Reducing macrophage proteoglycan sulfation increases atherosclerosis and obesity through enhanced type I interferon signaling
Open accessAbstract
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.
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In macrophages, HSPGs modulate inflammation through interferon-beta (IFN-β) via IFN-β sequestration, enabling proteoglycan sulfation to influence inflammatory responses.
“In macrophages, HSPGs modulate inflammation through interferon-beta (IFN-β) via IFN-β sequestration, enabling proteoglycan sulfation to influence inflammatory responses67.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [67]
In macrophages, HSPGs modulate inflammation through IFN-β; HSPGs sequester IFN-β, and the degree of proteoglycan sulfation can influence inflammatory responses.
“In macrophages, HSPGs modulate inflammation through interferon-beta (IFN-β); specifically, HSPGs sequester IFN-β, and the degree of proteoglycan sulfation can influence inflammatory responses63.”
From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [63]
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- Authors
- Gordts, P. L. S. M., Foley, E. M., Lawrence, R., Sinha, R., Lameda-Diaz, C., Deng, L., Nock, R., Glass, C. K., Erbilgin, A., Lusis, A. J., Witztum, J. L., & Esko, J. D.
- Affiliations
- University of California San Diego (US)
- University of California, Los Angeles (US)
- Corresponding author
- Esko, Jeffrey D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 20
- Issue
- 5
- Pages
- 813-826
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4254584
- OpenAlex
- W2094767051
- Cited by
- 86
- References
- 0
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 11 · 2023: 4 · 2022: 7 · 2021: 11 · 2020: 8 · 2019: 7 · 2018: 12 · 2017: 5 · 2016: 3 · 2015: 5
- FWCI
- 2.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- European Commission (273994)
- National Institutes of Health
- University of California, San Diego (HL107150)
- National Heart, Lung, and Blood Institute (HL3 0568, HL28481, P01HL107150, P01HL030568, HL-088093, P01HL088093, P01HL028481)
- National Cancer Institute (P30CA023100)
- National Institute of General Medical Sciences (R01GM033063, R37GM033063, GM-33063)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK074868)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- heparan sulfate proteoglycans, macrophages, atherosclerosis, obesity, type I interferon signaling, NDST1, sulfation, interferon-beta, STAT1 phosphorylation, foam cells, ACAT2, chemokine expression, macrophage activation, Ldlr-deficient mice, diet-induced obesity
- MeSH terms
- Animals, Diet, Atherogenic, Female, Gene Expression Regulation, Interferon Type I, Macrophages, Male, Models, Molecular, Obesity, Sulfotransferases, Signal Transduction, Heparan Sulfate Proteoglycans, Atherosclerosis, Mice
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