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.