NOX2 deficiency enhances priming and activation of the NLRP3 inflammasome - 25/10/23

Doi : 10.1016/j.jaci.2023.09.030

Blandine Monjarret, MSc ^a, Sara Shour, MSc ^a, Aissa Benyoucef, PhD ^a, Emilie Heckel, PhD ^a, Lorie Marchitto, MSc ^a, Jennifer W. Leiding, MD ^b,^c, Guilhem Cros, MD ^d, Isabel Fernandez, PhD ^e, Jean-Sebastien Joyal, MD, PhD ^a,^f,^g, Fabien Touzot, MD, PhD ^a,^e,^g,^⁎
^a CHU Sainte-Justine Research Center, Montreal, Quebec, Canada
^b Pediatric Infectious Disease and Immunology Arnold Palmer Hospital for Children at Orlando Health, Orlando, Fla
^c Department of Pediatrics, Division of Allergy and Immunology, Johns Hopkins University, Baltimore, Md
^d Centre Hospitalier de l’Université de Montréal, Université de Montréal, Montreal, Quebec, Canada
^e Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada
^f Department of Pathology and Cellular Biology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
^g Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada

^∗Corresponding author: Fabien Touzot, MD, PhD, CHU Sainte Justine Research Center, 3175 chemin de la côte Sainte-Catherine, Montréal, QC H3T1C5, Canada.CHU Sainte Justine Research Center3175 chemin de la côte Sainte-CatherineMontréalQCH3T1C5Canada

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Wednesday 25 October 2023

Graphical abstract

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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.

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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