on December 7, 2006
Published online before print December 7, 2006, doi: 10.1161/01.ATV.0000254673.55431.e6
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Submitted on January 11, 2006
Accepted on November 20, 2006
Granulocyte Macrophage Colony-Stimulating Factor Regulates Dendritic Cell Content of Atherosclerotic Lesions
Zory Shaposhnik ;
From the Department of Molecular and Medical Pharmacology (Z.S.), UCLA School of Medicine, Los Angeles, Calif; the Department of Medicine (X.W., M.W., B.J.B., A.J.L.), Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, and Molecular Biology Institute, UCLA School of Medicine, Los Angeles, Calif.
* To whom correspondence should be addressed. E-mail: jlusis{at}mednet.ucla.edu.
Objective--Recent evidence suggests that dendritic cells may play an important role in atherosclerosis. Based primarily on previous in vitro studies, we hypothesized that granulocyte macrophage colony-stimulating factor (GM-CSF)-deficient mice would have decreased dendritic cells in lesions.
Methods and Results--To test this, we characterized gene targeted GM-CSF-/- mice crossed to hypercholesterolemic low-density lipoprotein receptor null mice. Our results provide conclusive evidence that GM-CSF is a major regulator of dendritic cell formation in vivo. Aortic lesion sections in GM-CSF-/- low-density lipoprotein receptor null animals showed a dramatic 60% decrease in the content of dendritic cells as judged by CD11c staining but no change in the overall content of monocyte-derived cells. The GM-CSF-deficient mice exhibited a significant 20% to 50% decrease in the size of aortic lesions, depending on the location of the lesions. Other prominent changes in GM-CSF-/- mice were decreased lesional T cell content, decreased autoantibodies to oxidized lipids, and striking disruptions of the elastin fibers adjacent to the lesion.
Conclusion--Given that GM-CSF is dramatically induced by oxidized lipids in endothelial cells, our data suggest that GM-CSF serves to regulate dendritic cell formation in lesions and that this, in turn, influences inflammation, plaque growth and possibly plaque stability.
Key words: atherosclerosis • dendritic cells • elastin • GM-CSF • macrophages
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