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A. Montemari, L. Di Renzo, A. Cacciamani, G. Parisi, M. Labazi, F. Facchiano, M. Varano, M. Bartoli; Toll-Like Receptor 4 is Elevated in Human Monocytes of Diabetic Patients and is Associated with the Progression of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1340.
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Chronic inflammation has been implicated in the pathogenesis of diabetic retinopathy (DR). Toll-like receptors (TLRs) are critical modulators of the innate immunity response. While their function and activation has been characterized in uveitis and diseases affecting the anterior chamber, little is known about their contribution to retinal chronic disease such as DR. In particular, increased expression of TLR-4 and TLR2 has been demonstrated in immunocytes of diabetic patients; however it is not clear whether this mechanism is directly involved in the pathogenesis of DR.
Circulating monocytes and lymphocytes were isolated from patients affected by Type 1 (T1DM, n=14) and Type 2 (T2DM, n=23) diabetes mellitus and from age-matched healthy volunteers (NDM, n=14) and analyzed by FACS analysis to measure levels of TLR4 and RAGE in the surface of circulating immunocytes. Multiple ELISA screening was used to determine the values of cytokines found in the patients sera. Fluorescein angiography was performed to assess clinical evidence of retinopathy following standard protocols.
Monocytes and lymphocytes of T1DM and T2DM patients displayed increased TLR4 expression (1.8 fold, p<0.05) compared to NDM. Prominent TLR-4 expression was found in monocytes of T1DM and T2DM showing clinical signs of retinopathy. These increases in TLR4 expression correlated with augmented serum levels of IL-6 (2 folds, p<0.03), a known marker of inflammation. Furthermore, in T1DM patients TLR4 up-regulation in monocytic cells was also associated with significant increases in the expression levels of the Receptor for Advanced Glycation Product (RAGE) (1.5 folds, p<0.05), which has been previously associated with induction of TLR-4.
Alteration in the expression pattern of TLR-4 in diabetic patients, correlated with the appearance of clinical signs of retinopathy and was associated to increased circulating levels of IL-6 and RAGE. This is suggesting TLR-4 possible implication in the inflammatory pathogenic events leading to DR.
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