Neutrophil extracellular traps (NETs) are web-like structures of decondensed chromatin decorated with neutrophil granule proteins released by activated neutrophils. The phenomenon was first characterized by Volker Brinkmann and Arturo Zychlinsky at the Max Planck Institute for Infection Biology, and subsequent work has connected NETs to sterile inflammation and autoimmune disease. NETs play a dual role: they trap pathogens but also expose intracellular molecules that can become targets of the immune system.
Mechanisms linking NETs to autoimmunity
NETs expose nuclear and mitochondrial DNA, histones, myeloperoxidase, and neutrophil elastase—components normally hidden from the adaptive immune system. When these molecules persist in the extracellular space, they can act as autoantigens and drive autoantibody production. Research by Mariana J. Kaplan at the National Institute of Arthritis and Musculoskeletal and Skin Diseases highlights how impaired clearance and the presentation of NET-derived antigens promote loss of tolerance in systemic lupus erythematosus. Cristina Lood at the Karolinska Institute and colleagues described how oxidized mitochondrial DNA within NETs potently activates plasmacytoid dendritic cells and the type I interferon pathway, a central driver of many autoimmune syndromes.
Causes and failure of resolution
Triggers for excessive NET formation include infection, tissue injury, and chronic inflammatory signals; genetic susceptibility and environmental exposures can amplify NETosis in some individuals. A critical factor is defective removal: reduced DNase activity or impaired phagocytic clearance allows NETs to persist, increasing the chance of immune recognition. Multiple research teams, including investigators associated with Harvard Medical School, have shown that NETs also provide a scaffold for coagulation factors, linking NET persistence to thrombosis in autoimmune vasculopathies.
Consequences of unchecked NET activity include sustained interferon signaling, maturation of autoreactive B cells, endothelial damage, and microvascular occlusion. These processes contribute to organ-specific pathology in diseases such as systemic lupus erythematosus, ANCA-associated vasculitis, and antiphospholipid syndrome. Clinically, this translates into varied manifestations: skin lesions, glomerulonephritis, and heightened risk of arterial and venous thrombosis.
Understanding NET biology has therapeutic implications: strategies that enhance NET clearance, inhibit excessive NET formation, or neutralize NET-derived immunogens are under investigation. Recognizing that NET-driven autoimmunity intersects with sex, ancestry, and environmental factors underscores the need for culturally and territorially sensitive approaches to diagnosis, risk stratification, and treatment. Targeted interventions that restore balance between host defense and tolerance offer a path to reduce NET-associated autoimmune harm.