Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Medicine volume 17, pages 581–588 (2011)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Frangogiannis, N.G. The mechanistic basis of infarct healing. Antioxid. Redox Signal. 8, 1907–1939 (2006).

    Article  CAS  Google Scholar 

  2. Heymans, S. et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat. Med. 5, 1135–1142 (1999).

    Article  CAS  Google Scholar 

  3. Matsumura, S. et al. Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice. J. Clin. Invest. 115, 599–609 (2005).

    Article  CAS  Google Scholar 

  4. Nahrendorf, M. et al. Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial infarction. Circulation 113, 1196–1202 (2006).

    Article  CAS  Google Scholar 

  5. Wehrens, X.H. & Doevendans, P.A. Cardiac rupture complicating myocardial infarction. Int. J. Cardiol. 95, 285–292 (2004).

    Article  Google Scholar 

  6. Ley, K., Laudanna, C., Cybulsky, M.I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7, 678–689 (2007).

    Article  CAS  Google Scholar 

  7. Shimaoka, M. et al. Structures of the αL I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell 112, 99–111 (2003).

    Article  CAS  Google Scholar 

  8. Shamri, R. et al. Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines. Nat. Immunol. 6, 497–506 (2005).

    Article  CAS  Google Scholar 

  9. Evans, R. et al. Integrins in immunity. J. Cell Sci. 122, 215–225 (2009).

    Article  CAS  Google Scholar 

  10. Shaw, S.K. et al. Coordinated redistribution of leukocyte LFA-1 and endothelial cell ICAM-1 accompany neutrophil transmigration. J. Exp. Med. 200, 1571–1580 (2004).

    Article  CAS  Google Scholar 

  11. Salas, A., Shimaoka, M., Phan, U., Kim, M. & Springer, T.A. Transition from rolling to firm adhesion can be mimicked by extension of integrin αLβ2 in an intermediate affinity state. J. Biol. Chem. 281, 10876–10882 (2006).

    Article  CAS  Google Scholar 

  12. Vestweber, D. Adhesion and signaling molecules controlling the transmigration of leukocytes through endothelium. Immunol. Rev. 218, 178–196 (2007).

    Article  CAS  Google Scholar 

  13. Choi, E.Y. et al. Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science 322, 1101–1104 (2008).

    Article  CAS  Google Scholar 

  14. Bootcov, M.R. et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-β superfamily. Proc. Natl. Acad. Sci. USA 94, 11514–11519 (1997).

    Article  CAS  Google Scholar 

  15. Fairlie, W.D. et al. MIC-1 is a novel TGF-β superfamily cytokine associated with macrophage activation. J. Leukoc. Biol. 65, 2–5 (1999).

    Article  CAS  Google Scholar 

  16. Hsiao, E.C. et al. Characterization of growth-differentiation factor 15, a transforming growth factor β superfamily member induced following liver injury. Mol. Cell. Biol. 20, 3742–3751 (2000).

    Article  CAS  Google Scholar 

  17. Schober, A. et al. Expression of growth differentiation factor-15/ macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in the perinatal, adult and injured rat brain. J. Comp. Neurol. 439, 32–45 (2001).

    Article  CAS  Google Scholar 

  18. Kempf, T. et al. The transforming growth factor-β superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ. Res. 98, 351–360 (2006).

    Article  CAS  Google Scholar 

  19. Frank, D. et al. Gene expression pattern in biomechanically stretched cardiomyocytes: evidence for a stretch-specific gene program. Hypertension 51, 309–318 (2008).

    Article  CAS  Google Scholar 

  20. Wollert, K.C. et al. Prognostic value of growth-differentiation factor-15 in patients with non-ST-segment elevation acute coronary syndrome. Circulation 115, 962–971 (2007).

    Article  CAS  Google Scholar 

  21. Wollert, K.C. et al. Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non ST-elevation acute coronary syndrome. Circulation 116, 1540–1548 (2007).

    Article  Google Scholar 

  22. Bonaca, M.P. et al. Growth differentiation factor-15 and risk of recurrent events in patients stabilized after acute coronary syndrome. Observations from PROVE IT-TIMI 22. Arterioscler. Thromb. Vasc. Biol. 31, 203–210 (2011).

    Article  CAS  Google Scholar 

  23. Dransfield, I. & Hogg, N. Regulated expression of Mg2+ binding epitope on leukocyte integrin α subunits. EMBO J. 8, 3759–3765 (1989).

    Article  CAS  Google Scholar 

  24. Lum, A.F., Green, C.E., Lee, G.R., Staunton, D.E. & Simon, S.I. Dynamic regulation of LFA-1 activation and neutrophil arrest on intercellular adhesion molecule 1 (ICAM-1) in shear flow. J. Biol. Chem. 277, 20660–20670 (2002).

    Article  CAS  Google Scholar 

  25. Hyduk, S.J. et al. Phospholipase C, calcium and calmodulin are critical for α4β1 integrin affinity up-regulation and monocyte arrest triggered by chemoattractants. Blood 109, 176–184 (2007).

    Article  CAS  Google Scholar 

  26. Bergmeier, W. et al. Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III. J. Clin. Invest. 117, 1699–1707 (2007).

    Article  CAS  Google Scholar 

  27. Kinashi, T. et al. LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds. Blood 103, 1033–1036 (2004).

    Article  CAS  Google Scholar 

  28. Bolomini-Vittori, M. et al. Regulation of conformer-specific activation of the integrin LFA-1 by a chemokine-triggered Rho signaling module. Nat. Immunol. 10, 185–194 (2009).

    Article  CAS  Google Scholar 

  29. Abram, C.L. & Lowell, C.A. The ins and outs of leukocyte integrin signaling. Annu. Rev. Immunol. 27, 339–362 (2009).

    Article  CAS  Google Scholar 

  30. Opal, S.M. & DePalo, V.A. Anti-inflammatory cytokines. Chest 117, 1162–1172 (2000).

    Article  CAS  Google Scholar 

  31. Takagi, J. & Springer, T.A. Integrin activation and structural rearrangement. Immunol. Rev. 186, 141–163 (2002).

    Article  CAS  Google Scholar 

  32. Kinashi, T. & Katagiri, K. Regulation of immune cell adhesion and migration by regulator of adhesion and cell polarization enriched in lymphoid tissues. Immunology 116, 164–171 (2005).

    Article  CAS  Google Scholar 

  33. de Jager, S.C. et al. Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J. Exp. Med. 208, 217–225 (2011).

    Article  CAS  Google Scholar 

  34. van den Borne, S.W. et al. Increased matrix metalloproteinase-8 and -9 activity in patients with infarct rupture after myocardial infarction. Cardiovasc. Pathol. 18, 37–43 (2009).

    Article  CAS  Google Scholar 

  35. Ichihara, S. et al. Targeted deletion of angiotensin II type 2 receptor caused cardiac rupture after acute myocardial infarction. Circulation 106, 2244–2249 (2002).

    Article  CAS  Google Scholar 

  36. Shimazaki, M. et al. Periostin is essential for cardiac healing after acute myocardial infarction. J. Exp. Med. 205, 295–303 (2008).

    Article  CAS  Google Scholar 

  37. Westermann, D. et al. Biglycan is required for adaptive remodeling after myocardial infarction. Circulation 117, 1269–1276 (2008).

    Article  CAS  Google Scholar 

  38. Schellings, M.W. et al. Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction. J. Exp. Med. 206, 113–123 (2009).

    Article  CAS  Google Scholar 

  39. Palazzo, A.J., Jones, S.P., Anderson, D.C., Granger, D.N. & Lefer, D.J. Coronary endothelial P-selectin in pathogenesis of myocardial ischemia-reperfusion injury. Am. J. Physiol. 275, H1865–H1872 (1998).

    CAS  PubMed  Google Scholar 

  40. Palazzo, A.J. et al. Myocardial ischemia-reperfusion injury in CD18- and ICAM-1–deficient mice. Am. J. Physiol. 275, H2300–H2307 (1998).

    CAS  PubMed  Google Scholar 

  41. Baran, K.W. et al. Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study. Circulation 104, 2778–2783 (2001).

    Article  CAS  Google Scholar 

  42. Faxon, D.P., Gibbons, R.J., Chronos, N.A., Gurbel, P.A. & Sheehan, F. The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: the results of the HALT-MI study. J. Am. Coll. Cardiol. 40, 1199–1204 (2002).

    Article  CAS  Google Scholar 

  43. Dirksen, M.T., Laarman, G.J., Simoons, M.L. & Duncker, D.J. Reperfusion injury in humans: a review of clinical trials on reperfusion injury inhibitory strategies. Cardiovasc. Res. 74, 343–355 (2007).

    Article  CAS  Google Scholar 

  44. Giugliano, R.P. & Braunwald, E. Selecting the best reperfusion strategy in ST-elevation myocardial infarction: it's all a matter of time. Circulation 108, 2828–2830 (2003).

    Article  Google Scholar 

  45. Hsiao, E.C. et al. Characterization of growth-differentiation factor 15, a transforming growth factor β superfamily member induced following liver injury. Mol. Cell. Biol. 20, 3742–3751 (2000).

    Article  CAS  Google Scholar 

  46. Kempf, T. et al. The transforming growth factor-β superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ. Res. 98, 351–360 (2006).

    Article  CAS  Google Scholar 

  47. Scharffetter-Kochanek, K. et al. Spontaneous skin ulceration and defective T cell function in CD18 null mice. J. Exp. Med. 188, 119–131 (1998).

    Article  CAS  Google Scholar 

  48. Matsumura, S. et al. Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice. J. Clin. Invest. 115, 599–609 (2005).

    Article  CAS  Google Scholar 

  49. D'Angelo, M., Billings, P.C., Pacifici, M., Leboy, P.S. & Kirsch, T. Authentic matrix vesicles contain active metalloproteases (MMP). A role for matrix vesicle-associated MMP-13 in activation of transforming growth factor-β. J. Biol. Chem. 276, 11347–11353 (2001).

    Article  CAS  Google Scholar 

  50. Zarbock, A., Deem, T.L., Burcin, T.L. & Ley, K.G. αi2 is required for chemokine-induced neutrophil arrest. Blood 110, 3773–3779 (2007).

    Article  CAS  Google Scholar 

  51. Kuwano, Y., Spelten, O., Zhang, H., Ley, K. & Zarbock, A. Rolling on E- or P-selectin induces the extended, but not high affinity conformation of LFA-1 in neutrophils. Blood 116, 617–624 (2010).

    Article  CAS  Google Scholar 

  52. Bolomini-Vittori, M. et al. Regulation of conformer-specific activation of the integrin LFA-1 by a chemokine-triggered Rho signaling module. Nat. Immunol. 10, 185–194 (2009).

    Article  CAS  Google Scholar 

  53. Zarbock, A., Lowell, C.A. & Ley, K. Spleen tyrosine kinase Syk is necessary for E-selectin-induced αLβ2 integrin-mediated rolling on intercellular adhesion molecule-1. Immunity 26, 773–783 (2007).

    Article  CAS  Google Scholar 

  54. Dransfield, I. & Hogg, N. Regulated expression of Mg2+ binding epitope on leukocyte integrin α subunits. EMBO J. 8, 3759–3765 (1989).

    Article  CAS  Google Scholar 

  55. Sebzda, E., Bracke, M., Tugal, T., Hogg, N. & Cantrell, D.A. Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling. Nat. Immunol. 3, 251–258 (2002).

    Article  CAS  Google Scholar 

  56. Lum, A.F., Green, C.E., Lee, G.R., Staunton, D.E. & Simon, S.I. Dynamic regulation of LFA-1 activation and neutrophil arrest on intercellular adhesion molecule 1 (ICAM-1) in shear flow. J. Biol. Chem. 277, 20660–20670 (2002).

    Article  CAS  Google Scholar 

  57. Haverstick, D.M., Engelhard, V.H. & Gray, L.S. Three intracellular signals for cytotoxic T lymphocyte-mediated killing. Independent roles for protein kinase C, Ca2+ influx, and Ca2+ release from internal stores. J. Immunol. 146, 3306–3313 (1991).

    CAS  PubMed  Google Scholar 

  58. Zarbock, A. et al. PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcRγ to induce slow leukocyte rolling. J. Exp. Med. 205, 2339–2347 (2008).

    Article  CAS  Google Scholar 

Download references

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

Author notes

  1. Tibor Kempf, Alexander Zarbock, Dietmar Vestweber and Kai C Wollert: These authors contributed equally to this work.

Authors and Affiliations

  1. Hans Borst Center for Heart and Stem Cell Research, Hannover Medical School, Hannover, Germany

    Tibor Kempf, Christian Widera, Mortimer Korf-Klingebiel, L Christian Napp, Anna Kanwischer & Kai C Wollert

  2. Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

    Tibor Kempf, Christian Widera, Mortimer Korf-Klingebiel, L Christian Napp, Birte Hansen, Anna Kanwischer, Udo Bavendiek & Kai C Wollert

  3. Max Planck Institute of Molecular Biomedicine, University of Münster, Münster, Germany

    Alexander Zarbock, Stefan Butz, Anika Stadtmann, Jan Rossaint & Dietmar Vestweber

  4. Department of Anesthesiology and Critical Care Medicine, University of Münster, Münster, Germany

    Alexander Zarbock, Anika Stadtmann & Jan Rossaint

  5. Department of Pathology, University of Verona, Verona, Italy

    Matteo Bolomini-Vittori & Carlo Laudanna

  6. Department of Hematology and Oncology, Hannover Medical School, Hannover, Germany

    Gernot Beutel

  7. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    Martin Hapke & Martin G Sauer

  8. Cancer Research UK, London Research Institute, London, UK

    Nancy Hogg

Authors
  1. Tibor Kempf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander Zarbock
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christian Widera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefan Butz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anika Stadtmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan Rossaint
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matteo Bolomini-Vittori
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mortimer Korf-Klingebiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Christian Napp
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Birte Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anna Kanwischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Udo Bavendiek
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gernot Beutel
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Martin Hapke
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Martin G Sauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Carlo Laudanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Nancy Hogg
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Dietmar Vestweber
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Kai C Wollert
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding authors

Correspondence to Dietmar Vestweber or Kai C Wollert.

Ethics declarations

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11, Supplementary Table 1 and Supplementary Methods (PDF 1650 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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). https://doi.org/10.1038/nm.2354

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2354

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing