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GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice.
MedLine Citation:
PMID:  21516086     Owner:  NLM     Status:  Publisher    
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.
Tibor Kempf; Alexander Zarbock; Christian Widera; Stefan Butz; Anika Stadtmann; Jan Rossaint; Matteo Bolomini-Vittori; Mortimer Korf-Klingebiel; L Christian Napp; Birte Hansen; Anna Kanwischer; Udo Bavendiek; Gernot Beutel; Martin Hapke; Martin G Sauer; Carlo Laudanna; Nancy Hogg; Dietmar Vestweber; Kai C Wollert
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-4-24
Journal Detail:
Title:  Nature medicine     Volume:  -     ISSN:  1546-170X     ISO Abbreviation:  -     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-4-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1] Hans Borst Center for Heart and Stem Cell Research, Hannover Medical School, Hannover, Germany. [2] Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany. [3].
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