Increased adipose tissue expression of TLR8 in obese individuals with or without type-2 diabetes: significance in metabolic inflammation

Background: The innate immune Toll-like receptors (TLRs) 2/4 are important players in chronic low-grade inflammation called metabolic inflammation in obesity and type-2 diabetes (T2D). While TLR2/4 expression changes associated with metabolic inflammation are known, the adipose tissue expression of endocytic TLR8, which is expressed by all major macrophage subsets, remain unclear. We, therefore, determined the TLR8 mRNA/protein expression in the adipose tissue samples from lean, overweight, and obese individuals with or without T2D. Methods: Subcutaneous fat biopsy samples were collected from 49 non-diabetic (23 obese, 17 overweight, and nine lean) and 45 T2D (32 obese, ten overweight, and three lean) individuals. TLR8 gene expression was determined using real-time RT-PCR and TLR8 protein expression was assessed by both immunohistochemistry and confocal microscopy. The changes in TLR8 expression were compared with those of macrophage markers, proinflammatory cytokines/chemokines, and surface TLRs/adapter proteins. The data were analyzed using t-test/Mann-Whitney U-test, Pearson's correlation, and multiple regression test. Results: The data show that in obese non-diabetic/T2D individuals, TLR8 gene expression was significantly upregulated as compared with lean individuals which correlated with body mass index (BMI) and body fat percentage in non-diabetic population (P < 0.05). As expected, TLR8 adipose tissue protein expression in nondiabetic/T2D obese individuals was also higher than that of overweight/lean counterparts. In non-diabetic/T2D individuals, TLR8 gene expression associated (P < 0.05) with the expression of CD68, CD11c, CD86, and CD163 macrophage markers. Also, in these individuals, TLR8 gene expression correlated positively (P < 0.05) with adipose tissue expression of TNF-alpha, IL-18, and IL-8 as well as with systemic CRP levels (in non-diabetics). TLR8 expression was also associated with TLR4/TLR2 and MyD88 expression in the adipose tissue. Conclusions: The elevated adipose tissue expression of TLR8 in obesity/T2D has consensus with inflammatory signatures and may thus represent an immune marker of metabolic inflammation.