Figure 4. Formation of neutrophil extracellular traps and selected mediators associated with NETs that can participate in local arterial thrombosis.

NETs can bear proteins contained in neutrophil granules released during neutrophil activation. These proteins include those derived from azurophilic or primary granules including myeloperoxidase, Cathepsin G, neutrophil elastase (NE), and proteinase 3 (PR3), among other hydrolytic enzymes including a series of phospholipases that can generate biologically active lipid mediators of inflammation. NETs can also acquire proteins from extra-neutrophilic sources including tissue factor (TF) that can activate Factor VII and through activation of Factor Xa lead to local thrombin generation that produce fibrin locally. NE and other extracellular matrix-degrading proteins such as neutrophil collagenase and gelatinases can further degrade the basement membrane and underlying extracellular matrix macromolecules including basement membrane constituents and fibrillar collagens. (Elastin fragments may promote chemoattraction of further granulocytes.) Myeloperoxidase generates the highly pro-oxidant species hypochlorous acid (HOCl). Pro- interleukin-1-alpha (IL-1α) derived from neutrophils can bind to the DNA strands that comprise NETs. NETs can activate pro-inflammatory functions of endothelial cells through stimulation by IL-1α. The neutrophil serine proteinase Cathepsin G can enhance the local activity of IL-1α by cleaving the pro- form to produce the more active mature form of this pro-inflammatory cytokine. (Illustration Credit: Ben Smith).