Requirement for CD154 in the progression of atherosclerosis.
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.
Lutgens
E
E
Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, P. Debeyeln 25, PO Box 5800, 6202 AZ Maastricht, the Netherlands.
Gorelik
L
L
Daemen
M J
MJ
de Muinck
E D
ED
Grewal
I S
IS
Koteliansky
V E
VE
Flavell
R A
RA
D000818:Animals; D001161:Arteriosclerosis / Q000276:immunology*; D001483:Base Sequence; D023201:CD40 Ligand; D002784:Cholesterol / Q000097:blood; D017931:DNA Primers; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology; D014280:Triglycerides / Q000097:blood
D017931:DNA Primers; D008562:Membrane Glycoproteins; D014280:Triglycerides; D023201:CD40 Ligand; D002784:Cholesterol