Endothelial cell pyroptosis plays an important role in Kawasaki disease via HMGB1/RAGE/cathespin B signaling pathway and NLRP3 inflammasome activation
Endothelial cell pyroptosis plays an important role in Kawasaki disease via HMGB1/RAGE/cathespin B signaling pathway and NLRP3 inflammasome activation
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内皮细胞焦亡通过 HMGB1/RAGE/cathespin B 信号通路和 NLRP3 炎症小体激活在川崎病中发挥重要作用
DOI：
10.1038/s41419-019-2021-3
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发表时间：
2019-10-14
影响因子：
9
通讯作者：
Chu, Maoping
中科院分区：
文献类型：
--
作者：
Jia, Chang;Zhang, Jian;Chu, Maoping
川崎（Kawasaki disease，KD）是发达国家儿童心脏病最常见的病因，可导致永久性冠状动脉损伤和冠状动脉瘤等长期后遗症。鉴于KD的患病率和严重程度，有必要对其病理生理学进行进一步研究。内皮细胞损伤和炎症反应是导致KD冠状动脉内皮功能障碍的两个重要过程。然而，详细的机制在很大程度上是未知的。在这项研究中，我们调查了在KD的设置中的作用，并假设，焦亡可能在其病理生理学中发挥核心作用。KD患者的体内实验表明，与健康对照组（HC）相比，KD患者血清中的脓毒症相关蛋白（ASC、caspase-1、IL-1β、IL-18、GSDMD和乳酸脱氢酶（LDH））水平显著升高。免疫印迹分析显示，KD患儿血清中GSDMD和成熟IL-1β的表达明显升高。在体外，人脐静脉内皮细胞（HUVEC）暴露于KD血清处理的THP 1细胞导致NLRP 3炎性小体活化和随后的焦亡诱导，表现为caspase-1、GSDMD、GSDMD的裂解p30形式、IL-1β和IL-18的表达升高，LDH释放和TUNEL及碘化丙啶（PI）阳性细胞增加。此外，我们的研究结果表明，NLRP 3依赖的内皮细胞焦亡被激活的HMGB 1/cathepsin B信号。这些结果也在白念珠菌细胞壁提取物（CAWS）诱导的KD小鼠模型中得到了重现。总之，我们的研究结果表明，内皮细胞热凋亡可能在川崎病冠状动脉内皮损伤中发挥重要作用，为进一步阐明其病理生理学提供了新的证据。
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 byCandida albicanscell 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.