Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis

Saskia C.A. De Jager, Beatriz Bermúdez, Ilze Bot, Rory R. Koenen, Martine Bot, Annemieke Kavelaars, Vivian De Waard, Cobi J. Heijnen, Francisco J.G. Muriana, Christian Weber, Theo J.C. Van Berkel, Johan Kuiper, Se Jin Lee, Rocio Abia, Erik A.L. Biessen

Research output: Contribution to journalArticlepeer-review

Abstract

Growth differentiation factor (GDF) 15 is a member of the transforming growth factor β (TGF-β) superfamily, which operates in acute phase responses through a currently unknown receptor. Elevated GDF-15 serum levels were recently identified as a risk factor for acute coronary syndromes. We show that GDF-15 expression is up-regulated as disease progresses in murine atherosclerosis and primarily colocalizes with plaque macrophages. Hematopoietic GDF-15 deficiency in low density lipoprotein receptor-/- mice led to impaired initial lesion formation and increased collagen in later lesions. Although lesion burden in GDF-15-/- chimeras was unaltered, plaques had reduced macrophage infiltrates and decreased necrotic core formation, all features of improved plaque stability. In vitro studies pointed to a TGFβRII-dependent regulatory role of GDF-15 in cell death regulation. Importantly, GDF-15-/- macrophages displayed reduced CCR2 expression, whereas GDF-15 promoted macrophage chemotaxis in a strictly CCR2- and TGFβRII-dependent manner, a phenomenon which was not observed in G protein-coupled receptor kinase 2+/- macrophages. In conclusion, GDF-15 deletion has a beneficial effect both in early and later atherosclerosis by inhibition of CCR2-mediated chemotaxis and by modulating cell death. Our study is the first to identify GDF-15 as an acute phase modifier of CCR2/TGFβRII-dependent inflammatory responses to vascular injury.

Original languageEnglish (US)
Pages (from-to)217-225
Number of pages9
JournalJournal of Experimental Medicine
Volume208
Issue number2
DOIs
StatePublished - Feb 14 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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