Inflammation-Related Epigenetic Modification: The Bridge Between Immune and Metabolism in Type 2 Diabetes

Abstract

T2DM, as a typical metabolic inflammatory disease, is under the joint regulation of environmental factors and genetics, combining with a variety of epigenetic changes. Apart from epigenetic changes of islet β cells and glycometabolic tissues or organs, the inflammation-related epigenetics is also the core pathomechanism leading to β-cell dysfunction and insulin resistance. In this review, we focus on the epigenetic modification of immune cells' proliferation, recruitment, differentiation and function, providing an overview of the key genes which regulated by DNA methylation, histone modifications, and non-coding RNA in the respect of T2DM. Meanwhile, we further summarize the present situation of T2DM epigenetic research and elucidate its prospect in T2DM clinical diagnosis and treatment.

Keywords: DNA methylation; histone modifications; inflammation; macrophages; non-coding RNA; type 2 diabetes mellitus (T2DM).

Figure 1

Environmental factors could affect the epigenetics of immune cells to generate tissue inflammatory states and induce metabolic disorders. Adverse environmental factors could induce or aggravate the pro-inflammatory immune cell profile through the epigenetics, including the increase in M1-like Mϕs, Th1 cells, Th17 cells, CD8+ cells, ILC1s, B-2 cells, and the downregulation of M2-like Mϕs, Th2 cells, Treg, ILC2s, ILC3s and B-1 cells. This immunocytic cross-talk causes pathogenic inflammation via the release of cocktail pro-inflammatory cytokines (TNF-α, TNF-β, interleukin (IL)-1β, IL-2, IL-6, IL-17, IFN-α, IFN-γ) in intestine and glycol-metabolic tissues such as adipose tissue, liver, muscle, and pancreas, which further disturbs metabolism, ultimately resulting in pancreatic β-cell dysfunction and IR. ↑: up-regulated expression, ↓: down-regulated expression.

Figure 2

Changes in the Epigenetic Signature of Immune Cells in T2DM. In T2DM patients, the systemic and tissue-local inflammatory states mediated by the epigenetic regulation of monocytes and macrophages together with T cells, B cells plays a crucial role in insulin resistance. Altered global and gene-specific DNA methylation, histone modifications, as well as the expression of several non-coding RNAs are found to synergistically regulate the macrophage M1 pro-inflammatory phenotype, and the expression of genes encoding MCP-1/CCL-2, is up-regulated under the dual regulation of DNA methylation and histone modifications. Besides, the pro-inflammatory phenotype of T and B cells regulated by global and gene-specific DNA methylation and several miRNAs have also been reported in obese T2DM individuals.