Enhanced Adipose Expression of Interferon Regulatory Factor (IRF)-5 Associates with the Signatures of Metabolic Inflammation in Diabetic Obese Patients

Abstract

Interferon regulatory factors (IRFs) are emerging as the metabolic transcriptional regulators in obesity/type-2 diabetes (T2D). IRF5 is implicated with macrophage polarization toward the inflammatory M1-phenotype, nonetheless, changes in the adipose expression of IRF5 in T2D and relationship of these changes with other markers of adipose inflammation remain unclear. Therefore, we determined the IRF5 gene expression in subcutaneous adipose tissue samples from 46 T2D patients including 35 obese (Body Mass Index/BMI 33.83 ± 0.42 kg/m 2 ) and 11 lean/overweight individuals (BMI 27.55 ± 0.46 kg/m 2 ) using real-time qRT-PCR. IRF5 protein expression was assessed using immunohistochemistry and confocal microscopy. Fasting plasma glucose, insulin, HbA1c, C-reactive protein, cholesterol, low-and high-density lipoproteins (LDL/HDL), and triglycerides were measured using commercial kits. IRF5 gene expression was compared with that of signature inflammatory markers and several clinico-metabolic indicators. The data (mean ± SEM) show the enhanced adipose IRF5 gene (p = 0.03) and protein (p = 0.05) expression in obese compared to lean/overweight diabetic patients. Adipose IRF5 transcripts in diabetic obese individuals associated positively with those of TNF-α, IL-18, IL-23A, CXCL8, CCL2, CCL7, CCR1/5, CD11c, CD68, CD86, TLR4/7/10, Dectin-1, FGL-2, MyD88, NF-κB, IRF3, and AML1 (p < 0.05). In diabetic lean/overweight subjects, IRF5 expression associated with BMI, body fat %age, glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR, C-reactive protein (CRP), IL-5, and IL-1RL1 expression; while in all T2D patients, IRF5 expression correlated with that of IRF4, TLR2/8, and CD163. In conclusion, upregulated adipose tissue IRF5 expression in diabetic obese patients concurs with the inflammatory signatures and it may represent a potential marker for metabolic inflammation in obesity/T2D.

Repetitive Intermittent Hyperglycemia Drives the M1 Polarization and Inflammatory Responses in THP-1 Macrophages Through the Mechanism Involving the TLR4-IRF5 Pathway

“…First of all, we show that the expression of immune-metabolic transcriptional regulator IRF5 was found to be significantly upregulated in monocytes from diabetic patients compared to nondiabetic individuals and that these changes associated with the expression of hyperglycemia-induced clinical marker HbA1c and several inflammatory markers including TNF-α, IL-1β, and CCR2. These data are corroborated, at least in part, by our previous reports showing enhanced subcutaneous-adipose tissue IRF5 expression in individuals with obesity and/or T2D in association with an inflammatory immune profile in the adipose tissue as well as by the data showing that macrophages and not adipocytes were the IRF5 expressors [ 13 , 14 ]. In line with this, at least in part, an earlier study by Dalmas et al also reported that IRF5 is the orchestral conductor of macrophage/lymphocyte activation in obesity and is involved in the crosstalk between inflammatory and prodiabetogenic factors.…”

“…Previously, we showed that adipose IRF5 expression was higher in obese individuals compared to lean and overweight, which was found to associate with several metabolic and inflammatory markers [ 13 , 14 ]. We further showed by confocal microscopy that the adipose tissue macrophages and not the adipocytes expressed IRF5 transcripts [ 13 , 14 ]. In line with these observations, first, we show that, in our T2D patient cohort, adipose IRF5 gene expression was significantly higher than their nondiabetic counterparts ( p = 0.006, Figure 1 A).…”

“…The interferon regulatory factor (IRF) family plays a significant role in the regulation and differentiation of immune cells and adipocytes through different pattern recognition receptors (PRR) including toll-like receptors (TLRs) as well as in the expression of type I interferons (INF α/β) [ 11 , 12 ]. IRFs are also known as the key regulators of metabolic inflammation, and their expression levels are expected to influence the immunobiological consequences in patients with obesity and T2D [ 13 , 14 , 15 ]. The role of IRF5 in proinflammatory M1 macrophage polarization has been well documented [ 16 , 17 ].…”

Elevated adipose tissue associated IL-2 expression in obesity correlates with metabolic inflammation and insulin resistance

“…Once the conditions were established, all slides were analyzed using the same parameters. The resulting color markup of the analysis was confirmed for each slide 59,61 .…”

“…Relative gene expression to control, lean AT, was calculated using comparative Ct method as we previously described 56,58,59 . Results were normalized to GAPDH, and averages ± standard error of the mean (SEM) are shown relative to controls as indicated 60 .…”