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Updated: Jun 5, 2026
Culture of Macrophage Colony-stimulating Factor Differentiated Human Monocyte-derived Macrophages
Published on: June 30, 2016
Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage
Saskia C A de Jager1, Beatriz Bermúdez, Ilze Bot
1Biopharmaceutics, 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.
Insights
Growth Differentiation Factor (GDF) 15 influences atherosclerosis progression. Deleting GDF-15 benefits plaque stability by reducing macrophage migration and modulating cell death, offering therapeutic potential for cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Inflammation Research
- Molecular Medicine
Background:
- Growth Differentiation Factor (GDF) 15, a TGF-β superfamily member, is implicated in acute phase responses.
- Elevated GDF-15 serum levels are a risk factor for acute coronary syndromes.
- GDF-15 expression increases with atherosclerosis progression, localizing to plaque macrophages.
Purpose of the Study:
- To investigate the role of GDF-15 in atherosclerosis development and plaque stability.
- To elucidate the molecular mechanisms underlying GDF-15's function in vascular inflammation.
Main Methods:
- Utilized low-density lipoprotein receptor knockout mice with hematopoietic GDF-15 deficiency.
- Analyzed atherosclerotic lesion formation, composition (collagen, necrotic core), and macrophage infiltration.
- Performed in vitro studies on macrophage chemotaxis and cell death regulation, assessing CCR2 and TGFβRII dependence.
Main Results:
- GDF-15 deficiency impaired early lesion formation but increased collagen in later lesions.
- GDF-15 knockout reduced macrophage infiltrates and necrotic core size, enhancing plaque stability.
- GDF-15 promoted macrophage chemotaxis via CCR2 and TGFβRII, and modulated cell death.
Conclusions:
- GDF-15 deletion confers benefits in both early and advanced atherosclerosis.
- GDF-15 inhibition of CCR2-mediated chemotaxis and cell death modulation are key mechanisms.
- This study identifies GDF-15 as an acute phase modifier of inflammatory responses in vascular injury.
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