PMID- 34142053
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210619
IS  - 2589-0042 (Electronic)
IS  - 2589-0042 (Linking)
VI  - 24
IP  - 6
DP  - 2021 Jun 25
TI  - NLRC4 inhibits NLRP3 inflammasome and abrogates effective antifungal CD8(+) 
      T cell responses.
PG  - 102548
LID - 10.1016/j.isci.2021.102548 [doi]
LID - 102548
AB  - 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 E(2) 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.
CI  - (c) 2021 The Authors.
FAU - Souza, Camila O S
AU  - Souza COS
AD  - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, 
      University of Sao Paulo, Ribeirao Preto, SP, Brazil.
FAU - Ketelut-Carneiro, Natalia
AU  - Ketelut-Carneiro N
AD  - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, 
      University of Sao Paulo, Ribeirao Preto, SP, Brazil.
AD  - Program in Innate Immunity, Department of Medicine, University of Massachusetts 
      Medical School, Worcester, MA 01605, USA.
FAU - Milanezi, Cristiane M
AU  - Milanezi CM
AD  - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, 
      University of Sao Paulo, Ribeirao Preto, SP, Brazil.
FAU - Faccioli, Lucia H
AU  - Faccioli LH
AD  - Department of Clinical Analyses, Toxicology and Bromatological Science, School of 
      Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao 
      Preto, SP, Brazil.
FAU - Gardinassi, Luiz G
AU  - Gardinassi LG
AD  - Department of Biosciences and Technology, Institute of Tropical Pathology and 
      Public Health, Federal University of Goias, Goiania, GO, Brazil.
FAU - Silva, Joao S
AU  - Silva JS
AD  - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, 
      University of Sao Paulo, Ribeirao Preto, SP, Brazil.
AD  - Fiocruz-Bi-Institutional Translational Medicine Platform, Ribeirao Preto, SP, 
      Brazil.
LA  - eng
PT  - Journal Article
DEP - 20210518
PL  - United States
TA  - iScience
JT  - iScience
JID - 101724038
PMC - PMC8184506
OTO - NOTNLM
OT  - Immunology
OT  - Mycology
COIS- The authors declare no competing interests.
EDAT- 2021/06/19 06:00
MHDA- 2021/06/19 06:01
PMCR- 2021/05/18
CRDT- 2021/06/18 06:52
PHST- 2020/11/03 00:00 [received]
PHST- 2021/04/06 00:00 [revised]
PHST- 2021/05/14 00:00 [accepted]
PHST- 2021/06/18 06:52 [entrez]
PHST- 2021/06/19 06:00 [pubmed]
PHST- 2021/06/19 06:01 [medline]
PHST- 2021/05/18 00:00 [pmc-release]
AID - S2589-0042(21)00516-2 [pii]
AID - 102548 [pii]
AID - 10.1016/j.isci.2021.102548 [doi]
PST - epublish
SO  - iScience. 2021 May 18;24(6):102548. doi: 10.1016/j.isci.2021.102548. eCollection 
      2021 Jun 25.