NLRC4 inhibits NLRP3 inflammasome and abrogates effective antifungal CD8(+) T cell responses

Author(s)

Souza, Camila O. S. ^[1] ; Ketelut-Carneiro, Natalia ^{[1, 2]} ; Milanezi, Cristiane M. ^[1] ; Faccioli, Lucia H. ^[3] ; Gardinassi, Luiz G. ^[4] ; Silva, Joao S. ^{[1, 5]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Ribeirao Preto, SP - Brazil

^[2] Univ Massachusetts, Dept Med, Program Innate Immun, Med Sch, Worcester, MA 01605 - USA

^[3] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Bromatol Sci, Ribeirao Preto, SP - Brazil

^[4] Univ Fed Goias, Inst Trop Pathol & Publ Hlth, Dept Biosci & Technol, Goiania, Go - Brazil

^[5] Fiocruz Biinst Translat Med Platform, Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: ISCIENCE; v. 24, n. 6 JUN 25 2021.
• Web of Science Citations: 0

Abstract

The recognition of fungi by intracellular NOD-like receptors (NLRs) induces in-flammasome 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 showthatNLRC4 confers susceptibility to experimental PCM by regulating NLRP3-dependent cytokine production and thus protective effector mechanisms. Early after infection, NLRC4 suppresses prostaglandin E-2 production, and consequently reduces interleukin (IL)-1 beta release by macrophages and dendritic cells in the lungs. IL-1 beta 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. (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: 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
• 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: 15/21605-3 - The role of NLRC4 inflammasome in the control of Paracoccidioides brasiliensis
• Grantee: Camila de Oliveira Silva e Souza
• Support Opportunities: Scholarships in Brazil - Master