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Kawasaki disease (KD) is an acute febrile systemic vasculitis associated with the development of coronary artery lesion and coronary artery aneurysm. This condition is characterized by sustained vascular inflammation and endothelial dysfunction, in which pyroptosis serves as a pivotal driver of inflammatory response. However, the molecular mechanisms linking pyroptosis to endothelium injury and KD pathogenesis remain poorly understood. Analysis of public datasets revealed a marked decrease in T-cadherin (T-cad, CDH13) expression in cardiac tissues from KD patients and KD model mice compared to controls. In vitro and in vivo experiments revealed the reduced T-cad expression in both the treated human umbilical vein endothelial cells (HUVECs) and the abdominal aorta of Lactobacillus casei cell wall extract-induced KD mice. RNA sequencing analysis of HUVECs with siRNA-mediated T-cad knockdown showed significant enrichment of genes involved in pro-inflammatory cascades and pyroptosis-associated pathways. Western blot analysis further validated the upregulation of pyroptosis-associated proteins, including NLRP3, caspase-1, GSDMD, IL-1β, and IL-18, in the T-cad knockdown group compared to controls. These findings were supported by functional assays demonstrating the increased lactate dehydrogenase release, higher TUNEL-positive cells, and elevated reactive oxygen species (ROS) levels in the T-cad knockdown group. Collectively, our results indicate that inflammatory stimuli downregulate T-cad expression in endothelial cells, subsequently reducing superoxide dismutase 2 (SOD2) expression and its enzymatic activity. This leads to ROS accumulation, which activates the NLRP3 inflammasome and initiates pyroptosis. Thus, T-cad deficiency induces pyroptosis in HUVECs via the activation of the SOD2/ROS/NLRP3 pathway. These findings highlight the pivotal role of T-cad deprivation-mediated endothelial cell pyroptosis in the initiation and progression of KD, providing novel insights into its pathophysiology and potential therapeutic targets.
Lin et al. (Mon,) studied this question.