Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis
Martin B. Mortensen, … , Anders Nykjaer, Jacob F. Bentzon
Martin B. Mortensen, … , Anders Nykjaer, Jacob F. Bentzon
Published November 17, 2014
Citation Information: J Clin Invest. 2014;124(12):5317-5322. https://doi.org/10.1172/JCI76002.
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Brief Report Vascular biology

Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis

Abstract

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 (SORT1) 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 Sort1 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-γ. Moreover, macrophages and Th1 cells (both of which mediate atherosclerotic plaque formation) lacking sortilin had reduced secretion of IL-6 and IFN-γ, 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.

Authors

Martin B. Mortensen, Mads Kjolby, Stine Gunnersen, Jakob V. Larsen, Johan Palmfeldt, Erling Falk, Anders Nykjaer, Jacob F. Bentzon

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Figure 3

Sortilin deficiency in immune cells reduces atherosclerosis.

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Sortilin deficiency in immune cells reduces atherosclerosis. (A and B) P...
(A and B) Plasma cholesterol and distribution of cholesterol across size-fractionated lipoprotein classes in male and female BM-transplanted mice. (C and D) Lesions in the aortic arch (C) and in cross-sections of the aortic root (D) were reduced in male Sort1+/+Apoe–/– recipients of Sort1–/–Apoe–/– BM after 9 weeks of HFD. Scale bars: 1 mm (C); 250 μm (D). (E) Sortilin deficiency in immune cells (i.e., Sort1+/+Apoe–/– recipients of Sort1–/–Apoe–/– BM) also reduced aortic lesion coverage in female mice after 19 weeks of HFD. An additional reduction was seen in control Sort1–/–Apoe–/– recipients of Sort1–/–Apoe–/– BM (global sortilin deletion). (F and G) Plasma IL-6 and TNF-α levels were reduced in mice with sortilin-deficient immune cells. Data are mean ± SEM of n = 14–20 per group. *P < 0.05, **P < 0.01, ***P < 0.001, ANOVA with Newman-Keuls post-test.