NLRP 3 regulates platelet integrin a IIb β 3 outside-in signaling , hemostasis and arterial thrombosis

a lowto a high-affinity state (inside-out signaling) and enable platelet aggregation and thrombus formation through binding of soluble fibrinogen and other aIIbβ3 ligands. Ligand binding to aIIbβ3 also triggers aIIbβ3 outside-in signaling, leading to tyrosine phosphorylation of signaling proteins, including c-Src, spleen tyrosine kinase (Syk) and phospholipase Cγ2 (PLCγ2), and initiates downstream platelet responses, such as granule secretion, platelet spreading and clot retraction. Platelets also have roles in the inflammatory response and in inflammatory pathology associated with atherosclerosis, malarial or dengue infection and rheumatoid arthritis. Inflammasomes are multiprotein complexes that mediate responses to various inflammatory stimuli by controlling secretion of the pro-inflammatory cytokine, interleukin 1β (IL-1β). Upon stimulation, NLRP3 undergoes oligomerization, leading to conversion of pro-caspase-1 to active caspase-1, which then cleaves pro-IL-1β to mature IL-1β. For example, in dengue virus infection, platelet NLPR3 is activated, triggering IL-1β secretion. NLPR3 also contributes to platelet activation, aggregation and thrombus formation in vitro, as shown by caspase activity measurements and pharmacological inhibition or genetic ablation of the NLPR3-associated adaptor protein, Bruton tyrosine kinase (BTK). In this study using NLRP3deficient platelets, we demonstrated a specific contribution of NLRP3 to aIIbβ3 outside-in signaling, and hemostasis and arterial thrombosis in vivo.