期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 12, 页码 5317-5322出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI76002
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资金
- Independent Research Council I Health Sciences
- Lundbeck Foundation
- Aase og Ejnar Danielsens Fond
- Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Fond
- Grosserer L.F. Foghts Fond
- Fonden for Laegevidenskabens Fremme
Genome-wide association studies have identified a link between genetic variation at the human chromosomal locus 1p13.3 and coronary artery disease. The gene encoding sortilin (SORT?) has been implicated as the causative gene within the locus, as sortilin regulates hepatic lipoprotein metabolism. Here we demonstrated that sortilin also directly affects atherogenesis, independent of its regulatory role in lipoprotein metabolism. In a mouse model of atherosclerosis, deletion of Sort? did not alter plasma cholesterol levels, but reduced the development of both early and late atherosclerotic lesions. We determined that sortilin is a high-affinity receptor for the proinflammatory cytokines IL-6 and IFN-gamma. Moreover, macrophages and Th1 cells (both of which mediate atherosclerotic plaque formation) lacking sortilin had reduced secretion of IL-6 and IFN-gamma, but not of other measured cytokines. Transfer of sortilin-deficient BM into irradiated atherosclerotic mice reduced atherosclerosis and systemic markers of inflammation. Together, these data demonstrate that sortilin influences cytokine secretion and that targeting sortilin in immune cells attenuates inflammation and reduces atherosclerosis.
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