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(1). Increasing e vidence supports the importance of CD40-CD154 interactions in atheroscleros is(2,3), interactions originally known to be essential in major immune reac tions(4) and autoimmune diseases(5). CD40 is present on atheroma-derived ce lls in vitro and in human atheromata in situ(6). Ligation of CD40 on athero ma-associated cells in vitro activates the production of chemokines(6), cyt okines(6), matrix metalloproteinases(7,8), adhesion molecules(9,10) and tis sue factor: substances responsible for lesion progression and plaque destab ilization(1). Administration of antibody against CD154 to low-density lipop rotein receptor-deficient mice has been shown to reduce atherosclerosis and decrease T-lymphocyte and macrophage content; however, only initial lesion s were studied(3). Here, we determined the effect of genetic disruption of CD154 in ApoE(-/-) mice in both initial and advanced atherosclerotic lesion s. Plaque area was reduced 550%. In contrast to previous reports, initial l esion 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 CD 40-CD154 signaling is important in late atherosclerotic changes, such as li pid core formation and plaque destabilization.