Neutrophil Extracellular traps

Abstract

The polymorphonuclear (PMN) leukocyte, or neutrophil, has long been recognized as the infantry of the innate immune system, rapidly deploying to sights of injury and infection. Considerable knowledge has accumulated demonstrating how these cells contribute to inflammation and host-defense. In particular, the mechanisms of neutrophil recruitment, phagocytosis, NADPH oxidative burst and toxic granule dependent microbial killing have been elucidated in great detail. However, this conventional paradigm dramatically shifted with the observation that stimulated

PMN could release extracellular nucleic acids decorated with histones and granular proteins (neutrophil extracellular traps) capable of entrapping exogenous bacteria. Within the bloodstream, the capture of the pathogens, for the most part, remains a function of Kupffer cells within the liver vasculature. These cells express a specialized pathogen receptor, the Complement Receptor of the Immunoglobulin superfamily (CRIg), which has evolved to catch circulating pathogens under shear conditions. By contrast, neutrophils are not capable of directly catching circulating pathogens but by producing NETs, they can increase the catching capacity of the liver. The enzymes, peptidyl arginine deiminase type IV (PAD4) and neutrophil elastase (NE), have been implicated in the initial decondensation of DNA and the proteolytic degradation of the nuclear envelope. The DNA is then released through lysis, vesicular transport and degranulation or by some as yet unresolved catapulting mechanism. These additional NET components include nuclear proteins (histones), cytoskeletal proteins and granular proteins, including proteases and myeloperoxidase (MPO). Because of the cytotoxic mix of proteins and enzymes bound to NETs, these structures have been described as a double-edged sword, not only facilitating pathogen elimination, but also eliciting damage to bystander cells. Although histones have a potent antimicrobial action, they can also damage and kill endothelial and epithelial cells. Pathogenicity of NETs has also been implicated in the promotion of thrombosis as NETs serve as scaffolds for fibrin, von Willebrand factor (VWF) and thrombus formation.In addition, NETs may also have lasting effects by modulating tissue healing and even shaping the late (adaptive) immune response.

In the bloodstream DNase could simply breakdown the NETs. However, even  this latter point, that is, are all NET components removed with DNase, is really not known.

NET release during acute infection may have unintended, long-term side effects that must be considered. Here we consider the evidence that NET release may incite both autoimmune and vasculitic diseases.

Systemic lupus erythematosus (SLE, lupus) is a complex autoimmune disease, comprising a constellation of clinical manifestations of unknown cause. A review of the historical diagnostic tests for lupus provides intriguing, although inconclusive evidence that NETosis may play a pathophysiologic role in SLE. Rheumatoid arthritis (RA) is an autoimmune disease that targets joints, but it can also cause severe systemic and solid organ complications. PMN from RA patients were found to be more prone to produce NETs and RA serum was a strong inducer of NETosis. Moreover, NETosis resulted in the externalization of citrullinated autoantigens, thereby linking NET formation to rheumatoid arthritis.

There is reason to believe that better understanding of both mechanisms of NET release, and the NETs effects on the host immune system, could support the development of new potential therapeutic strategies for various diseases.