Neutrophil extracellular traps in gout, rheumatoid arthritis, and systemic lupus erythematosus: Mechanistic heterogeneity and therapeutic implications.

Neutrophil extracellular traps (NETs) have emerged as dynamic extracellular platforms that integrate innate immunity, adaptive immune activation, and immunothromboinflammation. Rather than representing a single cell-death pathway, NET formation constitutes a context-dependent continuum shaped by the coordinated activation of multiple mechanisms, including NADPH oxidase-derived reactive oxygen species, calcium signaling, mitochondrial reactive oxygen species, PAD4-mediated chromatin remodeling, and metabolic reprogramming. The mechanistic architecture and pathogenic consequences of NET formation vary substantially across inflammatory rheumatic diseases. In gouty arthritis, NETs may amplify NLRP3 inflammasome activation and exacerbate acute inflammation, whereas aggregated NETs can contribute to inflammatory resolution during remission. In rheumatoid arthritis, NETs are enriched in citrullinated autoantigens, thereby promoting anti-citrullinated protein antibody production and contributing to joint structural damage. In systemic lupus erythematosus, NETs containing oxidized mitochondrial DNA enhance nucleic acid sensing and type I interferon responses, while defective NET clearance further aggravates immune dysregulation and organ injury. We propose that NET imbalance in inflammatory rheumatic diseases should not be interpreted as a uniform NETosis process, but rather examined through a disease-specific, four-dimensional framework encompassing mechanisms of formation, molecular composition, clearance capacity, and immunological consequences. Therapeutic strategies targeting NETs are accordingly evolving from broad suppression of NET formation toward multilayered approaches that combine modulation of NET generation with restoration of NET clearance. Nevertheless, clinical translation remains constrained by infection risk, disruption of thromboinflammatory homeostasis, and insufficient patient stratification. Overall, NET imbalance is more likely to function as a disease-specific amplifier of inflammation than as a universal initiating factor. Future studies should establish disease-resolved molecular atlases of NETs and advance biomarker-guided precision intervention strategies.