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


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-?. 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-?.

SUBMITTER: Gordts PLSM 

PROVIDER: S-EPMC4254584 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

Gordts Philip L S M PLSM   Foley Erin M EM   Lawrence Roger R   Sinha Risha R   Lameda-Diaz Carlos C   Deng Liwen L   Nock Ryan R   Glass Christopher K CK   Erbilgin Ayca A   Lusis Aldons J AJ   Witztum Joseph L JL   Esko Jeffrey D JD  

Cell metabolism 20141104 5


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 sulfat  ...[more]

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