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

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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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Figure 1: Gdf15-knockout mice have an increased rate of fatal cardiac rupture after myocardial infarction.
Figure 2: Gdf-15 inhibits myeloid cell recruitment into the infarcted myocardium.
Figure 3: GDF-15 inhibits myeloid cell adhesion and transendothelial migration under static conditions.
Figure 4: GDF-15 inhibits leukocyte arrest under flow conditions and in vivo.
Figure 5: GDF-15 inhibits β2 integrin activation by activating Cdc42 and deactivating Rap1.
Figure 6: Blockade of leukocyte integrins or deficiency of β2 integrins in myeloid cells rescues the mortality of Gdf15-KO mice after myocardial infarction.

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Acknowledgements

K.C.W. was supported by the German Research Foundation (SFB 566), A.Z. by the German Research Foundation (AZ 428/3-1) and the Else Kröner Fresenius Foundation (2010_EKES.01), M.G.S. by the German Research Foundation (SFB 738) and D.V. by the Max Planck Society. We acknowledge A. Quint for expert technical assistance. We thank S.J. Lee (Johns Hopkins University) for providing the Gdf15-knockout mouse.

Author information

T.K. and A.Z. designed and carried out experiments, analyzed the data and contributed to the writing of the manuscript. C.W., S.B., A.S., J.R., M.K.-K., B.H., A.K. and M.H. carried out experiments. M.B.-V., L.C.N., U.B., G.B. and M.G.S. provided key reagents and experimental protocols. C.L. and N.H. provided key reagents and gave conceptual advice. D.V. and K.C.W. designed the study, supervised the experiments and wrote the manuscript.

Correspondence to Dietmar Vestweber or Kai C Wollert.

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Competing interests

T.K. and K.C.W. have filed an international patent application with the European Patent Office and have a contract with Roche Diagnostics to develop a GDF-15 assay for cardiovascular applications.

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Kempf, T., Zarbock, A., Widera, C. et al. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med 17, 581–588 (2011) doi:10.1038/nm.2354

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