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Marcus Hooper, John D Ash, ; The role of Toll-Like Receptor 4 (TLR4) and Müller cell MyD88 signaling in photoreceptor survival and function following light stress. . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3610.
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© ARVO (1962-2015); The Authors (2016-present)
Toll-like receptors (TLRs) are needed for the detection of stress-induced damage-associated molecular patterns (DAMPs), and have been implicated in neuroprotection. We have used bright light-induced preconditioning that can protect photoreceptors from light damage. The purpose of this study was to determine whether TLR4 was necessary for induction of protection and whether Müller cell TLR signaling was required for neuroprotection.<br />
For preconditioning (PC), mice were exposed to cyclic bright light for 6 days at 400 lux. For light damage (LD) mice were exposed to 1300 lux for 4 hours. Retinal photoreceptor function and a-wave amplitudes were determined by scotopic electroretinography (ERG). Retinal morphology was observed by Spectral Domain-Optical Coherence Tomography (OCT). TLR4 germline knockout mice were used to study the role of TLR4. GLAST Cre: MyD88f/f mice were used for Müller cell-specific knockout of MyD88. Induction of cre was done using intraperitoneal tamoxifen injections, and the deletion was assessed by PCR. Quantitative PCR was used to determine LIF expression levels. Unpaired two-tailed t-tests were used for statistical analysis.<br />
Mice with a deletion of TLR4 (TLR4-/- mice) display normal morphology and function, but had a reduced a-wave response (p < 0.01) 1 week following PC and LD (PCLD) relative to WT mice. Surprisingly, morphology and thickness of retinal layers, as observed by OCT were identical not significantly different from WT mice, suggesting no loss in rod cells. Three week following PCLD, TLR4-/- mice showed a modest recovery. Müller cell-specific MyD88 knockout mice still displayed PC-induced protection and did not recapitulate the phenotype seen in TLR4-/- mice.<br />
Data show that preconditioning promoted photoreceptor survival in the absence of TLR4, suggesting that TLR4 is not necessary for preconditioning-induced protection. However, the delayed recovery of rod function following preconditioning suggests that TLR4 plays an important role in regulating photoreceptor recovery from bright light stress. Müller cell knockout of MyD88 did not reduce preconditioning-induced protection or LIF expression. This result suggests that another cell in the retina is required for TLR-mediated induction of neuroprotection in light stress.<br />
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