GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice
GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice
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DOI：
10.1038/nm.2354
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发表时间：
2011-05-01
期刊：
影响因子：
82.9
通讯作者：
Wollert, Kai C.
中科院分区：
文献类型：
--
作者：
Kempf, Tibor;Zarbock, Alexander;Wollert, Kai C.
心肌梗死后的炎症细胞募集需要严格控制，以允许梗死愈合，同时避免致命的并发症，如心脏破裂。生长分化因子-15（GDF-15）是一种转化生长因子-β（TGF-β）相关的细胞因子，在小鼠和人类的梗死心脏中被诱导。我们发现Gdf 15缺陷小鼠冠状动脉结扎导致多形核白细胞（PMNs）向梗死心肌的募集增加，心脏破裂的发生率增加。相反，输注重组GDF-15抑制了心肌梗死后PMN的募集。在体外，GDF-15抑制PMN粘附、血流阻滞和跨内皮迁移。从机制上讲，GDF-15通过激活小GTdR Cdc 42和抑制小GTdR Rap 1的激活来抵消趋化因子触发的构象激活和PMN上β 2整联蛋白的聚集。Gdf-15缺陷小鼠体内活体显微镜检查表明，Gdf-15是防止过度的趋化因子激活的白细胞在内皮上停滞所必需的。骨髓细胞中β 2整合素的基因切除挽救了心肌梗死后Gdf 15缺陷小鼠的死亡率据我们所知，GDF-15是第一个被鉴定为通过直接干扰趋化因子信号传导和整联蛋白活化而抑制PMN募集的细胞因子。这种抗炎机制的丧失导致心肌梗死后致命的心脏破裂。
Inflammatory cell recruitment after myocardial infarction needs to be tightly controlled to permit infarct healing while avoiding fatal complications such as cardiac rupture. Growth differentiation factor-15 (GDF-15), a transforming growth factor-beta (TGF-beta)-related cytokine, is induced in the infarcted heart of mice and humans. We show that coronary artery ligation in Gdf15-deficient mice led to enhanced recruitment of polymorphonuclear leukocytes (PMNs) into the infarcted myocardium and an increased incidence of cardiac rupture. Conversely, infusion of recombinant GDF-15 repressed PMN recruitment after myocardial infarction. In vitro, GDF-15 inhibited PMN adhesion, arrest under flow and transendothelial migration. Mechanistically, GDF-15 counteracted chemokine-triggered conformational activation and clustering of beta(2) integrins on PMNs by activating the small GTPase Cdc42 and inhibiting activation of the small GTPase Rap1. Intravital microscopy in vivo in Gdf15-deficient mice showed that Gdf-15 is required to prevent excessive chemokine-activated leukocyte arrest on the endothelium. Genetic ablation of beta(2) integrins in myeloid cells rescued the mortality of Gdf15-deficient mice after myocardial infarction. To our knowledge, GDF-15 is the first cytokine identified as an inhibitor of PMN recruitment by direct interference with chemokine signaling and integrin activation. Loss of this anti-inflammatory mechanism leads to fatal cardiac rupture after myocardial infarction.