title: GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice.
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 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.
authors.affiliation: Hans Borst Center for Heart and Stem Cell Research, Hannover Medical School, Hannover, Germany.
authors.forename: Tibor
authors.initials: T
authors.lastname: Kempf
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.forename: Christian
authors.initials: C
authors.lastname: Widera
authors.forename: Stefan
authors.initials: S
authors.lastname: Butz
authors.forename: Anika
authors.initials: A
authors.lastname: Stadtmann
authors.forename: Jan
authors.initials: J
authors.lastname: Rossaint
authors.forename: Matteo
authors.initials: M
authors.lastname: Bolomini-Vittori
authors.forename: Mortimer
authors.initials: M
authors.lastname: Korf-Klingebiel
authors.forename: L Christian
authors.initials: LC
authors.lastname: Napp
authors.forename: Birte
authors.initials: B
authors.lastname: Hansen
authors.forename: Anna
authors.initials: A
authors.lastname: Kanwischer
authors.forename: Udo
authors.initials: U
authors.lastname: Bavendiek
authors.forename: Gernot
authors.initials: G
authors.lastname: Beutel
authors.forename: Martin
authors.initials: M
authors.lastname: Hapke
authors.forename: Martin G
authors.initials: MG
authors.lastname: Sauer
authors.forename: Carlo
authors.initials: C
authors.lastname: Laudanna
authors.forename: Nancy
authors.initials: N
authors.lastname: Hogg
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000235:genetics / Q000502:physiology; D002448:Cell Adhesion; D002465:Cell Movement; D055436:Growth Differentiation Factor 15 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016023:Integrins / Q000502:physiology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000473:pathology / Q000502:physiology; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009504:Neutrophils / Q000473:pathology / Q000502:physiology*; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D020827:rap1 GTP-Binding Proteins / Q000502:physiology
chemical_list: D018821:CD18 Antigens; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D016023:Integrins; D020764:cdc42 GTP-Binding Protein; D020827:rap1 GTP-Binding Proteins