NOX2 deficiency enhances priming and activation of the NLRP3 inflammasome - 25/10/23
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Graphical abstract |
Abstract |
Background |
Nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2) deficiency, or chronic granulomatous disease (CGD), is an inborn error of immunity associated with increased susceptibility to infection and inflammatory manifestations. The pathophysiologic mechanism leading to the increased inflammatory response in CGD remains elusive.
Objective |
We investigated the pathophysiologic mechanisms leading to NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation in NOX2 deficiency.
Methods |
We used NOX2-deficient human primary and CRISPR-engineered macrophages to show that NOX2 deficiency enhances the inflammatory response mainly by modulating the 2 steps of NLRP3 inflammasome activation: its transcriptional priming and its posttranslational triggering.
Results |
At the transcriptional level, NOX2-deficient phagocytes display increased priming of the NLRP3 inflammasome, as evidenced by increased transcription of NLRP3 and IL-1β through an IL-1β–dependent stimulation of the nuclear factor kappa–light-chain enhancer of activated B cells (aka NF-κB) pathway. At the posttranslational level, the absence of NOX2 triggers the NLRP3 inflammasome activation by increased K+ efflux and excessive release of mitochondrial DNA due to mitochondrial damage. Furthermore, NLRP3-driven pyroptosis in NOX2-deficient phagocytes further enhances NLRP3 activation by increasing K+ efflux.
Conclusion |
Our results unveil the role of NOX2 as a repressor of the inflammatory response at both transcriptional and posttranslational levels and pave the way for a more targeted approach to treating CGD patients with inflammatory manifestations.
Le texte complet de cet article est disponible en PDF.Key words : NOX2, reactive oxygen species, NLRP3, gasdermin D, K+ efflux, mitochondrial damage
Abbreviations used : APDC, ASC, ATP, CGD, CRISPR, Ctrl, DMF, GSDMD, HBSS, IL-1R, KO, LDH, LPS, mtDNA, mtROS, NADPH, NF-κB, N-GSDMD, NLRP3, NOX2, OCR, PMA, ROS, TcdA, TEA
Plan
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