Editors' ChoiceImmunology

Heparan Sulfate Proteoglycans Control Basal Inflammation

Sci. Signal.  18 Nov 2014:
Vol. 7, Issue 352, pp. ec320
DOI: 10.1126/scisignal.aaa3026

Macrophages produce a glycocalyx, which contains heparan sulfate proteoglycans. Gordts et al. engineered mice that could not fully sulfate heparan sulfate specifically in cells of the myeloid lineage by knocking out one of the two genes encoding a heparan sulfate biosynthetic enzyme, Ndst1. When crossed with mice that lack the low density lipoprotein (LDL) receptor (Ldlr-/-) and fed a high-fat diet, these double-deficient mice developed larger atherosclerotic plaques with an increase in macrophage content compared with the plaques of the Ldlr-/- mice fed the same diet. Macrophages isolated from the double-deficient mice fed a high-fat diet had a higher accumulation of cholesterol and lipid compared with macrophages from Ldlr-/- mice, and the double-deficient macrophages responded with greater cholesterol ester accumulation when exposed to aggregated LDL. Transcriptional profiling of the isolated Ldlr-/- macrophages and mRNA from plaques of the double-deficient mice indicated that the Ldlr-/- macrophages were of the M1 proinflammatory type and produced cytokines that function as chemoattractants. Indeed, the atherosclerotic lesions in the double-deficient mice exhibited enhanced accumulation of injected fluorescently tagged monocytes. Another gene with increased expression that contributed to the enhanced conversion of the double-deficient macrophages into foam cells was ACAT2, which encodes an enzyme involved in esterifying cholesterol. Pharmacologically blocking ACAT activity reduced the accumulation of cholesterol in response to aggregated LDL when applied to the isolated double-deficient macrophages. Enhanced activation of macrophages is also associated with diet-induced obesity, and the Ldlr-/- mice exhibited increased weight gain when fed a high-fat diet. Isolated Ldlr-/- macrophages produced a greater response to interferon-β (IFN-β), but heparan sulfate extracted from these macrophages bound less of this IFN than did heparan sulfate from wild-type macrophages. Thus, the authors propose that the heparan sulfate–containing glycocalyx limits autocrine IFN-β signaling by macrophages and, when compromised, this can produce hyperactivated macrophages, which can contribute to inflammation-associated diseases, such as atherosclerosis and obesity.

P. L. S. M. Gordts, E. M. Foley, R. Lawrence, R. Sinha, C. Lameda-Diaz, L. Deng, R. Nock, C. K. Glass, A. Erbilgin, A. J. Lusis, J. L. Witztum, J. D. Esko, Reducing macrophage proteoglycan sulfation increases atherosclerosis and obesity through enhanced type I interferon signaling. Cell Metab. 20, 813–826 (2014). [Online Journal]

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