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

Saskia C. A. de Jager*, Beatriz Bermudez, 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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Growth differentiation factor (GDF) 15 is a member of the transforming growth factor. (TGF-beta) 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 TGF beta RII-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 TGF beta RII-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/TGF beta RII-dependent inflammatory responses to vascular injury.
Original languageEnglish
Pages (from-to)217-225
JournalJournal of Experimental Medicine
Issue number2
Publication statusPublished - 14 Feb 2011

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