Figure 1.

Inflammation-induced platelet-mediated NET formation. The mechanisms leading to platelet-induced NET formation are highly dependent on the surrounding inflammatory conditions. Receptor-ligand binding, as well as soluble mediators, were identified to promote platelet-induced NETosis. Ligation of (soluble) P-sel and neutrophil PSGL-1 was shown to result in NET formation, and also activation of neutrophil Mac-1. SLC44A2 was recently identified as a mechanotransducer of NETosis. CXCR4 and CXCR7, expressed on platelets and neutrophils, may be important to induce NETosis, and functional Adora2b signaling seems indispensable for this. Thrombin-activated platelets not only recruit neutrophils into the inflamed tissue, but also stimulate neutrophils to form NETs. Platelet exosomes, carrying HMGB1 and miRNAs, induce NETosis in a RAGE- and autophagy-dependent manner. TLR9 activation via CpG oligonucleotides lead to the discharge of platelet CXCL4, but CXCL4 also heterodimerizes with CCL5 to induce NETs. Lastly, blocking the neutrophil thromboxane receptor diminished NETosis. CXCR, C-X-C motif chemokine receptor; CXCL4, C-X-C motif ligand 4; CCL5, CC-chemokine ligand 5; GP, glycoprotein; HMGB1, high mobility group box 1; miRNAs, microRNAs; PAR, protease-activated; P-sel, P-selectin; RAGE, receptor for advanced glycation end products; SDF-1, stromal cell-derived factor 1; sP-sel, soluble P-selectin; TLR9, toll-like receptor 9; TXA, thromboxane A; TXA2, thromboxane A₂.