How NETs Drive Autoimmune Disease and New Treatment Targets

A study published in Frontiers in Immunology reviewed the emerging role of neutrophil extracellular traps (NETs) in the development and progression of autoimmune diseases. The authors argue that NETs are central players in autoimmune pathology because they bridge innate and adaptive immunity, serve as sources of autoantigens, and directly damage tissues.

NETs are web-like DNA–protein structures released by neutrophils in response to stimuli such as cytokines, pathogens, or chemical triggers. Although NETs play a protective role in antimicrobial defense, excessive formation or impaired clearance contributes to autoimmune disease. Under normal conditions, neutrophils kill pathogens through phagocytosis and enzyme release. When confronted by large organisms that cannot be engulfed, they expel DNA, histones, and proteins like neutrophil elastase (NE) and myeloperoxidase (MPO) to form NETs, which immobilize and degrade pathogens extracellularly.

NETs promote inflammation by releasing DAMPs, histones, and proteases, further activating immune pathways and potentially supplying autoantigens that can bind autoantibodies. The authors detail how dysregulated NETs contribute to several autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), antiphospholipid syndrome (APS), and type 1 diabetes (T1D). NET accumulation and impaired clearance are also well-documented in ANCA-associated vasculitis (AAV) and psoriasis.

In RA, NETs form readily in the synovial fluid. Citrullinated histones within NETs can drive ACPA production, while NET-derived enzymes and cytokines contribute to cartilage damage. In SLE, NETs persist due to impaired degradation and contain enriched citrullinated histones and oxidized mitochondrial DNA, potent autoantigens that amplify interferon-driven inflammation and form a self-sustaining inflammatory loop.

In T1D, elevated NET markers appear early after disease onset. Neutrophils infiltrate the pancreas and release NETs that damage beta cells and activate innate and adaptive immune pathways. In APS, antiphospholipid antibodies can trigger NET release through β2-glycoprotein I–dependent mechanisms, and anti-NET antibodies may further impair NET clearance.

The authors also highlight therapeutic strategies targeting NETs, including inhibitors of ROS, PAD4, NE, and MPO that prevent NET formation. (ROS, NE, MPO, and PAD4 are all essential components of NETosis.) Additional approaches include enhancing NET clearance with DNase-based therapies and using biologics that modulate type I interferon signaling, since NETs strongly activate IFN pathways.

Citation

Tang, R., Yin, J., Qin, Z., Zhang, M., & Jia, X. (2025). NETs: a new target for autoimmune disease. Frontiers in immunology, 16, 1646527. https://doi.org/10.3389/fimmu.2025.1646527