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.


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.
Bavendiek
Udo
U
Donald W. Reynolds Cardiovascular Clinical Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass02115, USA.
Zirlik
Andreas
A
LaClair
Samantha
S
MacFarlane
Lindsey
L
Libby
Peter
P
Schönbeck
Uwe
U
D000818:Animals; D001012:Aorta, Abdominal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011973:Receptors, LDL / Q000235:genetics
D011973:Receptors, LDL; D023201:CD40 Ligand