趋化因子
心肌梗塞
细胞因子
医学
活体显微镜检查
整合素
小型GTPase
免疫学
内科学
炎症
细胞生物学
信号转导
生物
受体
微循环
作者
Tibor Kempf,Alexander Zarbock,Christian Widera,Stefan Butz,Anika Stadtmann,Jan Rossaint,Matteo Bolomini-Vittori,Mortimer Korf‐Klingebiel,L. Christian Napp,Bogi Hansen,Anna Kanwischer,Udo Bavendiek,Gernot Beutel,Martin Hapke,Martin G. Sauer,Carlo Laudanna,Nancy Hogg,Dietmar Vestweber,Kai C. Wollert
出处
期刊:Nature Medicine
[Springer Nature]
日期:2011-04-24
卷期号:17 (5): 581-588
被引量:408
摘要
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-β (TGF-β)-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 β(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 β(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.
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