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 & 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
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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.
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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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    Full-text · Article · Aug 2014 · PLoS ONE
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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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