Requirement for CD154 in the progression of atherosclerosis

Abstract

Atherosclerosis is a systemic disease of the large arteries, and activation of inflammatory pathways is important in its pathogenesis¹. Increasing evidence supports the importance of CD40–CD154 interactions in atherosclerosis^2,3, interactions originally known to be essential in major immune reactions⁴ and autoimmune diseases⁵. CD40 is present on atheroma-derived cells in vitro and in human atheromata in situ⁶. Ligation of CD40 on atheroma-associated cells in vitro activates the production of chemokines⁶, cytokines⁶, matrix metalloproteinases^7,8, adhesion molecules^9,10 and tissue factor⁷, substances responsible for lesion progression and plaque destabilization¹. 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 studied³. 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.