Neutrophil Extracellular DNA Traps in Response to Infection or Inflammation, and the Roles of Platelet Interactions

Abstract

Neutrophils present the host’s first line of defense against bacterial infections. These immune effector cells are mobilized rapidly to destroy invading pathogens by (a) reactive oxygen species (ROS)-mediated oxidative bursts and (b) via phagocytosis. In addition, their antimicrobial service is capped via a distinct cell death mechanism, by the release of their own decondensed nuclear DNA, supplemented with a variety of embedded proteins and enzymes. The extracellular DNA meshwork ensnares the pathogenic bacteria and neutralizes them. Such neutrophil extracellular DNA traps (NETs) have the potential to trigger a hemostatic response to pathogenic infections. The web-like chromatin serves as a prothrombotic scaffold for platelet adhesion and activation. What is less obvious is that platelets can also be involved during the initial release of NETs, forming heterotypic interactions with neutrophils and facilitating their responses to pathogens. Together, the platelet and neutrophil responses can effectively localize an infection until it is cleared. However, not all microbial infections are easily cleared. Certain pathogenic organisms may trigger dysregulated platelet–neutrophil interactions, with a potential to subsequently propagate thromboinflammatory processes. These may also include the release of some NETs. Therefore, in order to make rational intervention easier, further elucidation of platelet, neutrophil, and pathogen interactions is still needed.

Targeting Neutrophil Extracellular Trap Formation: Exploring Promising Pharmacological Strategies for the Treatment of Preeclampsia

“…There are several signalling pathways involved in NET formation [48]; one pathway involves the generation of ROS through the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Activation of the NADPH oxidase complex 2 (NOX2) triggers the Raf/MEK/ERK pathway and augments cytosolic ROS levels [49], resulting in citrullinated histone H3-dependent (Cit-Histone H3) lytic or suicidal NETosis, Figure 1. These lytic NETs are released by the presence of extracellular microbes, fungi, viruses, interferon, phorbol myristate acetate (PMA), IL-8, antibody-antigen complexes, autoantibodies, and concanavalin A. NOX2-independent pathways can lead to the formation of non-lytic NETs, also known as vital NETs [50].…”