Atherogenesis in Mice Does Not Require CD40 Ligand From Bone Marrow–Derived Cells

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Abstract
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 composit... Although previous studies established CD40L as a mediator of atherogenesis, its relevant cellular source remains unknown. The present study demonstrates that CD40L modulates atherogenesis in mice, primarily by its expression on nonhematopoietic cell types in bone marrow chimeras. This surprising finding has important pathophysiologic and therapeutic implications.