Neutrophil extracellular traps (NETs) in autoimmune diseases: A comprehensive review.

Neutrophil extracellular traps (NETs) are fibrous networks which protrude from the membranes of activated neutrophils. NETs are found in a variety of conditions such as infection, malignancy, atherosclerosis, and autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), psoriasis, and gout. Studies suggest that an imbalance between "NETosis," which is a process by which NETs are formed, and NET degradation may be associated with autoimmune diseases. Neutrophils, interleukin-8, ANCA and other inflammatory molecules are considered to play a key role in NET formation. Prolonged exposure to NETs-related cascades is associated with autoimmunity and increases the chance of systemic organ damage. In this review, we discuss the roles of various inflammatory molecules in relation to NETs. We also describe the role of NETs in the pathogenesis of autoimmune diseases and discuss the possibility of using targeted therapies directed to NETs and associated molecules to treat autoimmune diseases.

Lee KH ，Kronbichler A ，Park DD ，Park Y ，Moon H ，Kim H ，Choi JH ，Choi Y ，Shim S ，Lyu IS ，Yun BH ，Han Y ，Lee D ，Lee SY ，Yoo BH ，Lee KH ，Kim TL ，Kim H ，Shim JS ，Nam W ，So H ，Choi S ，Lee S ，Shin JI ... -  《-》

Neutrophil Extracellular Traps (NETs) Take the Central Stage in Driving Autoimmune Responses.

Fousert E ，Toes R ，Desai J 《-》

At the Bedside: Neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases.

Neutrophil extracellular traps are associated with a unique form of cell death distinct from apoptosis or necrosis, whereby invading microbes are trapped and killed. Neutrophil extracellular traps can contribute to autoimmunity by exposing autoantigens, inducing IFN-α production, and activating the complement system. The association of neutrophil extracellular traps with autoimmune diseases, particularly systemic lupus erythematosus, will be reviewed. Increased neutrophil extracellular trap formation is seen in psoriasis, antineutrophil cytoplasmic antibody-associated vasculitis, antiphospholipid antibody syndrome rheumatoid arthritis, and systemic lupus erythematosus. Neutrophil extracellular traps may promote thrombus formation in antineutrophil cytoplasmic antibody-associated vasculitis and antiphospholipid antibody syndrome. In systemic lupus erythematosus, increased neutrophil extracellular trap formation is associated with increased disease activity and renal disease, suggesting that neutrophil extracellular traps could be a disease activity marker. Neutrophil extracellular traps can damage and kill endothelial cells and promote inflammation in atherosclerotic plaques, which may contribute to accelerated atherosclerosis in systemic lupus erythematosus. As neutrophil extracellular traps induce IFN-α production, measuring neutrophil extracellular traps may estimate IFN-α levels and identify which systemic lupus erythematosus patients have elevated levels and may be more likely to respond to emerging anti-IFN-α therapies. In addition to anti-IFN-α therapies, other novel agents, such as N-acetyl-cysteine, DNase I, and peptidylarginine deiminase inhibitor 4, target neutrophil extracellular traps. Neutrophil extracellular traps offer insight into the pathogenesis of autoimmune diseases and provide promise in developing disease markers and novel therapeutic agents in systemic lupus erythematosus. Priority areas for basic research based on clinical research insights will be identified, specifically the potential role of neutrophil extracellular traps as a biomarker and therapeutic target in systemic lupus erythematosus.

Barnado A ，Crofford LJ ，Oates JC 《-》

Neutrophil extracellular traps generation and degradation in patients with granulomatosis with polyangiitis and systemic lupus erythematosus.

Pruchniak MP ，Ostafin M ，Wachowska M ，Jakubaszek M ，Kwiatkowska B ，Olesinska M ，Zycinska K ，Demkow U ... -  《-》

NETosis: At the crossroads of rheumatoid arthritis, lupus, and vasculitis.

Suicidal NETosis differs from other mechanisms of cell death by the release of a lattice, composed of DNA associated with proteins citrullinated by protein-arginine deiminase 4, from neutrophils. These 'NETs' are composed of granule-derived proteins with microbicidal activity. A similar type of release occurs during vital NETosis, in which anuclear neutrophils maintain their chemotactic ability and imprison live bacteria, even after NET extrusion. Mitochondrial NETosis is limited to the expulsion of oxidised mitochondrial DNA and cytoplasmic enzymes. NETs include the targets of most autoantibodies found in rheumatoid arthritis, lupus, and vasculitis. The clinical and biological overlaps sometimes observed between bronchectiasis and RA, RA and SLE, or SLE and vasculitis, implicate NETosis as a major triggering event common to these disorders. NETosis increases the possibility of association between autoantigens and infectious antigens in mucosal biofilms, impairing the clearance of pathogens and possibly triggering autoimmune reactions. NETosis aggravates these three conditions and increases endothelial damage and the risk of thrombosis. However, the pathogenesis of RA, SLE, and vasculitis is not confined to autoantibodies against NET components, and other mechanisms have been suggested to explain the breakdown of tolerance to NET autoantigens, such as hypercitrullination. The question of whether continuous presentation of autoantigens mixed with antigens from dormant intracellular pathogens (released following suicidal, vital, or mitochondrial NETosis) is required to induce and sustain autoimmunity must be addressed. Inhibiting NETois may not be sufficient to improve autoimmune disorders whereas such latent infections remain uncontrolled.

Berthelot JM ，Le Goff B ，Neel A ，Maugars Y ，Hamidou M ... -  《-》