Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice
Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice
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DOI：
10.1038/nm.1898
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发表时间：
2009-01-01
期刊：
影响因子：
82.9
通讯作者：
Weber, Christian
中科院分区：
文献类型：
--
作者：
Koenen, Rory R.;von Hundelshausen, Philipp;Weber, Christian
动脉粥样硬化的特征是由于趋化因子驱动的单核细胞募集引起的动脉壁慢性炎症（1-4）。活化的血小板可与趋化因子协同作用，加剧动脉粥样硬化形成;例如，通过沉积趋化因子血小板因子-4（PF 4，也称为CXCL 4）和RANTES（CCL 5），触发炎症内皮上的单核细胞停滞（5-9）。同源寡聚化是CCL 5的募集功能所必需的，并且趋化因子异源聚化最近已经作为另外的调节机制出现，如CXCL 8和CXCL 4活性的相互调节以及由CCL 5-CXCL 4相互作用引起的增强的单核细胞停滞所证明的（10-13）。CCL 5拮抗剂Met-RANTES可减少饮食诱导的动脉粥样硬化（9，14）;然而，CCL 5拮抗作用在治疗上可能不可行，如使用CCL 5缺陷小鼠的研究所示，这意味着直接CCL 5阻断将严重损害全身免疫应答，延迟巨噬细胞介导的病毒清除并损害正常T细胞功能（15，16）。在这里，我们确定了CCL 5-CXCL 4异聚体的结构特征，并设计了稳定的肽抑制剂，特异性破坏促炎性CCL 5-CXCL 4相互作用，从而减弱单核细胞募集并减少动脉粥样硬化，而没有上述副作用。这些结果确立了趋化因子异聚体的体内相关性，并显示了靶向异聚体形成以实现治疗效果的潜力。
Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment(1-4). Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXCL4) and RANTES (CCL5), triggering monocyte arrest on inflamed endothelium(5-9). Homo-oligomerization is required for the recruitment functions of CCL5, and chemokine heteromerization has more recently emerged as an additional regulatory mechanism, as evidenced by a mutual modulation of CXCL8 and CXCL4 activities and by enhanced monocyte arrest resulting from CCL5-CXCL4 interactions(10-13). The CCL5 antagonist Met-RANTES reduces diet-induced atherosclerosis(9,14); however, CCL5 antagonism may not be therapeutically feasible, as suggested by studies using Ccl5-deficient mice which imply that direct CCL5 blockade would severely compromise systemic immune responses, delay macrophage-mediated viral clearance and impair normal T cell functions(15,16). Here we determined structural features of CCL5-CXCL4 heteromers and designed stable peptide inhibitors that specifically disrupt proinflammatory CCL5-CXCL4 interactions, thereby attenuating monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects.