| First Author | de Jager SC | Year | 2011 |
| Journal | J Exp Med | Volume | 208 |
| Issue | 2 | Pages | 217-25 |
| PubMed ID | 21242297 | Mgi Jnum | J:176852 |
| Mgi Id | MGI:5292821 | Doi | 10.1084/jem.20100370 |
| Citation | de Jager SC, et al. (2011) Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J Exp Med 208(2):217-25 |
| abstractText | Growth differentiation factor (GDF) 15 is a member of the transforming growth factor beta (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 TGFbetaRII-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 TGFbetaRII-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/TGFbetaRII-dependent inflammatory responses to vascular injury. |
