Abstract
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.
Highlights
Kawasaki disease (KD) is an acute vasculitis and is the main cause of acquired heart disease in pediatric populations of developed countries[1]
Results showed that the levels of total ASC, caspase-1, IL-1β, IL-18, and Gasdermin D (GSDMD) were remarkably increased in sera from KD subjects compared with healthy controls (HCs) (Fig. 1a–e)
In the present study, we demonstrated that endothelial cells (ECs) pyroptosis is a crucial pathophysiological event in KD, and that activation of pyroptosis is triggered by high levels of High mobility group box 1 (HMGB1), leading to elevated expression of RAGE and cathepsin B activity, which results in NLRP3 inflammasome-dependent caspase-1-mediated pyroptotic cell death in the ECs (Fig. 8)
Summary
Kawasaki disease (KD) is an acute vasculitis and is the main cause of acquired heart disease in pediatric populations of developed countries[1]. 25% of KD patients would go on to develop coronary artery aneurysm[2], and even with prompt administration of IVIG, risk of coronary artery aneurysm remains unacceptable high. Official journal of the Cell Death Differentiation Association. Jia et al Cell Death and Disease (2019)10:778. Part of the difficulty of treating KD is due to its complex inflammatory pathophysiology. Previous studies reported that endothelial cell injury and inflammation are the two key pathological mechanisms for KD4,5. While some mechanisms for endothelial cell injury in KD, such as endothelial–mesenchymal transition (EndoMT)[2] and endothelial cell apoptosis[6,7], have been demonstrated, whether other mechanisms play a role in this complex inflammatory disease remains unknown
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