ArticleRedox biology2026
NADPH oxidase 2 (NOX2)-independent inducers of neutrophil extracellular traps promote resolution of chronic inflammation.
Article in Redox biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Reactive oxygen species (ROS) generated by NADPH oxidase 2 (NOX2) are essential for antimicrobial defense but also for the resolution of inflammation. NOX2 deficiency, as observed in chronic granulomatous disease (CGD), predisposes to persistent sterile inflammation. Current therapeutic strategies largely rely on nonspecific immunosuppression or require residual NOX2 activity, while systemic ROS-inducing therapies are limited by toxicity. Here, we present a NOX2-independent approach to restore inflammation-resolving ROS signaling using N-alkylaminoferrocene-based prodrugs (pro-NAAFs), which amplify pre-existing ROS rather than generating ROS indiscriminately. Among several candidates, prodrug 1 emerged as the most potent and well-tolerated ROS amplifier. In human neutrophils, prodrug 1 induced strong ROS production and neutrophil extracellular trap (NET) formation. These responses occurred independently of NOX2 and were maintained in CGD-derived neutrophils. Similar NOX2-independent ROS induction and NET formation were observed in immune cells from wild-type and NOX2-dysfunctional Ncf1∗∗ mice. Prodrug 1-induced NETs aggregated into high-density structures (aggNETs) capable of degrading pro-inflammatory mediators in vitro. Prodrug 1 also inhibited neutrophil inflammasome activation. In vivo, subcutaneous administration of prodrug 1 reduced inflammatory mediator levels in air pouches, promoted resolution of chronic arthritis in Ncf1∗∗ mice, and protected from bone destruction. Transcriptomic analyses indicated early suppression of inflammatory pathways and restoration of neutrophil maturation trajectories towards a wild-type-like state. While prodrug 1 increased protein oxidation markers, it shifted systemic oxysterol profiles towards an inflammation-resolving phenotype. These findings identify pro-NAAFs as NOX2-independent ROS amplifiers capable of restoring inflammatory resolution and highlight their therapeutic potential for chronic inflammatory conditions linked to NOX2-dysfunction.
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