GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice

T Kempf, A Zarbock, C Widera, S Butz, A Stadtmann… - Nature medicine, 2011 - nature.com
T Kempf, A Zarbock, C Widera, S Butz, A Stadtmann, J Rossaint, M Bolomini-Vittori…
Nature medicine, 2011nature.com
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 …
Abstract
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 β2 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 β2 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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