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Marcus Hooper, Clayton P Santiago, Raghav Ramchander, John D Ash; Toll-like receptor 2 promotes photoreceptor survival in acute retinal injury. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5894.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal stress can induce the expression of leukemia inhibitory factor (LIF), which protects photoreceptors from cell death. The mechanism of LIF induction has not been identified. Toll-like receptor 2 (TLR2) is a pattern recognition receptor that is activated by damage-associated molecular patterns (DAMPS). Injection of the TLR2 agonist PAM3CSK, has been shown to induce LIF expression in the retina which protects photoreceptors from light damage. In this project we use TLR2-/- mice to investigate the role of TLR2 in LIF induction and protection from light damage (LD). NF-kB is a transcription factor that is activated by TLR2 signaling.
All mice were treated in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. For LD, TLR2-/- and wild type (WT) mice were exposed to ≥ 1300 lux for 4 hours. Retinal photoreceptor function was measured using scotopic electroretinography (ERG). Retinal morphology and Outer nuclear layer (ONL) thickness were examined using Spectral Domain-Optical Coherence Tomography (OCT), and histology. Quantitative PCR was used to measure gene expression. Chromatin immunoprecipitation was used to examine NF-kB binding sites in the LIF gene.
Exposure to damaging light in WT mice results in elevated expression of LIF. LIF induction correlated with NF-kB binding within a chromatin region located in the first intron of the LIF gene, that we show is a potentent transcriptional enhancer of the LIF promoter. TLR2-/- mice failed to induce LIF expression following exposure to damageing light. Interestingly, male TLR2-/- mice exposed to damaging light have a greater reduction in ONL thickness than WT mice, and have a greater reduction in ERG a-waves. However, female TLR2-/- mice were similar to WT mice.
Our data show that induction of LIF can be mediated by TLR2 and NF-kB activation, and suggests that stressed photoreceptors activate TLR2 by release of DAMPS. The failed induction of LIF in TLR2-/- mice reduced photoreceptor survival in male mice but not female mice. The increase in sensitivity to LD is likely due to a concomitant deficiency in LIF induction in TLR2-/- mice. We do not know why males are more affected than females, but we have identified estrogen receptor binding sites in the LIF promoter as well, suggesting that there are multiple pathways that can induce LIF expression.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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