Thymic stromal lymphopoietin induces platelet mitophagy and promotes thrombosis in Kawasaki disease

IF 5.1 2区 医学 Q1 HEMATOLOGY British Journal of Haematology Pub Date : 2022-11-07 DOI:10.1111/bjh.18531
Lanyan Fu, Daniel Thomas MacKeigan, Qing Gong, Di Che, Yufen Xu, Lei Pi, Chaonan Sun, Hongyan Yu, Kaining Chen, Huazhong Zhou, Zhiyong Jiang, Zhouping Wang, Li Zhang, Eric G. Cerenzia, Heyu Ni, Xiaoqiong Gu
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引用次数: 2

Abstract

Kawasaki disease (KD) is an acute systemic vasculitis primarily affecting infants and children. Activated platelets predispose patients to coronary artery structural lesions that may lead to thrombotic cardiovascular events. To discover potential proteins underlying platelet activation in KD, we conducted a protein chip assay of 34 cytokines and discovered thymic stromal lymphopoietin (TSLP) was aberrantly expressed, which remained elevated after intravenous immunoglobulin G (IVIG) treatment and during convalescence in KD patients in comparison to healthy controls. Enzyme-linked immunosorbent assay (ELISA) corroborated the upregulation of TSLP in KD patients, which was exacerbated in convalescent patients complicated with thrombosis. TSLP receptors on platelets were also significantly upregulated in KD patients complicated with thrombosis. Platelet activation, apoptosis, and mitochondrial autophagy (mitophagy) were increased in convalescence KD patients complicated with thrombosis. In vitro, TSLP induced platelet activation and platelet mitophagy in healthy blood donors, as observed in KD patients. TSLP, similar to mitophagy agonist carbonyl cyanide 3-chlorophenyl hydrazone (CCCP), promoted thrombosis, which was attenuated by the mitophagy inhibitor Mdivi-1. Co-immunoprecipitation in TSLP-treated platelets revealed TSLP receptor (TSLPR) bound to mitophagy regulators, Parkin and Voltage Dependent Anion Channel Protein 1 (VDAC1).Thus, our results demonstrated that TSLP induced platelet mitophagy via a novel TSLPR/Parkin/VDAC1 pathway that promoted thrombosis in KD. These results suggest TSLP as a novel therapeutic target against KD-associated thrombosis.

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胸腺基质淋巴生成素诱导川崎病血小板有丝分裂并促进血栓形成
川崎病是一种主要影响婴儿和儿童的急性全身性血管炎。活化血小板易使患者发生冠状动脉结构病变,从而导致血栓性心血管事件。为了发现KD患者血小板活化的潜在蛋白,我们对34种细胞因子进行了蛋白芯片分析,发现KD患者胸腺基质淋巴生成素(TSLP)表达异常,在静脉注射免疫球蛋白G (IVIG)治疗后和恢复期,与健康对照组相比,TSLP表达异常。酶联免疫吸附试验(ELISA)证实了KD患者中TSLP的上调,并在合并血栓形成的恢复期患者中加剧。血小板上的TSLP受体在KD合并血栓患者中也显著上调。恢复期KD合并血栓患者血小板活化、细胞凋亡、线粒体自噬(mitophagy)增加。在体外,TSLP诱导健康献血者血小板活化和血小板有丝分裂,如在KD患者中观察到的。TSLP与线粒体自噬激动剂羰基氰化物- 3-氯苯基腙(CCCP)相似,促进血栓形成,线粒体自噬抑制剂Mdivi-1可减轻血栓形成。在TSLP处理的血小板中共免疫沉淀发现TSLP受体(TSLPR)与线粒体自噬调节因子Parkin和电压依赖性阴离子通道蛋白1 (VDAC1)结合。因此,我们的研究结果表明,TSLP通过新的TSLPR/Parkin/VDAC1途径诱导血小板有丝分裂,促进KD血栓形成。这些结果提示TSLP是一种治疗kd相关血栓形成的新靶点。
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来源期刊
CiteScore
8.60
自引率
4.60%
发文量
565
审稿时长
1 months
期刊介绍: The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.
期刊最新文献
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