PT  - JOURNAL ARTICLE
AU  - Gram, Anna M.
AU  - Wright, John A.
AU  - Pickering, Robert J.
AU  - Lam, Nathaniel L.
AU  - Booty, Lee M.
AU  - Webster, Steve J.
AU  - Bryant, Clare E.
TI  - <em>Salmonella</em> Flagellin Activates NAIP/NLRC4 and Canonical NLRP3 Inflammasomes in Human Macrophages
AID  - 10.4049/jimmunol.2000382
DP  - 2021 Feb 01
TA  - The Journal of Immunology
PG  - 631--640
VI  - 206
IP  - 3
4099  - http://www.jimmunol.org/content/206/3/631.short
4100  - http://www.jimmunol.org/content/206/3/631.full
SO  - J. Immunol.2021 Feb 01; 206
AB  - Salmonella infection leads to NAIP/NLRC4 and NLRP3 inflammasome activation.Flagellin activates the NAIP/NLRC4 and NLRP3 inflammasome in human macrophages.Flagellin mediates NLRP3 activation in a ROS- and/or cathepsin-dependent manner.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-1β 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.