Reducing Macrophage Proteoglycan Sulfation Increases Atherosclerosis and Obesity through Enhanced Type I Interferon Signaling

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 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 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. [Display omitted] •Reducing macrophage HSPG sulfation increases atherosclerosis and obesity•Altered HSPG sulfation increases expression of inflammatory genes•Increased inflammation promotes macrophage infiltration and foam cell conversion•Macrophage HSPGs sequester IFN-β and modulate activation of the cells Heparan sulfate proteoglycans (HSPGs) are important constituents of the macrophage glycocalyx and extracellular microenvironment. Gordts et al. show that HSPGs control basal activation of macrophages by sequestering IFN-β to maintain type I interferon signaling in a quiescent state. Decreased macrophage HSPG sulfation results in autocrine activation, obesity, T2DM, and atherosclerosis.