NETosis 在栓塞性疾病中的關鍵作用

Figure 1 Basic mechanism of NETosis and its downstream effects. (A) In general, two main intracellular pathways of NETosis are distinguished: (1) Induction of NADPH oxidase by protein kinase C (PKC) upon PMA stimulation causes excessive reactive oxygen species (ROS) generation, which is followed by MPO- and NE-dependent degradation of the cytoskeleton, disruption of the nucleosome packaging, and the disintegration of the nuclear membrane, and finally leads to the release of NETs. (2) Stimulation of PADI4 by increased Ca2+-levels upon ionomycin stimulation for instance induces citrullination of histones, which disrupts nucleosome stability and leads to chromatin decondensation. This, together with the disintegration of the nuclear and plasma membrane, results in the release of NETs. (B) Once expelled in the circulation, NETs and associated molecules affect several cells and processes namely (1) platelet activation and aggregation, (2) coagulation, (3) leukocyte activation and (4) endothelial cell (EC) activation or damage respectively. Altogether, these processes finally culminate in the development and progression of atherothrombosis and venous thromboembolism. Created with BioRender.com. 

Figure 2 “Two-hit” theory of development of atherosclerotic lesions involving NETosis and thrombo-inflammation. Upon endothelial cell activation by MMPs or apoptotic stimuli, pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs) and other ligands bind to pattern recognition receptors on the surface of endothelial cells. Subsequently, inflammatory cells and modified lipoproteins promote apoptosis of endothelial cells. In parallel, matrix metalloproteinases attack constituents of the basement membrane, which leads to disruption of the endothelial cell adhesion to the basement membrane, desquamation of the endothelium, and superficial erosion (first “hit”). Several processes are initiated once the endothelial erosion starts: (1) A desquamated and dying endothelial cell releases microparticles that bear tissue factor which initiates the blood coagulation cascade; (2) Exposed sub-endothelial matrix provides a substrate for neutrophil adhesion and activation, which results in neutrophil death and formation of NETs; (3) Exposure of the sub-endothelial extracellular matrix macromolecules activates platelets causing them to degranulate and release pro-inflammatory mediators, e.g. interleukin-6 (IL-6), RANTES, plasminogen activator inhibitor-1 (PAI-1), which enhances thrombosis, activates neutrophils and further promotes NETosis, a concept named thrombo-inflammation. Adapted from Quillard et al. (64) Created with BioRender.com.