Abstract
BackgroundThe 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.MethodsSubcutaneous 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.ResultsThe 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 non-diabetic/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-α, 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.ConclusionsThe elevated adipose tissue expression of TLR8 in obesity/T2D has consensus with inflammatory signatures and may thus represent an immune marker of metabolic inflammation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12950-016-0147-y) contains supplementary material, which is available to authorized users.
Highlights
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)
Increased adipose tissue TLR8 gene expression in diabetic/non-diabetic obese individuals Whereas the changes in TLR2/TLR4 expression in the adipose tissue are regarded as important actors in metabolic inflammation, the changes in the adipose tissue expression of endocytic TLR8 in obesity/T2D remain unclear
We found that in non-diabetic individuals, TLR8 mRNA expression in the adipose tissue was significantly upregulated in obese as compared with lean counterparts (P = 0.01) (Fig. 1a) and this increase correlated positively with phenotypes of corpulence, such as body mass index (BMI) (r = 0.36, P = 0.01) (Fig. 1b) and body fat percentage (r = 0.34, P = 0.02) (Fig. 1c)
Summary
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 determined the TLR8 mRNA/protein expression in the adipose tissue samples from lean, overweight, and obese individuals with or without T2D. Obesity is marked by a state of chronic low-grade inflammation, called metabolic inflammation, in which circulatory monocytes infiltrate the expanding adipose tissue and are differentiated into the adipose tissue macrophages (ATMs). Tumor necrosis factor (TNF)-α, IL-18, IL-8, and C-reactive protein (CRP) are considered potential risk factors for the development of type-2 diabetes (T2D) and its associated metabolic complications [4, 5]. TLR signaling, except TLR3, activates myeloid differentiation factor (MyD)-88 adapter protein which eventually leads to nuclear factor (NF)-κB activation after the macromolecular complex formation including IL1Rassociated kinase (IRAK)-1, IRAK-4, tumor necrosis factorassociated factor (TRAF)-6, and IκB kinase complex [14]
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