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Abigail S. Hackam, Hyun Yi; Novel Role For The Innate Immune Receptor Toll-like Receptor 4 (TLR4) In The Regulation Of The Wnt Signaling Pathway And Photoreceptor Apoptosis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1665.
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Innate immunity is proposed to play a role in the pathogenesis of age-related macular degeneration (AMD), but its precise contribution is unknown. Recent evidence has implicated innate immunity in reduced neuronal survival elsewhere in the CNS during various disease conditions. Here, we examined the role of the innate immunity receptor TLR4 in a cellular model of AMD.
Primary photoreceptor-Muller glia cocultures were prepared from C57Bl/6 mice. Photoreceptor viability was measured by Cell Titre Blue and caspase assays, in the presence of oxidative stress (0.4 mM H2O2) to simulate AMD-like injury. Wnt signaling was measured by luciferase reporter assays and Western blotting for phospho-LRP6.
TLR4 activation by lipopolysaccharide (LPS) (0.05-50 ug/ml) significantly reduced photoreceptor survival in primary Muller glia-photoreceptor cocultures exposed to oxidative stress, whereas blocking endogenous TLR4 activation protected against oxidative-stress induced cell death. With respect to mechanism, TLR4 suppressed Wnt signaling by 42% (p<0.05, n=5), decreased phosphorylation and activation of the Wnt receptor LRP6 by 50% (p<0.05, n=5) and blocked the protective effect of the Wnt3a ligand. Paradoxically, TLR4 activation prior to oxidative injury protected photoreceptors by five-fold (p<0.05, n=4) in a phenomenon known as preconditioning. Furthermore, expression of TNF-alpha and its receptors TNFR1 and TNFR2 decreased during preconditioning, and preconditioning was mimicked by TNF-alpha antagonists, but was independent of Wnt signaling.
TLR4 may regulate photoreceptor death at various stages of retinal injury in AMD by regulating the Wnt and TNF-alpha pathways. These data indicate a novel mechanism of neurotoxicity in the retina, and suggest that TLR4 signaling could be further investigated as a target for developing novel therapeutic strategies for AMD.
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