老年 Ldlr-/- 小鼠动脉粥样硬化斑块的性别双态性

IF 5.2 2区 医学 Q1 GERIATRICS & GERONTOLOGY Immunity & Ageing Pub Date : 2024-05-02 DOI:10.1186/s12979-024-00434-3
Virginia Smit, Jill de Mol, Mireia N. A. Bernabé Kleijn, Marie A. C. Depuydt, Menno P. J. de Winther, Ilze Bot, Johan Kuiper, Amanda C. Foks
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引用次数: 0

摘要

动脉粥样硬化是心血管疾病的主要病理基础,是一种慢性炎症性疾病,其特征是血管壁上的脂质堆积和免疫细胞反应,从而形成斑块。众所周知,动脉粥样硬化的发病率和表现因性别而异。然而,迄今为止,人们尚未对动脉粥样硬化斑块免疫景观的性别二态性进行高分辨率研究。在这项研究中,我们在单细胞水平上研究了老年 Ldlr-/- 小鼠动脉粥样硬化发展和主动脉免疫景观的性别差异。我们通过组织学分析比较了以饲料喂养的雌雄 Ldlr-/- 小鼠(22 个月大)的斑块形态。我们使用单细胞 RNA 序列分析和流式细胞术检测了老年 Ldlr-/- 小鼠主动脉中的 CD45+ 免疫细胞,探索了雌雄小鼠动脉粥样硬化环境中的免疫格局。我们发现,老年雌雄小鼠的斑块体积相当,与雄性小鼠相比,老年雌性小鼠的斑块含有更多的胶原蛋白和胆固醇结晶,但坏死核心和巨噬细胞含量较少。我们发现雌性小鼠主动脉中的免疫细胞浸润增加,并发现雌性小鼠斑块免疫细胞中富含促动脉粥样硬化标志物和炎症信号通路的表达。与雄性相比,雌性小鼠主动脉中的B细胞(Egr1、Cd83、Cd180)(包括年龄相关的B细胞)活化增强,此外,M1/M2巨噬细胞比例增加,其中Il1b+ M1样巨噬细胞显示出更多的促炎症表型(Nlrp3、Cxcl2、Mmp9)。相反,在男性主动脉中观察到与年龄相关的 Gzmk+CD8+ T 细胞、树突状细胞和 Trem2+ 巨噬细胞数量增加。总之,我们的研究结果突出表明,性别是导致小鼠动脉粥样硬化斑块环境免疫学差异的一个变量,并为进一步临床前研究性别对动脉粥样硬化病理生理学的影响提供了宝贵的见解。
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Sexual dimorphism in atherosclerotic plaques of aged Ldlr−/− mice
Atherosclerosis, the main underlying pathology of cardiovascular disease, is a chronic inflammatory disease characterized by lipid accumulation and immune cell responses in the vascular wall, resulting in plaque formation. It is well-known that atherosclerosis prevalence and manifestation vary by sex. However, sexual dimorphism in the immune landscape of atherosclerotic plaques has up to date not been studied at high-resolution. In this study, we investigated sex-specific differences in atherosclerosis development and the immunological landscape of aortas at single-cell level in aged Ldlr−/− mice. We compared plaque morphology between aged male and female chow diet-fed Ldlr−/− mice (22 months old) with histological analysis. Using single-cell RNA-sequencing and flow cytometry on CD45+ immune cells from aortas of aged Ldlr−/− mice, we explored the immune landscape in the atherosclerotic environment in males and females. We show that plaque volume is comparable in aged male and female mice, and that plaques in aged female mice contain more collagen and cholesterol crystals, but less necrotic core and macrophage content compared to males. We reveal increased immune cell infiltration in female aortas and found that expression of pro-atherogenic markers and inflammatory signaling pathways was enriched in plaque immune cells of female mice. Particularly, female aortas show enhanced activation of B cells (Egr1, Cd83, Cd180), including age-associated B cells, in addition to an increased M1/M2 macrophage ratio, where Il1b+ M1-like macrophages display a more pro-inflammatory phenotype (Nlrp3, Cxcl2, Mmp9) compared to males. In contrast, increased numbers of age-associated Gzmk+CD8+ T cells, dendritic cells, and Trem2+ macrophages were observed in male aortas. Altogether, our findings highlight that sex is a variable that contributes to immunological differences in the atherosclerotic plaque environment in mice and provide valuable insights for further preclinical studies into the impact of sex on the pathophysiology of atherosclerosis.
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来源期刊
Immunity & Ageing
Immunity & Ageing GERIATRICS & GERONTOLOGY-IMMUNOLOGY
CiteScore
10.20
自引率
3.80%
发文量
55
期刊介绍: Immunity & Ageing is a specialist open access journal that was first published in 2004. The journal focuses on the impact of ageing on immune systems, the influence of aged immune systems on organismal well-being and longevity, age-associated diseases with immune etiology, and potential immune interventions to increase health span. All articles published in Immunity & Ageing are indexed in the following databases: Biological Abstracts, BIOSIS, CAS, Citebase, DOAJ, Embase, Google Scholar, Journal Citation Reports/Science Edition, OAIster, PubMed, PubMed Central, Science Citation Index Expanded, SCImago, Scopus, SOCOLAR, and Zetoc.
期刊最新文献
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