Neutrophil extracellular traps
[2] Neutrophils are the immune system's first line of defense against infection and have conventionally been thought to kill invading pathogens through two strategies: engulfment of microbes and secretion of anti-microbials.
[2][5] NETs disarm pathogens with antimicrobial proteins such as neutrophil elastase, cathepsin G and histones that have a high affinity for DNA.
[6] NETs provide for a high local concentration of antimicrobial components and bind, disarm, and kill microbes extracellularly independent of phagocytic uptake.
The process is thought to begin with NADPH oxidase activation of protein-arginine deiminase 4 (PAD4) via reactive oxygen species (ROS) intermediaries.
[13] Azurophilic granule proteins such as myeloperoxidase (MPO) and neutrophil elastase (NE) then enter the nucleus and further the decondensation process, resulting in the rupture of the nuclear envelope.
[12] Suicidal NETosis was first described in a 2007 study that noted that the release of NETs resulted in neutrophil death through a different pathway than apoptosis or necrosis.
"[12] Vital NETosis is made possible through the blebbing of the nucleus, resulting in a DNA-filled vesicle that is exocytosed and leaves the plasma membrane intact.
[17] NETs might also have a deleterious effect on the host, because the extracellular exposure of histone complexes could play a role during the development of autoimmune diseases like systemic lupus erythematosus (SLE).
[20] NETs have also been associated with the production of IgG antinuclear double stranded DNA antibodies in children infected with P. falciparum malaria.
[21] Significantly higher levels of NETs have been detected in cancer patients compared to healthy controls, and have been associated with poor prognosis and clinical outcome.
[22] Preclinical research suggests that NETs are jointly responsible for cancer-related pathologies like thrombosis, organ failure and metastasis formation.
For instance, A study utilizing the cecal ligation and puncture (CLP) model demonstrated that CLP-induced NETs enhanced the trapping of circulating tumor cells and increased metastasis to the liver.
[26] Specifically, when Lewis lung carcinoma cells (LLC-H59) were injected via the intrasplenic route 24 hours after CLP, the mice exhibited a higher number of metastases compared to sham-operated controls.
A small study published in the journal JAMA Cardiology suggested that NETs played a major role in COVID-19 patients who developed ST-elevation myocardial infarctions.
