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Hyun Yi, Abigail Hackam; Preconditioning By Activation Of Toll-like Receptor 4 Protects Photoreceptors From Oxidative Stress. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1004.
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The innate immune response has been suggested to play a role in the pathogenesis of age-related macular degeneration (AMD). We demonstrated that activation of the innate immune receptor toll-like receptor 4 (TLR4) increases photoreceptor death. In contrast to the damaging effect of TLR4 activation during injury, preconditioning by TLR4 activation prior to an injury induces a mild inflammatory response that can protect against certain subsequent injuries in the brain and heart. In this study, we investigated whether preconditioning by TLR4 activation protects photoreceptors from dying after exposure to oxidative stress.
Primary retinal cultures containing photoreceptors and Muller glia were prepared from wild-type mice. TLR4 signaling was activated by 0.05-50 ug/ml lipopolysaccharide (LPS). Photoreceptor viability was measured by Cell Titre Blue assays. Wnt signaling was activated by the Wnt3a ligand. Expression of TNFalpha and its receptors was measured by QPCR.
Retinal cultures were incubated in LPS to activate TLR4 two hrs before challenge with 0.4 mM H2O2. Viability assays demonstrated significant protection with 0.5 and 5 ug/ml LPS, up to five-fold over H2O2 alone (p<0.05, n=4). Wnt3a (150 ng/ml) also protected photoreceptors from H2O2, and the combination of Wnt3a and 0.5 and 5 ug/ml LPS preconditioning had 70% greater protection than Wnt3a alone (p<0.05, n=4). We investigated the TNFalpha pathway as a potential mechanism of preconditioning. We showed that the expression of TNFalpha increased by 15-fold in the retina cultures (p<0.05, n=3), and the receptor TNFR2 increased by 5-fold (p<0.05, n=4).
We have demonstrated protection of retina cultures by showing that stimulating TLR4 prior to exposure to oxidative stress significantly reduced photoreceptor death. Therefore, these data indicate a novel mechanism of neuroprotection in the retina, and point to a potential therapeutic strategy.
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