EMBO：揭示单核细胞迁移至血管壁导致动脉粥样硬化机制

在一项新的研究中,来自德国慕尼黑大学和荷兰阿姆斯特丹学术医学中心的研究人员首次阐明促进动脉粥样硬化产生的单核细胞如何找到通向血管壁的路径,在那里,它们促进阻塞性沉积物形成.相关研究结果于2013年2月18日在线发表在EMBO Molecular Medicine期刊上,论文标题为"Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes".

动脉粥样硬化是导致人们死亡的最为常见的原因之一.它的特征是动脉内表面上的被称作动脉粥样硬化斑块(atherosclerotic plaque)的脂肪沉积物堆积,从而限制和可能最终阻断血液流动.这些沉积物也能够从它们的起源位点被排挤出而随后可能阻断心脏或大脑中的主要血管,从而导致威胁生命的心肌梗塞或中风.

单核细胞是一种重要的白细胞,已知显著性地促进动脉粥样硬化产生.它们被主动招募到动脉粥样硬化病变位点,并且通过维持一种慢性的炎症反应来促进脉粥样硬化斑块发展.

因此抑制单核细胞招募提供一种破坏动脉粥样硬化斑块堆积的方法.然而,人们首先知道单核细胞如何被招募到血管壁中.如今,在这项研究中,慕尼黑大学心血管疾病预防与流行病学学院的Christian Weber教授和Maik Drechsler博士、慕尼黑大学心血管病预防学院研究员Oliver S?hnlein和来自阿姆斯特丹学术医学中心的一个研究小组合作开展研究,并证实受体分子CCR1和CCR5至关重要地参与这种过程：单核细胞被招募到血管壁中.该过程由一系列不同的步骤组成,包括附着到形成动脉壁的内皮细胞上和它们随后通过在相邻的内皮细胞之间渗透而进入血液中,接着通过结合它们各自的配体而激活这些受体.

这些新的发现纠正了人们普遍持有的关于受体CCR2在招募单核细胞中确切功能的看法.Oliver S?hnlein说,"与人们迄今为止所持有的观点不同的是,这种受体并不调控单核细胞渗透进血管壁中；相反,如另一种趋化因子受体CXCR2一样,它控制这些细胞从骨髓中迁移到血液中."

因此,这两种受体分子CCR1和CCR5代表着一种大有希望的靶标来开发出新的治疗动脉粥样硬化的方法,其中这些方法将使用直接或间接抑制它们与它们各自的结合伴侣相互作用的试剂.

DOI:10.1002/emmm.201201717
PMC:
PMID:

Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes

Oliver Soehnlein1,2,3,?,*,Maik Drechsler1,3,?,Yvonne D?ring1,3,Dirk Lievens1,3,Helene Hartwig1,Klaus Kemmerich1,Almudena Ortega-Gómez1,Manuela Mandl1,Santosh Vijayan3,Delia Projahn1,Christoph D. Garlichs4,Rory R. Koenen1,5,Mihail Hristov1,Esther Lutgens1,6,Alma Zernecke7,8,9,?,Christian Weber1,3,5,8,?,*

We used a novel approach of cytostatically induced leucocyte depletion and subsequent reconstitution with leucocytes deprived of classical (inflammatory/Gr1hi) or non-classical (resident/Gr1lo) monocytes to dissect their differential role in atheroprogression under high-fat diet (HFD). Apolipoprotein E-deficient (Apoe?/?) mice lacking classical but not non-classical monocytes displayed reduced lesion size and macrophage and apoptotic cell content. Conversely, HFD induced a selective expansion of classical monocytes in blood and bone marrow. Increased CXCL1 levels accompanied by higher expression of its receptor CXCR2 on classical monocytes and inhibition of monocytosis by CXCL1-neutralization indicated a preferential role for the CXCL1/CXCR2 axis in mobilizing classical monocytes during hypercholesterolemia. Studies correlating circulating and lesional classical monocytes in gene-deficient Apoe?/? mice, adoptive transfer of gene-deficient cells and pharmacological modulation during intravital microscopy of the carotid artery revealed a crucial function of CCR1 and CCR5 but not CCR2 or CX3CR1 in classical monocyte recruitment to atherosclerotic vessels. Collectively, these data establish the impact of classical monocytes on atheroprogression, identify a sequential role of CXCL1 in their mobilization and CCR1/CCR5 in their recruitment.