Abstract
Atherosclerosis is a major underlying cause of cardiovascular disease. Previous studies showed that inhibition of the co-stimulatory CD40 ligand (CD40L)-CD40 signaling axis profoundly attenuates atherosclerosis. As CD40L exerts multiple functions depending on the cell-cell interactions involved, we sought to investigate the function of the most relevant CD40L-expressing cell types in atherosclerosis: T cells and platelets. Atherosclerosis-prone mice with a CD40L-deficiency in CD4+ T cells display impaired Th1 polarization, as reflected by reduced interferon-γ production, and smaller atherosclerotic plaques containing fewer T-cells, smaller necrotic cores, an increased number of smooth muscle cells and thicker fibrous caps. Mice with a corresponding CD40-deficiency in CD11c+ dendritic cells phenocopy these findings, suggesting that the T cell-dendritic cell CD40L-CD40 axis is crucial in atherogenesis. Accordingly, sCD40L/sCD40 and interferon-γ concentrations in carotid plaques and plasma are positively correlated in patients with cerebrovascular disease. Platelet-specific deficiency of CD40L does not affect atherogenesis but ameliorates atherothrombosis. Our results establish divergent and cell-specific roles of CD40L-CD40 in atherosclerosis, which has implications for therapeutic strategies targeting this pathway.
Highlights
1,11 ✉, Atherosclerosis is a major underlying cause of cardiovascular disease
For further analysis of the CD40 ligand (CD40L)-CD40 T cell—dendritic cell (DC) axis in atherosclerosis, we generated mice deficient for CD40 in CD11c+ DCs, which were backcrossed to Apoe−/− mice (Supplementary Fig. 2a)
Deficiency of either T cell CD40L or CD40 on DCs strongly reduces lesion size, as well as plaque inflammation, resulting in a favorable stable atherosclerotic plaque phenotype with smaller necrotic cores and an increased fibrous cap thickness
Summary
1,11 ✉, Atherosclerosis is a major underlying cause of cardiovascular disease. Previous studies showed that inhibition of the co-stimulatory CD40 ligand (CD40L)-CD40 signaling axis profoundly attenuates atherosclerosis. Genetic deficiency or antibody-mediated inhibition of CD40L is highly effective in reducing atherosclerosis, even in established disease conditions, by generating plaques that are rich in collagen and contain a limited amount of immune cells resembling the murine equivalent of a stable, clinically safe, plaque[13,14,15,16]. Inhibition of CD40L resulted in unstable thrombi, which are embolized and cause thrombo-embolic events[17,18]. To reduce these severe effects, targeted approaches are necessary; the cell source requirements for CD40L in atherosclerosis remain unclear.
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