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Manuela Bartoli, Folami Lamoke, Anna Lisa Montemari, Chaunte Stampley, Wan Jin Jahng, Babak Baban; Evidence of Inflammasome Activation in the Human Diabetic Retina. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5428.
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Chronic subclinical inflammation is a key pathogenic event in the induction and progression of diabetic retinopathy (DR). Recently, It has been shown, that metabolic stress can trigger the intracellular formation of the inflammasome. These are large intracellular clusters of immunomodulators, such as Toll-like receptors (TLRs), NOD-like receptors (NLRs) and the thioredoxin inhibitory protein (TXNIP). Formation of inflammasome leads to activation of caspase 1 and proteolytic activation of the pro-inflammatory cytokines IL-1beta and IL-18. Here we have performed studies to determine whether inflammasome activation is involved in human DR.
Post-mortem human eyes from diabetic (n=7) and non diabetic (n=6) donors were obtained from Georgia Eye Bank. Retinal extracts were processed for Western blotting analysis, immunoprecipitation and Mass spectrometry. Paraffin embedded and frozen retinal sections were analyzed by immunohistochemistry. Caspase 1 activity was measured using a fluorimetric method.
We have found that the expression of TLR4, NLRP3 and TXNIP were up-regulated in the post-mortem human diabetic retina in comparison with the normoglycemic control donors. Increased expression of these constituents of the inflammasome correlated with enhanced caspase 1 expression and activity as well as increased levels of IL-1beta. Furthermore, immunoprecipitation and mass spectrometry showed the association of TXNIP with TLRs and NLRP3 in the diabetic retinas.
Activation of inflammasome in response to metabolic stress is an emerging concept explaining pathological inflammatory processes in response to metabolic imbalance. The results of our studies by demonstrating the up-regulation and reciprocal interaction of inflammasome constituents along with activation of caspase 1 in the human diabetic retina, strongly implicate the inflammasome in the pathogenesis of DR.
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