Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment.
Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment.
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DOI：
10.1161/circresaha.116.305825
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发表时间：
2015-02-27
影响因子：
20.1
通讯作者：
Soehnlein O
中科院分区：
文献类型：
--
作者：
Drechsler M;de Jong R;Rossaint J;Viola JR;Leoni G;Wang JM;Grommes J;Hinkel R;Kupatt C;Weber C;Döring Y;Zarbock A;Soehnlein O
趋化因子控制的动脉白细胞募集是动脉粥样硬化的关键过程。甲酰肽受体2（FPR 2）是识别促炎和促分解配体的化学引诱物受体。FPR 2及其前分解配体膜联蛋白A1对动脉粥样硬化病变形成的作用在很大程度上是不确定的。由于FPR 2配体的矛盾性，我们在这里研究FPR 2及其解析配体膜联蛋白A1在动脉粥样硬化形成中的作用。FPR 2或其配体膜联蛋白A1的缺失增强动脉粥样硬化病变形成、动脉髓样细胞粘附和募集。从机制上讲，我们确定膜联蛋白A1作为内源性抑制剂的整合素激活诱发的趋化因子CCL 5，CCL 2和CXCL 1。具体而言，膜联蛋白A1片段Ac 2 -26通过抑制小GT受体Rap 1的活化来抵消由CCL 5、CCL 2和CXCL 1诱发的髓样细胞上整合素的构象活化和聚集。Ac 2 -26的体内给药以FPR 2依赖性方式大大减少了骨髓细胞的动脉募集。在存在CCR 5、CCR 2或CXCR 2的选择性拮抗剂的情况下也观察到这种作用，而当同时拮抗所有3种趋化因子受体时，Ac 2 -26没有作用。最后，用Ac 2 -26重复治疗减少了动脉粥样硬化病变大小和病变巨噬细胞积聚。指导膜联蛋白A1-FPR 2轴包含一种靶向动脉白细胞募集的新方法。由于Ac 2 -26能够抵消由各种趋化因子引起的整联蛋白活化，因此与阻断单个趋化因子受体相比，Ac 2 -26的递送在抑制动脉白细胞募集方面可能是上级的。
Chemokine-controlled arterial leukocyte recruitment is a crucial process in atherosclerosis. Formyl peptide receptor 2 (FPR2) is a chemoattractant receptor that recognizes proinflammatory and proresolving ligands. The contribution of FPR2 and its proresolving ligand annexin A1 to atherosclerotic lesion formation is largely undefined. Because of the ambivalence of FPR2 ligands, we here investigate the role of FPR2 and its resolving ligand annexin A1 in atherogenesis. Deletion of FPR2 or its ligand annexin A1 enhances atherosclerotic lesion formation, arterial myeloid cell adhesion, and recruitment. Mechanistically, we identify annexin A1 as an endogenous inhibitor of integrin activation evoked by the chemokines CCL5, CCL2, and CXCL1. Specifically, the annexin A1 fragment Ac2-26 counteracts conformational activation and clustering of integrins on myeloid cells evoked by CCL5, CCL2, and CXCL1 through inhibiting activation of the small GTPase Rap1. In vivo administration of Ac2-26 largely diminishes arterial recruitment of myeloid cells in a FPR2-dependent fashion. This effect is also observed in the presence of selective antagonists to CCR5, CCR2, or CXCR2, whereas Ac2-26 was without effect when all 3 chemokine receptors were antagonized simultaneously. Finally, repeated treatment with Ac2-26 reduces atherosclerotic lesion sizes and lesional macrophage accumulation. Instructing the annexin A1-FPR2 axis harbors a novel approach to target arterial leukocyte recruitment. With the ability of Ac2-26 to counteract integrin activation exerted by various chemokines, delivery of Ac2-26 may be superior in inhibition of arterial leukocyte recruitment when compared with blocking individual chemokine receptors.