Systematic Evaluation of the Cellular Innate Immune Response During the Process of Human Atherosclerosis.
Systematic Evaluation of the Cellular Innate Immune Response During the Process of Human Atherosclerosis.
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DOI：
10.1161/jaha.115.002860
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发表时间：
2016-06-16
影响因子：
5.4
通讯作者：
Lindeman JH
中科院分区：
文献类型：
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作者：
van Dijk RA;Rijs K;Wezel A;Hamming JF;Kolodgie FD;Virmani R;Schaapherder AF;Lindeman JH
先天免疫的概念在动脉粥样硬化领域得到了广泛认可，动脉粥样硬化主要由巨噬细胞决定。尽管目前对该过程的认识主要基于小鼠模型，但动脉粥样硬化微环境和相关炎症反应与人类存在根本差异。有鉴于此，我们对正常、非进行性和进行性人类动脉粥样硬化斑块中先天免疫反应的细胞方面进行了表征。对 110 个特征明确的人肾周围主动脉斑块进行了先天免疫反应的系统分析，并对特定巨噬细胞亚型（M1 和 M2 谱系）及其激活标记物、新蝶呤和人白细胞抗原 D 相关抗原 (HLA-DR) 以及树突状细胞 (DC)、自然杀伤 (NK) 细胞、肥大细胞、中性粒细胞和嗜酸性粒细胞进行了免疫染色。正常主动脉缺乏低密度脂蛋白、巨噬细胞、DC、NK 细胞、肥大细胞、嗜酸性粒细胞和中性粒细胞。早期，动脉粥样硬化病变表现出 (CD68+) 巨噬细胞的异质群体，其中 25% 为双阳性“M1”（CD68+/诱导型一氧化氮合酶 [iNOS]+/CD163−），13% 为“M2”双阳性（CD68+/iNOS -/CD163+），17% 为 (M1) iNOS (M2)/CD163 和CD68，剩余的（约 40%）仅对 CD68 进行染色。进行性纤维粥样硬化病变，包括易损斑块，显示 NK 细胞和肌成束蛋白阳性细胞数量增加，主要位于中膜和外膜，而 M1/M2 比率和巨噬细胞活化水平（HLA-DR 和新蝶呤）保持不变。相反，稳定（纤维化）斑块显示巨噬细胞和细胞活化显着减少，同时 NK 细胞、DC 和中性粒细胞也减少。巨噬细胞“M1”和“M2”亚群与肌成束蛋白阳性 DC 一起，与人类主动脉进行性和脆弱性动脉粥样硬化性疾病密切相关。这里的观察结果支持比基于小鼠数据的现有范式更复杂的巨噬细胞异质性理论，并进一步表明（定义不明确的）巨噬细胞亚型的参与或比之前考虑的更大的巨噬细胞可塑性动态范围。
The concept of innate immunity is well recognized within the spectrum of atherosclerosis, which is primarily dictated by macrophages. Although current insights to this process are largely based on murine models, there are fundamental differences in the atherosclerotic microenvironment and associated inflammatory response relative to humans. In this light, we characterized the cellular aspects of innate immune response in normal, nonprogressive, and progressive human atherosclerotic plaques. A systematic analysis of innate immune response was performed on 110 well‐characterized human perirenal aortic plaques with immunostaining for specific macrophage subtypes (M1 and M2 lineage) and their activation markers, neopterin and human leukocyte antigen–antigen D related (HLA‐DR), together with dendritic cells (DCs), natural killer (NK) cells, mast cells, neutrophils, and eosinophils. Normal aortae were devoid of low‐density lipoprotein, macrophages, DCs, NK cells, mast cells, eosinophils, and neutrophils. Early, atherosclerotic lesions exhibited heterogeneous populations of (CD68+) macrophages, whereby 25% were double positive “M1” (CD68+/ inducible nitric oxide synthase [iNOS]+/CD163−), 13% “M2” double positive (CD68+/iNOS −/CD163+), and 17% triple positive for (M1) iNOS (M2)/CD163 and CD68, with the remaining (≈40%) only stained for CD68. Progressive fibroatheromatous lesions, including vulnerable plaques, showed increasing numbers of NK cells and fascin‐positive cells mainly localized to the media and adventitia whereas the M1/M2 ratio and level of macrophage activation (HLA‐DR and neopterin) remained unchanged. On the contrary, stabilized (fibrotic) plaques showed a marked reduction in macrophages and cell activation with a concomitant decrease in NK cells, DCs, and neutrophils. Macrophage “M1” and “M2” subsets, together with fascin‐positive DCs, are strongly associated with progressive and vulnerable atherosclerotic disease of human aorta. The observations here support a more complex theory of macrophage heterogeneity than the existing paradigm predicated on murine data and further indicate the involvement of (poorly defined) macrophage subtypes or greater dynamic range of macrophage plasticity than previously considered.