TY - JOUR
T1 - Requirement for CD154 in the progression of atherosclerosis
AU - Lutgens, Esther
AU - Gorelik, Leonid
AU - Daemen, Mat J.A.P.
AU - De Muinck, Ebo D.
AU - Grewal, Iqbal S.
AU - Koteliansky, Victor E.
AU - Flavell, Richard A.
N1 - Funding Information:
Acknowledgments We thank C. Hughes for the original generation of the CD154 knockout mice. Part of this research was sponsored by the Wynand Pon Foundation, Leusden, the Netherlands. R.A.F. is an investigator and L.G. is an Associate of the Howard Hughes Medical Insitute. I.S.G. was supported by a Juvenile Diabetes Fellowship.
PY - 1999/11
Y1 - 1999/11
N2 - Atherosclerosis is a systemic disease of the large arteries, and activation of inflammatory pathways is important in its pathogenesis. Increasing evidence supports the importance of CD40-CD154 interactions in atherosclerosis, interactions originally known to be essential in major immune reactions and autoimmune diseases. CD40 is present on atheroma-derived cells in vitro and in human atheromata in situ. Ligation of CD40 on atheroma- associated cells in vitro activates the production of chemokines, cytokines, matrix metalloproteinases, adhesion molecules and tissue factor, substances responsible for lesion progression and plaque destabilization. Administration of antibody against CD154 to low-density lipoprotein receptor-deficient mice has been shown to reduce atherosclerosis and decrease T-lymphocyte and macrophage content; however, only initial lesions were studied. Here, we determined the effect of genetic disruption of CD154 in ApoE(-/-) mice in both initial and advanced atherosclerotic lesions. Plaque area was reduced 550%. In contrast to previous reports, initial lesion development was not affected. Advanced plaques in CD154(-/-)ApoE(-/-) mice had a less-lipid- containing, collagen-rich, stable plaque phenotype, with a reduced T- lymphocyte/macrophage content. These data indicate that CD40-CD154 signaling is important in late atherosclerotic changes, such as lipid core formation and plaque destabilization.
AB - Atherosclerosis is a systemic disease of the large arteries, and activation of inflammatory pathways is important in its pathogenesis. Increasing evidence supports the importance of CD40-CD154 interactions in atherosclerosis, interactions originally known to be essential in major immune reactions and autoimmune diseases. CD40 is present on atheroma-derived cells in vitro and in human atheromata in situ. Ligation of CD40 on atheroma- associated cells in vitro activates the production of chemokines, cytokines, matrix metalloproteinases, adhesion molecules and tissue factor, substances responsible for lesion progression and plaque destabilization. Administration of antibody against CD154 to low-density lipoprotein receptor-deficient mice has been shown to reduce atherosclerosis and decrease T-lymphocyte and macrophage content; however, only initial lesions were studied. Here, we determined the effect of genetic disruption of CD154 in ApoE(-/-) mice in both initial and advanced atherosclerotic lesions. Plaque area was reduced 550%. In contrast to previous reports, initial lesion development was not affected. Advanced plaques in CD154(-/-)ApoE(-/-) mice had a less-lipid- containing, collagen-rich, stable plaque phenotype, with a reduced T- lymphocyte/macrophage content. These data indicate that CD40-CD154 signaling is important in late atherosclerotic changes, such as lipid core formation and plaque destabilization.
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U2 - 10.1038/15271
DO - 10.1038/15271
M3 - Article
C2 - 10546000
AN - SCOPUS:0032740818
SN - 1078-8956
VL - 5
SP - 1313
EP - 1316
JO - Nature Medicine
JF - Nature Medicine
IS - 11
ER -