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Lalit P. Singh, Takhellambam S. Devi; TXNIP Regulates Aberrant ECM Expression and Impaired Innate Immune Responses in Early Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3579.
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Alterations in extracellular matrix (ECM) expression in injury and disease are recognized as sterile danger signals or damage-associated molecular patterns (DAMPs) by membrane-associated pattern recognition receptors (PRRs) such as toll-like receptor TLR4 and purinergic receptor P2X7R. This evokes the host innate immune response and produces pro-inflammatory cytokines. Here, we investigate whether TXNIP-mediated aberrant ECM expression induces retinal innate immune responses in early diabetic retinopathy.
Streptozocin-induced Sprague-Dawley diabetic male rats (~6 weeks old) were maintained for 4 weeks. Intravitreal injection of siRNA was used to knock down TXNIP expression in the right eye of diabetic rats while the left eye received saline as diabetes controls. RT-qPCR, Western blotting and immunohistochemistry were employed to measure mRNA/protein expression and localization in retinal tissues and frozen sections.
Diabetes increases ECM expression for fibronectin and laminin γ1 in the retina, which correlate with enhanced TLR4 and P2X7R levels in the diabetic rat retina vs. retinas from non-diabetic normal rats. We also observed an activation of the transcription factor NF-ΚB and histone H3 lysine 9 acetylation in diabetic retinas that are implicated in pro-inflammatory gene induction. In concert, interleukin (IL)-1β) expression is significantly enhanced in the diabetic rat retina vs. the normal rat retina. TXNIP knock down by siRNA reduces ECM and IL-1β expression in the diabetic rat retina versus the corresponding saline-treated diabetes control retina.
TXNIP mediates aberrant ECM expression and impaired innate immune responses in the diabetic retina, which may ultimately lead to chronic sterile inflammation and disease progression of diabetic retinopathy.
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