NLRP3 Inflammasome Activation Mediates Coronary Artery Lesions in Kawasaki Disease by Inducing Endothelial Cells Pyroptosis and Glycocalyx Injury

INTRODUCTION: To investigate the mechanism by which NOD-like receptor heat protein domain-associated protein 3 (NLRP3) activation mediates coronary endothelial dysfunction at different stages of Kawasaki disease (KD). METHODS: Blood samples were collected from patients in the acute stage and convalescent stage of KD, as well as healthy/febrile controls. The mRNA expression of NLRP3 and Caspase-1 were detected by qRT-PCR. Serum levels of IL-1β, syndecan-1 (SDC-1), hyaluronic acid (HA), metalloproteinase-9 (MMP-9), and metalloproteinase-1 (TIMP-1) were quantified via ELISA, and Spearman correlation analysis was conducted. In vitro, human coronary artery endothelial cells (HCAECs) were treated with KD patient serum combined with NLRP3 activator/inhibitor treatment. Cell viability (CCK-8) and cell migration (Transwell) were assessed. The relative protein expression of pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD-N) were detected by Western blot. The concentrations of cytokine secretion (IL-1β/IL-18), matrix metabolism (MMP-9/TIMP-1), glycocalyx components (SDC-1/HA) were evaluated by ELISA. RESULTS: The levels of NLRP3 mRNA, Caspase-1 mRNA, IL-1β, MMP-9, TIMP-1, SDC-1 and HA in patients with acute KD were significantly higher than those in the healthy/febrile control group (p < 0.01), and these indicators were positively correlated with NLRP3 activation (p < 0.01). KD serum significantly suppressed the proliferation/migration of HCAEC (p < 0.01), induced pyroptosis (upregulated NLRP3/Caspase-1/GSDMD-N), and increased IL-1β/IL-18 secretion with concomitant elevated levels of MMP-9/TIMP-1/SDC-1/HA. NLRP3 inhibitors can reverse the above-mentioned damaging effects (p < 0.01). CONCLUSIONS: NLRP3 inflammasome activation during the progression of KD can cause coronary endothelial injury by inducing inflammatory imbalance, endothelial cells pyroptosis, and glycocalyx injury. Targeting NLRP3 represents a promising therapeutic strategy.