Abstract
Purpose: :
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.
Methods: :
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.
Results: :
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.
Conclusions: :
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.
Keywords: diabetic retinopathy • extracellular matrix • inflammation