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Introduction
Sterile inflammation, a chronic low-grade systemic inflammation, is the main cause of comorbidities such as retinopathy and nephropathy that are associated with diabetes. Sterile inflammation is associated with increased systemic levels of pro-inflammatory cytokines, including elevated interleukin (IL)-1β, which drives several comorbidities (Chen & Nunez, 2010; Filgueiras, Serezani & Jancar, 2015 ). The IL-1 receptor is a member of the toll-like receptor (TLR) family, and like most TLRs, its signaling pathway is dependent on the adaptor molecule myeloid differentiation factor 88 (MyD88) (Takeuchi & Akira, 2002 ).
We have previously shown that macrophages from type 1 diabetic (T1D) mice express increased levels of MyD88 and its transcription factor signal transducer and activator of transcription (STAT) 1, which is dependent on the production of the inflammatory lipid mediator leukotriene B4 (LTB4). Our results showed that the elevated systemic levels of LTB4 found in T1D mice promote the binding of STAT1 to MyD88 promoter, leading to enhanced MyD88 expression in macrophages. Increased STAT/MyD88 expression potentiates macrophages TLR/IL1β receptors response. Moreover, the sterile inflammation in T1D mice characterized by increased systemic levels of TNF-α and IL-1β, is dependent on the LTB4-induced STAT1/MyD88 axis (Filgueiras, Brandt et al., 2015 ). Because some long-term diabetes complications develop even in insulin-treated patients who exhibit improved glucose control, it is thought that epigenetic mechanisms associated with diabetes are responsible, a process characterized as "metabolic memory" (Ceriello, 2009; Cooper & El-Osta, 2010 ).
Epigenetic mechanisms are typically mediated through chromatin dynamics. Chromatin is a highly organized structure in which DNA is wrapped around a histone octamer unit. The structure of chromatin plays a central role in controlling transcription of genes. Chromatin structure is dynamic, and is tightly regulated by several epigenetic mechanisms including histone modifications. Histones can be acetylated at multiple lysine residues, and the specific combination of acetylated lysines determines the accessibility of the DNA template to the transcriptional machinery enabling gene expression. Thus, acetylation is generally associated with increased transcriptional activity. Histone acetyltransferases (HATs) mediate histone acetylation, whereas, histone deacetylases (HDACs) reduce transcription by removing acetyl groups from lysine residues (Kouzarides, 2007; Li, Carey, & Workman, 2007 ).
Accumulating evidence suggests that in both diabetic animals and human patients, key aspects of regulating the transcription...