CXCL12/CXCR4 axis mediates CD8 + T cell overactivation in the progression of viral myocarditis.

IF 6.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Li Zhang, Keyu Liu, Xiuyun Duan, Shan Zhou, Hailin Jia, Yingnan You, Bo Han
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引用次数: 0

Abstract

Background: Myocarditis is a common inflammatory heart disease in children and young adults, with fulminant myocarditis (FM) being the most severe form due to its rapid onset and high mortality rate. However, the precise pathological immune subsets and molecular change in myocarditis, particularly FM, remain unknown.

Methods: We performed single-cell RNA sequencing of pediatric peripheral blood mononuclear cells during the acute and recovery phases of FM. A viral myocarditis (MC) mouse model was established using CVB3. Deletion and adoptive transfer of CD8+T cells, as well as blockade of CXCR4, were conducted in vivo. CD8+T cells were sorted and cultivated in vitro, then stimulated with CXCL12 and CXCR4 antagonists to investigate the mechanism of CD8+T cell overactivation.

Results: CD8+T cells show significant activation, amplification, enhanced cytotoxicity, and increased chemotactic ability in FM. Deletion of CD8+T cells alleviates myocardial injury and improves cardiac function in MC mice, while adoptive transfer of CD8+T cells from MC mice aggravates myocardial inflammation and injury. The transcriptomic analysis reveals elevated CXCR4 expression in CD8+T cells in acute FM. In vitro experiments demonstrate that the CXCL12/CXCR4 axis drives the overactivation and cytotoxicity of CD8+T cells. In vivo treatment with a CXCR4 antagonist effectively reduces CD8+T cell accumulation in the heart, alleviates myocardial inflammation, and improves cardiac function in MC mice.

Conclusions: These findings provide deeper insights into the immune landscape of pediatric FM, uncovering a novel role of the CXCL12/CXCR4 axis in driving CD8+T cell responses in myocarditis. Furthermore, they highlight the CXCL12/CXCR4 axis as a promising therapeutic target for myocarditis treatment.

CXCL12/CXCR4轴介导CD8 + T细胞在病毒性心肌炎进展中的过度激活。
背景:心肌炎是儿童和青壮年常见的一种炎症性心脏病,暴发性心肌炎(FM)发病迅速,死亡率高,是最严重的一种。然而,心肌炎,特别是FM的确切病理免疫亚群和分子变化仍然未知。方法:我们对小儿外周血单核细胞在急性期和恢复期进行了单细胞RNA测序。采用CVB3建立病毒性心肌炎(MC)小鼠模型。在体内进行了CD8+T细胞的缺失和过继转移,以及CXCR4的阻断。体外培养CD8+T细胞,分别用CXCL12和CXCR4拮抗剂刺激CD8+T细胞,探讨CD8+T细胞过度活化的机制。结果:CD8+T细胞在FM中表现出明显的活化、扩增、细胞毒性增强和趋化能力增强。缺失CD8+T细胞可减轻MC小鼠心肌损伤,改善心功能,而过继性转移CD8+T细胞可加重心肌炎症和损伤。转录组学分析显示急性FM患者CD8+T细胞中CXCR4表达升高。体外实验表明,CXCL12/CXCR4轴驱动CD8+T细胞的过度活化和细胞毒性。在体内用CXCR4拮抗剂治疗可有效减少CD8+T细胞在心脏中的积累,减轻心肌炎症,改善MC小鼠的心功能。结论:这些发现为儿童FM的免疫景观提供了更深入的见解,揭示了CXCL12/CXCR4轴在心肌炎中驱动CD8+T细胞反应中的新作用。此外,他们强调CXCL12/CXCR4轴是治疗心肌炎的一个有希望的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Translational Medicine
Journal of Translational Medicine 医学-医学:研究与实验
CiteScore
10.00
自引率
1.40%
发文量
537
审稿时长
1 months
期刊介绍: The Journal of Translational Medicine is an open-access journal that publishes articles focusing on information derived from human experimentation to enhance communication between basic and clinical science. It covers all areas of translational medicine.
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