NOX2 deficiency enhances priming and activation of the NLRP3 inflammasome.
K(+) efflux
NLRP3
NOX2
gasdermin D
mitochondrial damage
reactive oxygen species
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
05 Oct 2023
05 Oct 2023
Historique:
received:
22
06
2023
revised:
18
08
2023
accepted:
15
09
2023
pubmed:
8
10
2023
medline:
8
10
2023
entrez:
7
10
2023
Statut:
aheadofprint
Résumé
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. We investigated the pathophysiologic mechanisms leading to NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation in NOX2 deficiency. 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. 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 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.
Sections du résumé
BACKGROUND
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
OBJECTIVE
We investigated the pathophysiologic mechanisms leading to NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation in NOX2 deficiency.
METHODS
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
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
CONCLUSION
CONCLUSIONS
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.
Identifiants
pubmed: 37805023
pii: S0091-6749(23)01242-3
doi: 10.1016/j.jaci.2023.09.030
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.