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.
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GDF-15 inhibits apoptosis and inflammation, and protects the heart from injury.
“GDF-15 has also been shown to inhibit apoptosis and inflammation, and protects the heart from injury (36–38).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [37]
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- Authors
- Kempf, T., Zarbock, A., Widera, C., Butz, S., Stadtmann, A., Rossaint, J., Bolomini-Vittori, M., Korf-Klingebiel, M., Napp, L. C., Hansen, B., Kanwischer, A., Bavendiek, U., Beutel, G., Hapke, M., Sauer, M. G., Laudanna, C., Hogg, N., Vestweber, D., & Wollert, K. C.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- University of Münster (DE)
- University of Verona (IT)
- Cancer Research UK (GB)
- Corresponding author
- Vestweber, Dietmar
- Wollert, Kai C
- ORCID
- Venue
- Nature Medicine
- Published
- 2011-04-24
- Volume
- 17
- Issue
- 5
- Pages
- 581-588
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2010044292
- Cited by
- 518
- References
- 53
- Citations by year
- 2026: 21 · 2025: 30 · 2024: 50 · 2023: 32 · 2022: 38 · 2021: 32 · 2020: 52 · 2019: 27 · 2018: 29 · 2017: 31 · 2016: 33 · 2015: 42 · 2014: 32 · 2013: 29 · 2012: 29
- FWCI
- 23.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- GDF15, myocardial infarction, leukocyte recruitment, beta2 integrins, leukocyte transmigration, polymorphonuclear leukocytes, cardiac rupture, Cdc42, Rap1, chemokine signaling, anti-inflammatory cytokines, leukocyte adhesion, transendothelial migration, myeloid cells
- MeSH terms
- Animals, Cell Adhesion, Cell Movement, Male, Mice, Inbred C57BL, Myocardial Infarction, Neutrophils, Signal Transduction, Integrins, Mice, Knockout, CD18 Antigens, cdc42 GTP-Binding Protein, rap1 GTP-Binding Proteins, Myeloid Cells, Mice, Growth Differentiation Factor 15, Mice, 129 Strain
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