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Kawasaki disease (KD) is the most common cause of pediatric cardiac disease in developed countries, and can lead to permanent coronary artery damage and long term sequelae such as coronary artery aneurysms. Given the prevalence and severity of KD, further research is warranted on its pathophysiology. It is known that endothelial cell damage and inflammation are two essential processes resulting in the coronary endothelial dysfunction in KD. However, detailed mechanisms are largely unknown. In this study, we investigated the role of pyroptosis in the setting of KD, and hypothesized that pyroptosis may play a central role in its pathophysiology. In vivo experiments of patients with KD demonstrated that serum levels of pyroptosis-related proteins, including ASC, caspase-1, IL-1β, IL-18, GSDMD and lactic dehydrogenase (LDH), were significantly increased in KD compared with healthy controls (HCs). Moreover, western blot analysis showed that the expression of GSDMD and mature IL-1β was notably elevated in KD sera. In vitro, exposure of human umbilical vein endothelial cells (HUVECs) to KD sera-treated THP1 cells resulted in the activation of NLRP3 inflammasome and subsequent pyroptosis induction, as evidenced by elevated expression of caspase-1, GSDMD, cleaved p30 form of GSDMD, IL-1β and IL-18, and increased LDH release and TUNEL and propidium iodide (PI)-positive cells. Furthermore, our results showed that NLRP3-dependent endothelial cell pyroptosis was activated by HMGB1/RAGE/cathepsin B signaling. These findings were also recapitulated in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). Together, our findings suggest that endothelial cell pyroptosis may play a significant role in coronary endothelial damage in KD, providing novel evidence that further elucidates its pathophysiology.

BackgroundKawasaki disease (KD) is now the most common cause of acquired cardiac disease in children due to permanent coronary artery damage with unknown etiology. The study sought to determine the role of blood microRNA miR‐223 in KD and KD‐induced injuries in vascular endothelial cells (ECs) as well as the mechanisms involved.Methods and ResultsMicroRNA profiles in serum from patients with KD and from healthy controls were assessed by microarray analysis. We noted that multiple serum microRNAs were aberrantly expressed in KD, among them miR‐223, which was the most upregulated abundant serum microRNA. We found that bone marrow–derived blood cells (leukocytes and platelets) were able to secrete miR‐223 into serum. Vascular ECs had no endogenous miR‐223; however, the blood cell–secreted serum miR‐223 could enter into the vascular ECs in the vascular walls. The exogenous miR‐223 had strong biological effects on EC functions via its target genes such as IGF1R. Interestingly, KD‐induced EC injuries were related to increased miR‐223 because they were inhibited by miR‐223 knockdown. Finally, these observations were verified using miR‐223 knockout mice and the chimeric mice generated by transplantation of bone marrow from miR‐223 knockout mice into wild‐type mice.ConclusionsIn KD patients, the levels of blood cell–derived miR‐223 in ECs are significantly increased. The increased miR‐223 in ECs could work as a novel endocrine genetic signal and participate in vascular injury of KD. MiR‐223 may provide a novel mechanism and a new therapeutic target for vascular complication of KD.

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