Winkels Holger, Meiler Svenja, Smeets Esther, Lievens Dirk, Engel David, Spitz Charlotte, Bürger Christina, Rinne Petteri, Beckers Linda, Dandl Angelika, Reim Sigrid, Ahmadsei Maiwand, Van den Bossche Jan, Holdt Lesca M, Megens Remco T A, Schmitt Martin, de Winther Menno, Biessen Eric A, Borst Jannie, Faussner Alexander, Weber Christian, Lutgens Esther, Gerdes Norbert
Norbert Gerdes, PhD, Institute for Cardiovascular Prevention, Ludwig-Maximilians University Munich, Pettenkoferstrasse 9, 80336 Munich, Germany, Tel.: +49 89 4400 54672, Email:
Thromb Haemost. 2017 Jan 5;117(1):164-175. doi: 10.1160/TH16-04-0318. Epub 2016 Oct 27.
The co-stimulatory 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 metabolically 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.
共刺激分子CD70在活化的免疫细胞上表达，已知其通过受体CD27调节T细胞、B细胞和NK细胞的反应。到目前为止，仅有有限的数据描述CD70在动脉粥样硬化中的作用。我们观察到，破裂的人类颈动脉粥样硬化斑块比稳定的颈动脉粥样硬化斑块显示出更高的CD70表达，并且小鼠动脉粥样硬化病变中的CD70表达定位于巨噬细胞。缺乏CD70会损害骨髓来源巨噬细胞的炎症能力（例如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，并使巨噬细胞代谢不活跃且易于凋亡。此外，CD70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，分别损害氧化型低密度脂蛋白（oxLDL）的摄取和胆固醇流出。与接受对照骨髓的小鼠相比，用CD70缺陷型骨髓重建的高脂血症Apoe小鼠的坏死核心大小、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、以普通饮食喂养的CD70缺陷型Apoe小鼠表现出更大的动脉粥样硬化病变，其特征是细胞数量减少和斑块表型更晚期。总之，CD70促进巨噬细胞功能和活力，对oxLDL的有效吞噬和流出至关重要。CD70缺陷会导致更晚期的动脉粥样硬化病变。我们的数据表明，CD70至少部分地通过调节巨噬细胞功能来减轻动脉粥样硬化。
