Figure 4.

Proposed Role of the NLRP3 Inflammasome and IL-1 in Venous Thrombogenesis

Early in thrombogenesis, multiple DAMPs and PAMPs (eg, extracellular FNA, ROS, proinflammatory cytokines), promote inflammasome activation in innate immune cells, primarily macrophages, and neutrophils. IL-1β and IL-18 released by infiltrating leukocytes induce endothelial IL-1 production and expression of adhesion molecules and prothrombotic factors, facilitating platelet recruitment. In a feed-forward loop, activation of platelet NLRP3 inflammasome, mediated by TLR4 and BKT, induces platelet IL-1 release and aggregation. IL-1α is abundantly released after vascular injury and, serving as an “alarmin,” sustains thromboinflammation. Macrophage NLRP3 activation leads to pyroptosis with release of TF, potently triggering coagulation with thrombin generation and fibrin formation. Neutrophil NLRP3 activation results, through PAD4, in NETosis. In turn, NETs sustain NLRP3 activation and IL-1 production. NETs and neutrophil-derived enzymes promote factor XII autoactivation and disrupt endogenous anticoagulant pathways (TFPI, AT), thus boosting thrombin generation. The DNA core of NETs interacts with VWF and fibrin providing a scaffold, resistant to fibrinolysis, for thrombus stability and growth. Created with BioRender.com. AT = antithrombin; BTK = Bruton's tyrosine kinase; eATP = extracellular ATP; GSDMD = gasdermin D; DAMPs = damage-associated molecular-patterns; eATP = extracellular ATP; IL = interleukin; NE = neutrophil elastase; NET = neutrophil extracellular traps; NLRP3 = NACHT-, LRR- and pyrin domain-containing protein 3; NF-kB = nuclear factor-kappa B; PAD4 = peptidylarginine deiminase 4; PAMPs = pathogen-associated molecular-patterns; PSGL-1 = P-selectin glycoprotein ligand-1; P2X7R = P2X7 receptor; ROS = reactive oxygen species; TF = tissue factor; TFPI = tissue factor pathway inhibitor; TLR4 = Toll-like receptor 4; VWF = von Willebrand factor; other abbreviations as in Figure 2.