At the Bedside: Neutrophil Extracellular Traps (NETs) as Targets for Biomarkers and Therapies in Autoimmune Diseases

J Leukoc Biol. 2016 Feb;99(2):265-78. doi: 10.1189/jlb.5BT0615-234R. Epub 2015 Dec 11.

Abstract

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.

Keywords: autoimmunity; systemic lupus erythematosus; type I IFN.

Publication types

  • Review

MeSH terms

  • Acetylcysteine / therapeutic use
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / drug therapy
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / immunology
  • Antibodies, Monoclonal / therapeutic use
  • Antimalarials / therapeutic use
  • Apoptosis / immunology
  • Atherosclerosis / etiology
  • Atherosclerosis / prevention & control
  • Autoantigens / immunology
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / immunology*
  • Biomarkers
  • Deoxyribonuclease I / therapeutic use
  • Extracellular Traps / drug effects
  • Extracellular Traps / immunology*
  • Female
  • Humans
  • Hydrolases / antagonists & inhibitors
  • Immunosuppressive Agents / therapeutic use
  • Interferon-alpha / antagonists & inhibitors
  • Interferon-alpha / biosynthesis
  • Lupus Erythematosus, Systemic / complications
  • Lupus Erythematosus, Systemic / drug therapy
  • Lupus Erythematosus, Systemic / immunology
  • Molecular Targeted Therapy*
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Pregnancy
  • Pregnancy Complications / immunology
  • Pregnancy Complications / prevention & control
  • Protein Processing, Post-Translational / drug effects
  • Protein-Arginine Deiminase Type 4
  • Protein-Arginine Deiminases
  • Thrombophilia / etiology
  • Thrombophilia / immunology
  • Thrombosis / prevention & control
  • Translational Medical Research / methods
  • Translational Medical Research / trends
  • Vitamin D / therapeutic use

Substances

  • Antibodies, Monoclonal
  • Antimalarials
  • Autoantigens
  • Biomarkers
  • Immunosuppressive Agents
  • Interferon-alpha
  • Vitamin D
  • Hydrolases
  • Deoxyribonuclease I
  • PADI4 protein, human
  • Protein-Arginine Deiminase Type 4
  • Protein-Arginine Deiminases
  • Acetylcysteine