Abstract
S100A8/9 and S100A12 are emerging biomarkers for disease activity of autoimmune and cardiovascular diseases. We demonstrated previously that S100A12 accelerates atherosclerosis accompanied by large cholesterol deposits in atherosclerotic lesions of apoE-null mice. The objective of this study was to ascertain whether S100/calgranulin influences cholesterol homeostasis in macrophages. Peritoneal macrophages from transgenic mice expressing human S100A8/9 and S100A12 in myeloid cells [human bacterial artificial chromosome (hBAC)/S100] have increased lipid content and reduced ABCG1 expression and [(3)H]cholesterol efflux compared with WT littermates. This was associated with a 6-fold increase in plasma interleukin (IL)-22 and increased IL-22 mRNA in splenic T cells. These findings are mediated by the receptor for advanced glycation endproducts (RAGE), because hBAC/S100 mice lacking RAGE had normal IL-22 expression and normal cholesterol efflux. In vitro, recombinant IL-22 reduced ABCG1 expression and [(3)H]cholesterol efflux in THP-1 macrophages, while recombinant S100A12 had no effect on ABCG1 expression. In conclusion, S100/calgranulin has no direct effect on cholesterol efflux in macrophages, but rather promotes the secretion of IL-22, which then directly reduces cholesterol efflux in macrophages by decreasing the expression of ABCG1.
Highlights
S100A8/9 and S100A12 are emerging biomarkers for disease activity of autoimmune and cardiovascular diseases
A potential role for human bacterial artificial chromosome containing S100 genes (S100)/calgranulins in mediating “plaque instability” is suggested by multiple findings: 1) that S100A12 is expressed in macrophages and smooth muscle cells in coronary artery plaques of patients with sudden cardiac death [12]; 2) that increased S100A9 mRNA levels are present in platelets of patients with ST-elevation myocardial infarction [13]; and 3) that serum concentrations of S100/calgranulin are positively associated with cardiovascular morbidity after myocardial infarction [14]
Newly isolated peritoneal macrophages from human bacterial artificial chromosome (hBAC)/S100 showed slightly more intracellular lipid content upon staining with Oil Red O compared with control cells (Fig. 1Da, b)
Summary
S100A8/9 and S100A12 are emerging biomarkers for disease activity of autoimmune and cardiovascular diseases. Peritoneal macrophages from transgenic mice expressing human S100A8/9 and S100A12 in myeloid cells [human bacterial artificial chromosome (hBAC)/S100] have increased lipid content and reduced ABCG1 expression and [3H]cholesterol efflux compared with WT littermates. This was associated with a 6-fold increase in plasma interleukin (IL)-22 and increased IL-22 mRNA in splenic T cells. A potential role for S100/calgranulins in mediating “plaque instability” is suggested by multiple findings: 1) that S100A12 is expressed in macrophages and smooth muscle cells in coronary artery plaques of patients with sudden cardiac death [12]; 2) that increased S100A9 mRNA levels are present in platelets of patients with ST-elevation myocardial infarction [13]; and 3) that serum concentrations of S100/calgranulin are positively associated with cardiovascular morbidity after myocardial infarction [14]
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