title: 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-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.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Philip L S M
authors.initials: PLSM
authors.lastname: Gordts
authors.affiliation: 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.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Foley
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Lawrence
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Risha
authors.initials: R
authors.lastname: Sinha
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lameda-Diaz
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Liwen
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Nock
authors.affiliation: 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.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.affiliation: Department of Cardiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ayca
authors.initials: A
authors.lastname: Erbilgin
authors.affiliation: Department of Cardiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.affiliation: 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.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004036:Diet, Atherogenic / Q000009:adverse effects; D005260:Female; D005786:Gene Expression Regulation; D019812:Heparan Sulfate Proteoglycans / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009765:Obesity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D015238:Sulfotransferases / Q000235:genetics
chemical_list: D019812:Heparan Sulfate Proteoglycans; D007370:Interferon Type I; D015238:Sulfotransferases; C021350:heparitin sulfotransferase