Salmonella Flagellin Activates NAIP/NLRC4 and Canonical NLRP3 Inflammasomes in Human Macrophages.
J Immunol
; 206(3): 631-640, 2021 02 01.
Article
in En
| MEDLINE
| ID: mdl-33380493
Infection of human macrophages with Salmonella enterica serovar Typhimurium (S. Typhimurium) leads to inflammasome activation. Inflammasomes are multiprotein complexes facilitating caspase-1 activation and subsequent gasdermin D-mediated cell death and IL-1ß and IL-18 cytokine release. The NAIP/NLRC4 inflammasome is activated by multiple bacterial protein ligands, including flagellin from the flagellum and the needle protein PrgI from the S. Typhimurium type III secretion system. In this study, we show that transfected ultrapure flagellin from S Typhimurium induced cell death and cytokine secretion in THP-1 cells and primary human monocyte-derived macrophages. In THP-1 cells, NAIP/NLRC4 and NLRP3 played redundant roles in inflammasome activation during infection with S. Typhimurium. Knockout of NAIP or NLRC4 in THP-1 cells revealed that flagellin, but not PrgI, now activated the NLRP3 inflammasome through a reactive oxygen species- and/or cathepsin-dependent mechanism that was independent of caspase-4/5 activity. In conclusion, our data suggest that NLRP3 can be activated by flagellin to act as a "safety net" to maintain inflammasome activation under conditions of suboptimal NAIP/NLRC4 activation, as observed in THP-1 cells, possibly explaining the redundant role of NLRP3 and NAIP/NLRC4 during S. Typhimurium infection.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Salmonella typhi
/
Typhoid Fever
/
Calcium-Binding Proteins
/
Neuronal Apoptosis-Inhibitory Protein
/
CARD Signaling Adaptor Proteins
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Inflammasomes
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NLR Family, Pyrin Domain-Containing 3 Protein
/
Macrophages
Limits:
Humans
Language:
En
Journal:
J Immunol
Year:
2021
Document type:
Article
Affiliation country:
Reino Unido
Country of publication:
Estados Unidos