CD70 limits atherosclerosis and promotes macrophage function
CD70 limits atherosclerosis and promotes macrophage function
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DOI：
10.1160/th16-04-0318
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发表时间：
2016-10
影响因子：
6.7
通讯作者：
H. Winkels;Svenja Meiler;E. Smeets;D. Lievens;D. Engel;Charlotte Spitz;C. Bürger;P. Rinne;Linda Beckers;Angelika Dandl;S. Reim;M. Ahmadsei;J. van den Bossche;L. Holdt;R. Megens;Martin M. N. Schmitt;M. D. de Winther;E. Biessen;J. Borst;A. Faussner;C. Weber;E. Lutgens;N. Gerdes
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文献类型：
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作者：
H. Winkels;Svenja Meiler;E. Smeets;D. Lievens;D. Engel;Charlotte Spitz;C. Bürger;P. Rinne;Linda Beckers;Angelika Dandl;S. Reim;M. Ahmadsei;J. van den Bossche;L. Holdt;R. Megens;Martin M. N. Schmitt;M. D. de Winther;E. Biessen;J. Borst;A. Faussner;C. Weber;E. Lutgens;N. Gerdes
共刺激分子CD 70在活化的免疫细胞上表达，已知其通过受体CD 27调节T、B和NK细胞的应答。到目前为止，只有有限的数据描述CD 70在动脉粥样硬化中的作用。我们观察到破裂的人颈动脉粥样硬化斑块显示出比稳定的颈动脉粥样硬化斑块更高的CD 70表达，并且小鼠动脉粥样硬化中的CD 70表达定位于巨噬细胞。CD 70的缺乏损害了炎症能力（e. G.活性氧和一氧化氮的产生），增加M1样和M2样巨噬细胞标志物，并使巨噬细胞代谢失活和易于凋亡。此外，CD 70缺陷型巨噬细胞表达的清道夫受体和ABC转运蛋白水平降低，分别损害氧化低密度脂蛋白（oxLDL）和胆固醇流出的摄取。与接受对照骨髓的小鼠相比，用CD 70缺陷骨髓重建的高脂血症Apoe −/−小鼠显示坏死核心大小、斑块面积和病变巨噬细胞数量显著增加。因此，与Apoe−/−小鼠相比，18周龄的普通饲料喂养的CD 70缺陷型Apoe−/−小鼠显示出更大的动脉粥样化，其特征在于细胞构成更低和斑块表型更晚期。总之，CD 70促进巨噬细胞的功能和活力，是有效的吞噬和oxLDL流出的关键。CD 70缺乏导致更晚期的动脉粥样硬化。我们的数据表明，CD 70至少部分通过调节巨噬细胞功能来减轻动脉粥样硬化。注：本文的审稿过程由G. Y. H.利普主编本文的补充材料可在www.thrombosis-online.com上查阅。
Summary The costimulatory molecule CD70 is expressed on activated immune cells and is known to modulate responses of T, B, and NK cells via its receptor CD27. Until now, there is only limited data describing the role of CD70 in atherosclerosis. We observed that ruptured human carotid atherosclerotic plaques displayed higher CD70 expression than stable carotid atherosclerotic plaques, and that CD70 expression in murine atheroma localized to macrophages. Lack of CD70 impaired the inflammatory capacity (e. g. reactive oxygen species and nitric oxide production) of bone marrow-derived macrophages, increased both M1-like and M2-like macrophage markers, and rendered macrophages meta-bolically inactive and prone to apoptosis. Moreover, CD70-deficient macrophages expressed diminished levels of scavenger receptors and ABC-transporters, impairing uptake of oxidised low-density lipoprotein (oxLDL) and cholesterol efflux, respectively. Hyperlipidaemic Apoe −/− mice reconstituted with CD70-deficient bone marrow displayed a profound increase in necrotic core size, plaque area, and number of lesional macrophages as compared to mice receiving control bone marrow. Accordingly, 18 week-old, chow diet-fed CD70-deficient Apoe−/−mice displayed larger atheroma characterised by lower cellularity and more advanced plaque phenotype than Apoe−/− mice. In conclusion, CD70 promotes macrophage function and viability and is crucial for effective phagocytosis and efflux of oxLDL. Deficiency in CD70 results in more advanced atheroma. Our data suggest that CD70 mitigates atherosclerosis at least in part by modulating macrophage function. Note: The review process for this manuscript was fully handled by G. Y. H. Lip, Editor in Chief. Supplementary Material to this article is available online at www.thrombosis-online.com.