免疫球蛋白通过抑制过度激活的先天性免疫反应减轻暴发性心肌炎的病情

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2024-10-23 DOI:10.1111/bph.17372
Jianpei Wen, Huihui Li, Yufei Zhou, Hengzhi Du, Guo Hu, Zheng Wen, Du Tang, Yanwen Wang, Xinwu Cui, Zhou Zhou, Dao Wen Wang, Chen Chen
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引用次数: 0

摘要

背景和目的:暴发性心肌炎(FM)是一种心肌炎性疾病,可由病毒性疾病或自身免疫性疾病引起。本研究确定了免疫调节药物对 FM 的治疗效果:实验方法:通过腹腔注射柯萨奇病毒B3诱导A/JGpt小鼠发生FM,然后每天腹腔注射免疫球蛋白。第七天,通过超声心动图和心导管检查确定心脏结构和功能。进行了单细胞 RNA 测序(scRNA-seq)以评估心脏中的 CD45+ 细胞:免疫球蛋白是一种典型的免疫调节药物,它能显著降低FM小鼠的死亡率并明显改善其心脏功能。SCRNA-seq显示,免疫球蛋白治疗能有效调节心脏免疫平衡,尤其是通过减轻过度激活的先天性免疫反应。在细胞水平上,免疫球蛋白主要靶向 Plac8+ 单核细胞和 S100a8+ 中性粒细胞,抑制它们的促炎活性,增强抗原处理和呈递能力,从而提高抗病毒免疫反应的效率和效力。免疫球蛋白的益处是通过调节多种信号通路介导的,包括免疫细胞上的相关受体、炎症细胞趋化方向、抗原递呈和抗病毒作用。随后,由免疫球蛋白操纵的Bst2-ILT7配体-受体介导的细胞相互作用在体内得到了进一步证实:免疫球蛋白治疗通过抑制过度激活的先天性免疫反应,明显减轻了调频诱导的心脏炎症并改善了心脏功能。
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Immunoglobin attenuates fulminant myocarditis by inhibiting overactivated innate immune response.

Background and purpose: Fulminant myocarditis (FM) is a myocardial inflammatory disease that can result from either viral diseases or autoimmune diseases. In this study, we have determined the treatment effects of immunomodulatory drugs on FM.

Experimental approach: FM was induced in A/JGpt mice by intraperitoneal administration of coxsackievirus B3, after which immunoglobins were administered daily by intraperitoneal injection. On the seventh day, the cardiac structure and function were determined using echocardiography and cardiac catheterisation. Single-cell RNA sequencing (scRNA-seq) was performed to evaluate CD45+ cells in the heart.

Key results: Immunoglobin, a typical immunomodulatory drug, dramatically reduced mortality and significantly improved cardiac function in mice with FM. ScRNA-seq revealed that immunoglobin treatment effectively modulated cardiac immune homeostasis, particularly by attenuating overactivated innate immune responses. At the cellular level, immunoglobin predominantly targeted Plac8+ monocytes and S100a8+ neutrophils, suppressing their proinflammatory activities, and enhancing antigen processing and presentation capabilities, thereby amplifying the efficiency and potency of the immune response against the virus. Immunoglobin benefits are mediated by the modulation of multiple signalling pathways, including relevant receptors on immune cells, direction of inflammatory cell chemotaxis, antigen presentation and anti-viral effects. Subsequently, Bst2-ILT7 ligand-receptor-mediated cellular interactions manipulated by immunoglobin were further confirmed in vivo.

Conclusions and implications: Immunoglobin treatment significantly attenuated FM-induced cardiac inflammation and improved cardiac function by inhibiting overactivated innate immune responses.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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