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