Abstract
The number of diabetic patients in Europe and world-wide is growing. Diabetes confers a 2-fold higher risk for vascular disease. Lack of insulin production (Type 1 diabetes, T1D) or lack of insulin responsiveness (Type 2 diabetes, T2D) causes systemic metabolic changes such as hyperglycemia (HG) which contribute to the pathology of diabetes. Monocytes and macrophages are key innate immune cells that control inflammatory reactions associated with diabetic vascular complications. Inflammatory programming of macrophages is regulated and maintained by epigenetic mechanisms, in particular histone modifications. The aim of our study was to identify the epigenetic mechanisms involved in the hyperglycemia-mediated macrophage activation. Using Affymetrix microarray profiling and RT-qPCR we identified that hyperglycemia increased the expression of S100A9 and S100A12 in primary human macrophages. Expression of S100A12 was sustained after glucose levels were normalized. Glucose augmented the response of macrophages to Toll-like receptor (TLR)-ligands Palmatic acid (PA) and Lipopolysaccharide (LPS) i.e., pro-inflammatory stimulation. The abundance of activating histone Histone 3 Lysine 4 methylation marks (H3K4me1, H3K4me3) and general acetylation on histone 3 (AceH3) with the promoters of these genes was analyzed by chromatin immunoprecipitation. Hyperglycemia increased acetylation of histones bound to the promoters of S100A9 and S100A12 in M1 macrophages. In contrast, hyperglycemia caused a reduction in total H3 which correlated with the increased expression of both S100 genes. The inhibition of histone methyltransferases SET domain-containing protein (SET)7/9 and SET and MYND domain-containing protein (SMYD)3 showed that these specifically regulated S100A12 expression. We conclude that hyperglycemia upregulates expression of S100A9, S100A12 via epigenetic regulation and induces an activating histone code on the respective gene promoters in M1 macrophages. Mechanistically, this regulation relies on action of histone methyltransferases SMYD3 and SET7/9. The results define an important role for epigenetic regulation in macrophage mediated inflammation in diabetic conditions.
Highlights
Diabetes confers an about 2-fold higher risk for cardiovascular disease [1, 2]
It is known that S100A8 and S100A9 mRNA levels decline during monocyte differentiation into macrophage [65]
Monocytes presented the greatest mean expression levels of both S100A9 and S100A12 regardless of glucose. Both genes declined during monocytes to macrophage maturation and S100A12 was downregulated much stronger than S100A9 (360-fold and 5.4-fold, respectively, for ns, NG after 6 days) (Figure 1A)
Summary
Diabetes confers an about 2-fold higher risk for cardiovascular disease [1, 2]. Type 1 diabetes (T1D) is an autoimmune disease in which the immune system destroys pancreatic beta cells and renders patients dependent on insulin administration. Obesity is a strong predictor for T2D, while T2D itself increases risks for cardiovascular disease and cancer Both in T1D and T2D the chronic exposure to increased glucose serum levels (hyperglycemia) causes pathophysiological changes that are largely of an inflammatory nature [3, 4]. Macrophages are important in homeostasis of metabolism of tissues as well as whole body metabolism whereas on the other side, the intrinsic metabolism of the cell shapes its activation state [5, 6]. Macrophages respond to their environment with either pro-inflammatory (M1) or anti-inflammatory (M2) fashion and can be polarized in both directions, defined
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