Endothelial NLRP3 inflammasome activation drives immunothrombosis in Streptococcus pyogenes infection.

Streptococcus pyogenes (Strep A), a formidable human pathogen, is notorious for causing life-threatening diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome, often complicated by thrombosis and coagulation abnormalities. While macrophage inflammasome activation has been widely studied in Strep A pathogenesis, the contribution of vascular endothelial cells-key regulators of immunity and coagulation-remains largely unexplored. This study aimed to determine whether endothelial NLRP3 inflammasome activation drives immunothrombosis during invasive Strep A infection and to define the roles of streptolysin O (SLO) and streptolysin S (SLS) in this mechanism. Using a murine intramuscular infection model in wild-type and NOD-like receptor family pyrin domain-containing 3 (NLRP3)-deficient mice together with infection of human microvascular endothelial cells with wild-type or toxin-deficient Strep A strains, we found that Strep A robustly activated the endothelial NLRP3 inflammasome, leading to caspase-1 activation, IL-1β secretion, endothelial pyroptosis, and a cascade of immunothrombotic events. Genetic ablation of NLRP3 or pharmacological inhibition of caspase-1 significantly attenuated inflammasome activation, immunothrombosis, and tissue injury. Both SLO and SLS were essential for these pathogenic effects. These findings illuminate a hitherto unrecognized endothelial inflammasome-mediated axis in Strep A infection and pave the way for innovative therapeutic strategies targeting endothelial immune responses to combat invasive streptococcal diseases.