Increased Expression of the Innate Immune Receptor TLR10 in Obesity and Type-2 Diabetes: Association with ROS-Mediated Oxidative Stress

Abstract

Background/Aims: Metabolic diseases such as obesity and type-2 diabetes (T2D) are known to be associated with chronic low-grade inflammation called metabolic inflammation together with an oxidative stress milieu found in the expanding adipose tissue. The innate immune Toll-like receptors (TLR) such as TLR2 and TLR4 have emerged as key players in metabolic inflammation; nonetheless, TLR10 expression in the adipose tissue and its significance in obesity/T2D remain unclear. Methods: TLR10 gene expression was determined in the adipose tissue samples from healthy non-diabetic and T2D individuals, 13 each, using real-time RT-PCR. TLR10 protein expression was determined by immunohistochemistry, confocal microscopy, and flow cytometry. Regarding in vitro studies, THP-1 cells, peripheral blood mononuclear cells (PBMC), or primary monocytes were treated with hydrogen peroxide (H₂O₂) for induction of reactive oxygen species (ROS)-mediated oxidative stress. Superoxide dismutase (SOD) activity was measured using a commercial kit. Data (mean±SEM) were compared using unpaired student’s t-test and P<0.05 was considered significant. Results: The adipose tissue TLR10 gene/protein expression was found to be significantly upregulated in obesity as well as T2D which correlated with body mass index (BMI). ROS-mediated oxidative stress induced high levels of TLR10 gene/protein expression in monocytic cells and PBMC. In these cells, oxidative stress induced a time-dependent increase in SOD activity. Pre-treatment of cells with anti-oxidants/ROS scavengers diminished the expression of TLR10. ROS-induced TLR10 expression involved the nuclear factor-kappaB (NF-κB)/mitogen activated protein kinase (MAPK) signaling as well as endoplasmic reticulum (ER) stress. H₂O₂-induced oxidative stress interacted synergistically with palmitate to trigger the expression of TLR10 which associated with enhanced expression of proinflammatory cytokines/chemokine. Conclusion: Oxidative stress induces the expression of TLR10 which may represent an immune marker for metabolic inflammation.

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

“…In line with this finding, increased expression of TLRs 1-9 and TLRs 11-13 was reported in two murine models of obesity [55]. Whereas in obese/T2D individuals, we have already reported the increased expression of several TLRs including TLR-2, -4, -7, -8, and -10 [28,[56][57][58]. The present data show the congruence between adipose tissue expression of IRF5 and most TLRs in obesity/T2D.…”

Fibrinopeptide A Induces Expression of C-Reactive Protein via the ROS-ERK1/2/ P38-NF-κB Signal Pathway in Vascular Smooth Muscle Cells

“…Low concentration of ROS is permanently produced in cells, which plays a role as signal molecules. Researches show that ROS participate in the production of many inflammatory cytokines by the different signal pathways such as MAPK and NF-κB [37, 38]. In the study, we found that FPA stimulated the production of superoxide anion in VSMCs, and the NADPH oxidase inhibitor DPI, mitochondrial respiratory complex II inhibitor TTFA and antioxidant NAC all inhibited FPA-induced the generation of superoxide anion in VSMCs, suggesting that the NADPH oxidase pathway and mitochondria-derived signal pathway are involved in FPA-elicited ROS generation.…”

Decreased TLR3 in Hyperplastic Adipose Tissue, Blood and Inflamed Adipocytes is Related to Metabolic Inflammation

“…In consensus with such inflammatory signatures and immune activation, elevated AT expression of TLR8 has been also reported in metabolically compromised subjects [30]. Finally, TLR10 has been considered the only orphan human TLR, with no confirmed ligand nor biological function until the findings of Song Jiang and coworkers, supporting the idea that TLR10 may display some anti-inflammatory properties [31], and the approach recently performed in human AT by Syndhu et al [32], suggestive of a relationship with metabolic inflammation.…”