Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4-CXCR7.
Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4-CXCR7.
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DOI：
10.1038/cddis.2015.233
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发表时间：
2015-11-19
影响因子：
9
通讯作者：
Gawaz M
中科院分区：
文献类型：
--
作者：
Chatterjee M;von Ungern-Sternberg SN;Seizer P;Schlegel F;Büttcher M;Sindhu NA;Müller S;Mack A;Gawaz M
血小板储存和释放CXCL12 (SDF-1)，它控制造血祖细胞向内皮细胞或巨噬细胞泡沫细胞的分化。CXCL12连接CXCR4和CXCR7，调节单核细胞/巨噬细胞功能。本研究揭示了CXCR4-CXCR7在介导血小板来源的CXCL12对单核细胞功能、存活和分化的影响中的相对作用。与MCP-1不同，连接CXCR4 - CXCR7的CXCL12和巨噬细胞迁移抑制因子（MIF）诱导了受体的动态双向运输，导致趋化过程中CXCR4内化和CXCR7外化，从而影响受体的相对可用性。在体内，我们发现小鼠腹膜炎诱导后腹膜液中血小板和血小板-巨噬细胞共聚集体的积累增强。与外周血相比，浸润单核细胞中CXCL12、CXCR4和CXCR7的相对表面表达也增强。来自胶原粘附血小板的血小板衍生的CXCL12和重组CXCL12通过CXCR4参与特异性诱导单核细胞趋化。静态和动态动脉血流条件下，单核细胞与固定的CXCL12和富集CXCL12的活化血小板表面的粘附主要通过CXCR7介导，并通过中和血小板衍生的CXCL12进行拮抗调节。单核细胞和培养源性m1 - M2巨噬细胞吞噬血小板，当CXCR4-CXCR7参与时，培养源性m1巨噬细胞的吞噬电位高于M2。CXCR7是促进单核细胞存活的主要受体，通过血小板来源的CXCL12抑制bh3诱导的细胞凋亡（磷脂酰丝氨酸暴露、caspase-3激活、线粒体跨膜电位丧失）。在与血小板共培养实验中，单核细胞主要分化为CD163+巨噬细胞，在CXCL12中和和CXCR4/CXCR7阻断抗体的作用下，巨噬细胞被减弱。此外，OxLDL被血小板摄取会诱导血小板凋亡，就像其他血小板激动剂TRAP和胶原相关肽（CRP）一样。CXCL12促进单核细胞和M1-M2巨噬细胞吞噬凋亡血小板，并通过CXCR4和CXCR7促进其向泡沫细胞分化。因此，血小板来源的CXCL12可以通过CXCR4和CXCR7的不同参与来调节单核巨噬细胞功能，表明在血小板聚集部位的炎症中起重要作用。
Platelets store and release CXCL12 (SDF-1), which governs differentiation of hematopoietic progenitors into either endothelial or macrophage-foam cells. CXCL12 ligates CXCR4 and CXCR7 and regulates monocyte/macrophage functions. This study deciphers the relative contribution of CXCR4–CXCR7 in mediating the effects of platelet-derived CXCL12 on monocyte function, survival, and differentiation. CXCL12 and macrophage migration inhibitory factor (MIF) that ligate CXCR4–CXCR7 induced a dynamic bidirectional trafficking of the receptors, causing CXCR4 internalization and CXCR7 externalization during chemotaxis, thereby influencing relative receptor availability, unlike MCP-1. In vivo we found enhanced accumulation of platelets and platelet-macrophage co-aggregates in peritoneal fluid following induction of peritonitis in mice. The relative surface expression of CXCL12, CXCR4, and CXCR7 among infiltrated monocytes was also enhanced as compared with peripheral blood. Platelet-derived CXCL12 from collagen-adherent platelets and recombinant CXCL12 induced monocyte chemotaxis specifically through CXCR4 engagement. Adhesion of monocytes to immobilized CXCL12 and CXCL12-enriched activated platelet surface under static and dynamic arterial flow conditions were mediated primarily through CXCR7 and were counter-regulated by neutralizing platelet-derived CXCL12. Monocytes and culture-derived-M1–M2 macrophages phagocytosed platelets, with the phagocytic potential of culture-derived-M1 macrophages higher than M2 involving CXCR4–CXCR7 participation. CXCR7 was the primary receptor in promoting monocyte survival as exerted by platelet-derived CXCL12 against BH3-mimetic induced apoptosis (phosphatidylserine exposure, caspase-3 activation, loss of mitochondrial transmembrane potential). In co-culture experiments with platelets, monocytes predominantly differentiated into CD163+ macrophages, which was attenuated upon CXCL12 neutralization and CXCR4/CXCR7 blocking antibodies. Moreover, OxLDL uptake by platelets induced platelet apoptosis, like other platelet agonists TRAP and collagen-related peptide (CRP). CXCL12 facilitated phagocytosis of apoptotic platelets by monocytes and M1–M2 macrophages, also promoted their differentiation into foam cells via CXCR4 and CXCR7. Thus, platelet-derived CXCL12 could regulate monocyte-macrophage functions through differential engagement of CXCR4 and CXCR7, indicating an important role in inflammation at site of platelet accumulation.