Deficiency of 5-HT2B receptors alleviates atherosclerosis by regulating macrophage phenotype through inhibiting interferon signalling.

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Yahan Liu, Zhipeng Wang, Li Fang, Yaohua Xu, Beilei Zhao, Xuya Kang, Yanqing Zhao, Jintao Han, Yan Zhang, Erdan Dong, Nanping Wang
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Abstract

Background and purpose: Elevated levels of 5-HT have been correlated with coronary artery disease and cardiac events, suggesting 5-HT is a potential novel factor in the development of atherosclerotic cardiovascular disease. However, the underlying pathological mechanisms of the 5-HT system in atherosclerosis remain unclear. The 5-HT2B receptor (5-HT2BR), which establishes a positive feedback loop with 5-HT, has been identified as a contributor to pathophysiological processes in various vascular disorders. In this study, we investigated the immunological impact of 5-HT2BR in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice.

Experimental approach: Plasma levels of 5-HT were measured in mice using an ELISA kit. Atherosclerotic plaque formation, macrophage infiltration and inflammatory signalling were assessed in ApoE-/- mice by employing both pharmacological inhibition and genetic deficiency of 5-HT2BR. Inflammasome activation was elucidated using peritoneal macrophages isolated from 5-HT2BR-deficient mice.

Key results: An upregulation of 5-HT2BR expression was observed in the aortas of ApoE-/- mice, exhibiting a strong correlation with the presence of macrophages in plaques. Atherosclerosis was attenuated in mice through pharmacological inhibition and genetic deficiency of 5-HT2BR. Additionally, a significant reduction in atherosclerotic plaque size was achieved through bone marrow reconstitution with 5-HT2BR-deficient cells. 5-HT2BR-deficient macrophages showed attenuated interferon (IFN) signalling, NLRP3 inflammasome activation, and interleukin-1β release. Moreover, macrophages primed with 5-HT2BR deficiency displayed an anti-inflammatory phenotype.

Conclusion and implications: These findings support the hypothesis that 5-HT2BR in macrophages plays a causal role in the development of atherosclerosis, revealing a novel perspective for potential therapeutic strategies in atherosclerosis-related diseases.

Abstract Image

缺乏 5-HT2B 受体可通过抑制干扰素信号调节巨噬细胞表型,从而缓解动脉粥样硬化。
背景和目的:5-羟色胺水平的升高与冠状动脉疾病和心脏事件相关,这表明 5-HT 是动脉粥样硬化性心血管疾病发生发展的潜在新因素。然而,5-HT 系统在动脉粥样硬化中的潜在病理机制仍不清楚。5-HT2B受体(5-HT2BR)与5-HT建立了正反馈环路,已被确定为各种血管疾病病理生理过程的促成因素。在这项研究中,我们研究了 5-HT2BR 对易患动脉粥样硬化的载脂蛋白 E 缺失(ApoE-/-)小鼠的免疫学影响:实验方法:使用ELISA试剂盒测定小鼠血浆中5-HT的水平。通过药物抑制和遗传性5-HT2BR缺失,评估载脂蛋白E-/-小鼠动脉粥样硬化斑块的形成、巨噬细胞浸润和炎症信号传导。利用从5-HT2BR缺陷小鼠体内分离的腹腔巨噬细胞阐明了炎症体的激活:主要结果:在载脂蛋白E-/-小鼠的主动脉中观察到5-HT2BR表达上调,这与斑块中巨噬细胞的存在密切相关。通过药物抑制和基因缺失 5-HT2BR 可减轻小鼠的动脉粥样硬化。此外,通过用5-HT2BR缺陷细胞进行骨髓重组,动脉粥样硬化斑块的大小也明显缩小。5-HT2BR缺陷型巨噬细胞的干扰素(IFN)信号、NLRP3炎性体激活和白细胞介素-1β释放均有所减弱。此外,缺乏 5-HT2BR 的巨噬细胞显示出抗炎表型:这些发现支持了巨噬细胞中的 5-HT2BR 在动脉粥样硬化的发展中起着因果作用的假设,为动脉粥样硬化相关疾病的潜在治疗策略提供了新的视角。
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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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