Platelet-derived microparticles stimulated by anti-β2GPI/β2GPI complexes induce pyroptosis of endothelial cells in antiphospholipid syndrome

Abstract Platelet microparticles (PMPs) are vesicles that are released by platelets into the extracellular space and play a role in antiphospholipid antibody syndromes. PMPs have recently been recognized as a new and viable cell. There is growing evidence that the anti-β2 glycoprotein (GPI)/β2GPI complex is associated with aberrant activation of PMPs. Although studies suggest that aberrant activation of PMPs may lead to inflammatory necrosis of endothelial cells, the underlying mechanisms remain unclear. We found that although the difference in the number of PMPs was not statistically significant, NLR family pyrin domain containing 3 (NLRP3) within PMPs was increased during stimulation of anti-β2GPI/β2GPI complexes. Furthermore, we demonstrated that anti-β2GPI/β2GPI complex-induced PMPs effectively stimulated endothelial cell pyroptosis via the NLRP3/nuclear factor (NF)-κB/gasdermin D (GSDMD) signaling pathway as well as the NLRP3/Caspase-1 signaling pathway. Additionally, inhibition of NLRP3 expression in PMPs effectively reduced the inflammatory response and pyroptosis in endothelial cells. Our data suggest that PMPs aberrantly activated by anti-β2GPI/β2GPI complexes play a vital role in endothelial cell pyroptosis, and these studies provide major insights into the mechanisms of thrombosis during the treatment of antiphospholipid antibody syndrome. Plain Language Summary What is the context? Antiphospholipid syndrome (APS), an acquired autoimmune disease of unknown etiology. Clinical manifestations include arteriovenous thrombosis, recurrent miscarriages and thrombocytopenia. Endothelial cell damage is common in APS Anti-β2 glycoprotein I antibody, one of the most common APS antibodies, is the main target antigen of anti-β2GPI. Studies have shown that the anti-β2GPI/β2GPI complex accelerates inflammatory cell necrosis. Pyroptosis, also known as inflammatory cell necrosis, is a new form of cell death. Pyroptosis is caused by the activation of the NLRP3 inflammasome, which manifests itself as swelling, lysis and perforation of the cell membrane. Platelet micro-particles (PMPs) are vesicular components that are released extracellularly by platelet activation and are the most abundant and common type of circulating particles in the blood, causing an inflammatory response in the endothelium. There is limited evidence that anti-β2GPI/β2GPI complexes can accelerate endothelial cell pyroptosis by mediating platelet activation to produce PMPs. However, more research is needed to investigate the specific mechanisms by which PMPs cause endothelial cell pyroptosis. What is new? This is the first study on the role of NLRP3 in PMPs. NLRP3 expression in PMPs was increased by stimulation of anti-β2GPI/β2GPI complexes. NLRP3 in PMPs is closely associated with GSDMD-N, a protein involved in endothelial pyroptosis. Anti-β2GPI/β2GPI stimulated PNPs induce pyroptosis via NLRP3/NF-κB/GSDMD and NLRP3/Caspase-1/IL-1β axis. What is the impact? The aim of this study was to investigate the specific mechanism of endothelial cell pyroptosis induced by platelet-released PMPs activated by anti-β2GPI/β2GPI complexes. This finding provides new ideas on the mechanism of endothelial cell scorching in APS and provides a new drug target for the clinical treatment of APS.