Atherogenesis in mice does not require CD40 ligand from bone marrow-derived cells

Objective - Recent research suggests a central role for CD40 ligand ( CD40L) in atherogenesis. However, the relevant cellular source of this proinflammatory cytokine remains unknown. To test the hypothesis that CD40L expressed on hematopoietic cell types ( eg, macrophages, lymphocytes, platelets) is crucial to atherogenesis, we performed bone marrow reconstitution experiments using low- density receptor- deficient ( ldlr (-/-)) and ldlr (-/-) /cd40l (-/-) compound- mutant mice. Methods and Results - As expected, systemic lack of CD40L in hypercholesterolemic ldlr (-/-) mice significantly reduced the development of atherosclerotic lesions in the aortic arch, aortic root, and abdominal aorta compared with ldlr (-/-) mice. Furthermore, atheromata in ldlr (-/-) /cd40l (-/-) mice showed reduced accumulation of macrophages and lipids and increased content in smooth muscle cells and collagen compared with ldlr (-/-) mice. Surprisingly, reconstitution of irradiated ldlr (-/-) mice with ldlr (-/-) /cd40l (-/-) bone marrow did not affect the size or composition of atherosclerotic lesions in the root or arch of hypercholesterolemic ldlr (-/-) mice. Moreover, lipid deposition in the abdominal aorta diminished only marginally compared with mouse aortas reconstituted with ldlr (-/-) bone marrow. Conclusions - These experiments demonstrate that CD40L modulates atherogenesis, at least in mice, primarily by its expression on nonhematopoietic cell types rather than monocytes, T lymphocytes, or platelets, a surprising finding with important pathophysiologic and therapeutic implications.