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 language | English (US) |
|---|---|
| Pages (from-to) | 217-225 |
| Number of pages | 9 |
| Journal | Journal of Experimental Medicine |
| Volume | 208 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 14 2011 |
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ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
Cite this
Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. / De Jager, Saskia C A; Bermúdez, Beatriz; Bot, Ilze; Koenen, Rory R.; Bot, Martine; Kavelaars, Annemieke; De Waard, Vivian; Heijnen, Cobi J.; Muriana, Francisco J G; Weber, Christian; Van Berkel, Theo J C; Kuiper, Johan; Lee, Se Jin; Abia, Rocio; Biessen, Erik A L.
In: Journal of Experimental Medicine, Vol. 208, No. 2, 14.02.2011, p. 217-225.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis
AU - De Jager, Saskia C A
AU - Bermúdez, Beatriz
AU - Bot, Ilze
AU - Koenen, Rory R.
AU - Bot, Martine
AU - Kavelaars, Annemieke
AU - De Waard, Vivian
AU - Heijnen, Cobi J.
AU - Muriana, Francisco J G
AU - Weber, Christian
AU - Van Berkel, Theo J C
AU - Kuiper, Johan
AU - Lee, Se Jin
AU - Abia, Rocio
AU - Biessen, Erik A L
PY - 2011/2/14
Y1 - 2011/2/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79951708423&partnerID=8YFLogxK
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U2 - 10.1084/jem.20100370
DO - 10.1084/jem.20100370
M3 - Article
C2 - 21242297
AN - SCOPUS:79951708423
VL - 208
SP - 217
EP - 225
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 2
ER -