Increased Toll-Like Receptor (TLR) 2 and TLR4 Expression in Monocytes from Patients with Type 1 Diabetes: Further Evidence of a Proinflammatory State

Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, Sacramento, California 95817, USA.
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.21). 02/2008; 93(2):578-83. DOI: 10.1210/jc.2007-2185
Source: PubMed


Type 1 diabetes (T1DM) is associated with increased cardiovascular mortality. It is a pro-inflammatory state as evidenced by increased circulating biomarkers and monocyte activity. The toll-like receptors (TLRs) are pattern recognition receptors, expressed abundantly on monocytes. TLR2 and TLR4 are important in atherosclerosis. However, there is a paucity of data examining TLR2 and TLR4 expression in T1DM and examining its contribution to the proinflammatory state.
Thus, we examined TLR2 and TLR4 expression in monocytes from T1DM patients compared with controls (n = 31 per group).
The study was performed at the University of California Davis Medical Center.
Healthy controls (n = 31) and T1DM patients (n = 31) were included in the study.
TLR2 and TLR4 surface expression and mRNA were significantly increased in T1DM monocytes compared with controls. Downstream targets of TLR, nuclear factor kappaB, myeloid differentiation factor 88, Trif, and phosphorylated IL-1 receptor-associated kinase were significantly up-regulated in T1DM. Finally, the release of IL-1beta and TNF-alpha was significantly increased in monocytes from T1DM compared with controls and correlated with TLR2 and TLR4 expression (P < 0.005). In addition, TLR2 and TLR4 expression was significantly correlated to glycosylated hemoglobin, carboxymethyllysine, and nuclear factor kappaB (P < 0.02).
Thus, we make the novel observation that TLR2 and TLR4 expression and signaling are increased in T1DM and contribute to the proinflammatory state.

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Available from: Steven C Griffen, Oct 10, 2015
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    • "Another essential element of the innate immune system is the Toll Like Receptor (TLR) system, which consists of a group of transmembrane proteins expressed in immune and in nonimmune cells, whose role is to recognize components of foreign pathogens. TLRs have been associated with T1D development in mouse and in human studies [35] [36], thus underlining the importance of innate immune system in diabetes etiology. Emerging data have identified miRNAs as important regulators of development and function of innate immune components in addition to the aforementioned adaptive immune cells. "
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    ABSTRACT: MicroRNAs are small noncoding RNA molecules that regulate gene expression in all cell types. Therefore, these tiny noncoding RNA molecules are involved in a wide range of biological processes, exerting functional effects at cellular, tissue, and organ level. In pancreatic islets of Langerhans, including beta-cells, microRNAs are involved in cell differentiation as well as in insulin secretion, while in immune cells they have been shown to play pivotal roles in development, activation, and response to antigens. Indeed, it is not surprising that microRNA alterations can lead to the development of several diseases, including type 1 diabetes (T1D). Type 1 diabetes is the result of a selective autoimmune destruction of insulin-producing beta-cells, characterized by islet inflammation (insulitis), which leads to chronic hyperglycemia. Given the growing importance of microRNA in the pathophysiology of T1D, the aim of this review is to summarize the most recent data on the potential involvement of microRNAs in autoimmune diabetes. Specifically, we will focus on three different aspects: (i) microRNAs as regulators of immune homeostasis in autoimmune diabetes; (ii) microRNA expression in pancreatic islet inflammation; (iii) microRNAs as players in the dialogue between the immune system and pancreatic endocrine cells.
    09/2015; 2015(61):1-11. DOI:10.1155/2015/749734
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    • "The roles of the TLR4 signaling pathway in the processes underlying inflammatory vascular diseases including atherosclerosis [14], diabetes [26]–[28] or pre-eclampsia [29], [30] have been reported. While several studies have addressed the contribution of adaptive immunity to the pathophysiology of hypertension, there are few studies regarding the role of the innate immune system in the context of this pathology [31]–[33]. "
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    ABSTRACT: Hypertension is considered as a low-grade inflammatory disease, with adaptive immunity being an important mediator of this pathology. TLR4 may have a role in the development of several cardiovascular diseases; however, little is known about its participation in hypertension. We aimed to investigate whether TLR4 activation due to increased activity of the renin-angiotensin system (RAS) contributes to hypertension and its associated endothelial dysfunction. For this, we used aortic segments from Wistar rats treated with a non-specific IgG (1 µg/day) and SHRs treated with losartan (15 mg/kg·day), the non-specific IgG or the neutralizing antibody anti-TLR4 (1 µg/day), as well as cultured vascular smooth muscle cells (VSMC) from Wistar and SHRs. TLR4 mRNA levels were greater in the VSMC and aortas from SHRs compared with Wistar rats; losartan treatment reduced those levels in the SHRs. Treatment of the SHRs with the anti-TLR4 antibody: 1) reduced the increased blood pressure, heart rate and phenylephrine-induced contraction while it improved the impaired acetylcholine-induced relaxation; 2) increased the potentiation of phenylephrine contraction after endothelium removal; and 3) abolished the inhibitory effects of tiron, apocynin and catalase on the phenylephrine-induced response as well as its enhancing effect of acetylcholine-induced relaxation. In SHR VSMCs, angiotensin II increased TLR4 mRNA levels, and losartan reduced that increase. CLI-095, a TLR4 inhibitor, mitigated the increases in NAD(P)H oxidase activity, superoxide anion production, migration and proliferation that were induced by angiotensin II. In conclusion, TLR4 pathway activation due to increased RAS activity is involved in hypertension, and by inducing oxidative stress, this pathway contributes to the endothelial dysfunction associated with this pathology. These results suggest that TLR4 and innate immunity may play a role in hypertension and its associated end-organ damage.
    PLoS ONE 08/2014; 9(8):e104020. DOI:10.1371/journal.pone.0104020 · 3.23 Impact Factor
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    • "TLR4 and/or 2 are required for the development of kidney damage in response to ischemia-reperfusion injury [8], [9], cisplatin-induced nephrotoxicity [10] and glomerulonephritis [11], [12]. Increased expression of TLR2 and 4 has been found in monocytes from patients with type 1 and 2 diabetes mellitus [13], [14], suggesting TLR2 and 4 may play an important role in the inflammatory milieu which characterizes diabetes. Recent experimental studies support this concept as TLR2 or TLR4 deficiency attenuated the pro-inflammatory state generated in wild-type mice with STZ-induced diabetes [15]–[19]. "
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    ABSTRACT: Toll like receptor (TLR) 4 has been reported to promote inflammation in diabetic nephropathy. However the role of TLR4 in the complicated pathophysiology of diabetic nephropathy is not understood. In this study, we report elevated expression of TLR4, its endogenous ligands and downstream cytokines, chemokines and fibrogenic genes in diabetic nephropathy in WT mice with streptozotocin (STZ) diabetes. Subsequently, we demonstrated that TLR4-/- mice were protected against the development of diabetic nephropathy, exhibiting less albuminuria, inflammation, glomerular hypertrophy and hypercellularity, podocyte and tubular injury as compared to diabetic wild-type controls. Marked reductions in interstitial collagen deposition, myofibroblast activation (α-SMA) and expression of fibrogenic genes (TGF-β and fibronectin) were also evident in TLR4 deficient mice. Consistent with our in vivo results, high glucose directly promoted TLR4 activation in podocytes and tubular epithelial cells in vitro, resulting in NF-κB activation and consequent inflammatory and fibrogenic responses. Our data indicate that TLR4 activation may promote inflammation, podocyte and tubular epithelial cell injury and interstitial fibrosis, suggesting TLR4 is a potential therapeutic target for diabetic nephropathy.
    PLoS ONE 05/2014; 9(5):e97985. DOI:10.1371/journal.pone.0097985 · 3.23 Impact Factor
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