Program in Innate Immunity, Department of Medicine
Amino Acids, Peptides, and Proteins | Bacterial Infections and Mycoses | Fungi | Immunology and Infectious Disease
The recognition of fungi by intracellular NOD-like receptors (NLRs) induces inflammasome assembly and activation. Although the NLRC4 inflammasome has been extensively studied in bacterial infections, its role during fungal infections is unclear. Paracoccidioidomycosis (PCM) is a pathogenic fungal disease caused by Paracoccidioides brasiliensis. Here, we show that NLRC4 confers susceptibility to experimental PCM by regulating NLRP3-dependent cytokine production and thus protective effector mechanisms. Early after infection, NLRC4 suppresses prostaglandin E2 production, and consequently reduces interleukin (IL)-1beta release by macrophages and dendritic cells in the lungs. IL-1beta is required to control fungal replication via induction of the nitric oxide synthase 2 (NOS2) pathway. At a later stage of the disease, NLRC4 impacts IL-18 release, dampening robust CD8(+)IFN-gamma(+) T cell responses and enhancing mortality of mice. These findings demonstrate that NLRC4 promotes disease by regulating the production of inflammatory cytokines and cellular responses that depend on the NLRP3 inflammasome activity.
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Copyright 2021 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI of Published Version
Souza COS, Ketelut-Carneiro N, Milanezi CM, Faccioli LH, Gardinassi LG, Silva JS. NLRC4 inhibits NLRP3 inflammasome and abrogates effective antifungal CD8+ T cell responses. iScience. 2021 May 18;24(6):102548. doi: 10.1016/j.isci.2021.102548. PMID: 34142053; PMCID: PMC8184506. Link to article on publisher's site
Souza CO, Ketelut-Carneiro N, Milanezi CM, Faccioli LH, Gardinassi LG, Silva JS. (2021). NLRC4 inhibits NLRP3 inflammasome and abrogates effective antifungal CD8(+) T cell responses. Open Access Publications by UMMS Authors. https://doi.org/10.1016/j.isci.2021.102548. Retrieved from https://escholarship.umassmed.edu/oapubs/4742
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