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Cell Metab. 2014 Nov 4;20(5):813-826. doi: 10.1016/j.cmet.2014.09.016. Epub 2014 Nov 4.

Reducing macrophage proteoglycan sulfation increases atherosclerosis and obesity through enhanced type I interferon signaling.

Author information

1
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
4
Department of Cardiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
5
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
6
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jesko@ucsd.edu.

Abstract

Heparan sulfate proteoglycans (HSPGs) are an important constituent of the macrophage glycocalyx and extracellular microenvironment. To examine their role in atherogenesis, we inactivated the biosynthetic gene N-acetylglucosamine N-deacetylase-N-sulfotransferase 1 (Ndst1) in macrophages and crossbred the strain to Ldlr(-/-) mice. When placed on an atherogenic diet, Ldlr(-/-)Ndst1(f/f)LysMCre(+) mice had increased atherosclerotic plaque area and volume compared to Ldlr(-/-) mice. Diminished sulfation of heparan sulfate resulted in enhanced chemokine expression; increased macrophages in plaques; increased expression of ACAT2, a key enzyme in cholesterol ester storage; and increased foam cell conversion. Motif analysis of promoters of upregulated genes suggested increased type I interferon signaling, which was confirmed by elevation of STAT1 phosphorylation induced by IFN-β. The proinflammatory macrophages derived from Ndst1(f/f)LysMCre(+) mice also sensitized the animals to diet-induced obesity. We propose that macrophage HSPGs control basal activation of macrophages by maintaining type I interferon reception in a quiescent state through sequestration of IFN-β.

PMID:
25440058
PMCID:
PMC4254584
DOI:
10.1016/j.cmet.2014.09.016
[Indexed for MEDLINE]
Free PMC Article

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