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 1

Macrophage and Th1 cell function.

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Macrophage and Th1 cell function. (A) Fluorescent LDL-loaded BMMs. Scale...
(A) Fluorescent LDL-loaded BMMs. Scale bars: 10 μm. (B) BMMs were cultured from Sort1+/+ (n = 10) and Sort1–/– (n = 9) mice and incubated with Atto-633–labeled oxidized (oxLDL), aggregated (agLDL), or native LDL for 20 hours. Foam cell formation was quantified by flow cytometry as mean fluorescence intensity among 10,000 macrophages from each mouse. (C) Activation of Sort1+/+ and Sort1–/– BMMs, induced by LPS for the indicated times and assessed by phosphorylation of MAPKs, revealed no differences. (D–G) After 6 hours of LPS stimulation, the amount of IL-6 was significantly reduced in media from Sort1–/– versus Sort1+/+ BMMs (D), whereas TNF-α secretion (E) and iNOS (F) and Il6 (G) mRNA expression were unaffected. (H and I) Culture medium (CM) from activated Sort1–/– Th1 cells contained less IFN-γ than did Sort1+/+ Th1 cells (H) and was less efficient in priming BMMs to secrete TNF-α after LPS activation (I). Representative results from 3 independent experiments (mean ± SEM; n = 6–9 per group). **P < 0.01, ***P < 0.0001, Student’s t test (D and I) or Mann-Whitney test (I).