Format

Send to

Choose Destination
J Exp Med. 2011 Feb 14;208(2):217-25. doi: 10.1084/jem.20100370. Epub 2011 Jan 17.

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

Author information

1
Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, Netherlands. s.de.jager@lacdr.leidenuniv.nl

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.

PMID:
21242297
PMCID:
PMC3039852
DOI:
10.1084/jem.20100370
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center