Neutrophil Extracellular Traps in Systemic Lupus Erythematosus: Pathogenic Mechanisms, Crosstalk with Oxidative Stress, and Antioxidant Therapeutic Potential

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder marked by autoantibody production and immune complex (IC) formation, leading to widespread inflammation and tissue damage. Neutrophil extracellular traps (NETs) — web-like structures of DNA, histones, and antimicrobial proteins — support innate immunity but drive SLE pathogenesis when dysregulated. This review examines SLE-specific NET mechanisms, their crosstalk with oxidative stress, and their therapeutic potential as antioxidants. SLE patients exhibit excessive NET formation, driven by proinflammatory low-density granulocytes (LDG) and ICs, and impaired NET clearance (reduced DNase1/DNase1L3 activity or anti-nuclease autoantibodies), leading to circulating NET accumulation. These NETs act as autoantigen reservoirs, forming pathogenic NET–ICs that amplify autoimmunity. Oxidative stress (via NADPH oxidase) and various mitochondrial reactive oxygen species (ROS) promote NETosis; antioxidants (both enzymatic and non-enzymatic) can inhibit NET formation by scavenging ROS or blocking NADPH oxidase. Preclinical studies show that curcumin, resveratrol, and mitochondrial-targeted MitoQ reduce NETs and lupus nephritis; clinical trials confirm that curcumin and N-acetylcysteine (NAC) lower SLE activity and proteinuria, supporting their potential as safe adjuvant therapies. However, high-dose vitamin E may exacerbate autoimmunity. Future research should clarify NET mechanisms in SLE and optimize antioxidant therapies (e.g., bioavailability, safe dosage and long-term safety).