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Summary 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−/−Ndst1f/fLysMCre+ 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 up-regulated genes suggested increased Type I Interferon signaling, which was confirmed by elevation of STAT1 phosphorylation induced by IFN-β. The pro-inflammatory macrophages derived from Ndst1f/fLysMCre+ 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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