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

Nat Med. 2011 May;17(5):581-8. doi: 10.1038/nm.2354. Epub 2011 Apr 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD18 Antigens / genetics
  • CD18 Antigens / physiology
  • Cell Adhesion
  • Cell Movement
  • Growth Differentiation Factor 15 / deficiency
  • Growth Differentiation Factor 15 / genetics
  • Growth Differentiation Factor 15 / physiology*
  • Integrins / physiology*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / pathology
  • Myeloid Cells / physiology
  • Myocardial Infarction / genetics
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology*
  • Neutrophils / pathology
  • Neutrophils / physiology*
  • Signal Transduction
  • cdc42 GTP-Binding Protein / physiology
  • rap1 GTP-Binding Proteins / physiology


  • CD18 Antigens
  • Gdf15 protein, mouse
  • Growth Differentiation Factor 15
  • Integrins
  • cdc42 GTP-Binding Protein
  • rap1 GTP-Binding Proteins