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Abigail Hackam, Kristy Hamlin, Lee Kissel, Joeli Roth, Amit Patel; Pharmacologic and genetic inhibition of the TLR/Myd88 branch of the innate immune system reduces retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4545.
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© ARVO (1962-2015); The Authors (2016-present)
Toll-like receptors (TLR) and interleukin (IL)-1 receptors (IL-1R) are major families of innate immunity receptors that signal through the adaptor protein MyD88 to coordinate the inflammatory response to injury and stress. The contribution of TLR/IL-1R/MyD88 signaling to inherited photoreceptor degeneration is not known. In this study, we investigated the role of the MyD88 branch of the innate immune system during photoreceptor death, and determined the therapeutic potential of blocking MyD88, in the rd10 mouse model of inherited retinal degeneration.
The rd10 mice were bred with Myd88 knockout mice (both purchased from Jackson Labs) to produce rd10 mice homozygous for wildtype or deleted MyD88. MyD88 inhibitory and control peptides were purchased from Imgenex and injected IP. Retina function was analysed with ERGs, molecular analyses were by Western blotting, and microglia were detected on retina sections by immunostaining for IBA-1.
ERGs showed increased scotopic and photopic responses and lower time-to-peak times in rd10 mice lacking MyD88 (MyD-/-;rd10) compared with rd10 with wildtype MyD88 (MyD+/+;rd10) at post-natal day 30 (p<0.05, n=5). Elevated cone transducin levels were also observed in the MyD-/-;rd10 mice, consistent with photoreceptor survival (p<0.05, n=5). We also demonstrated that MyD88-/-;rd10 retinas had significantly higher β-catenin levels (n=4, p<0.05), suggesting enhanced activation of canonical Wnt/β-catenin signaling could be a potential mechanism of neuroprotection after loss of MyD88. We also showed that pharmacologic inhibition of MyD88 in rd10 mice significantly increased scotopic and photopic b-wave amplitudes one week after injection, compared with the control peptide (n=8, p<0.05), and reduced microglia numbers in the outer nuclear layer by two-fold (p<0.05, n=3).
MyD88 is a novel negative regulator of photoreceptor survival in a mouse model of inherited retinal degeneration. We propose a model in which TLR/IL-1R/MyD88 signaling are activated after photoreceptor injury and lead to microglial activation and retinal degeneration, and thus blocking MyD88 protects photoreceptors. Systemic delivery of the Myd88 inhibitor was effective, suggesting a potential therapeutic strategy for retinal degenerations.
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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