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Ana J. Chucair-Elliott, Michael H. Elliott, Jiangang Wang, John D. Ash; A Unique Stress Response Pathway in the Retina Down-regulates the Visual Cycle and Protects the RPE from Damage Induced by Sodium Iodate. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4785. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Leukemia inhibitory factor (LIF) is an endogenously released stress neurocytokine, implicated in the protection of photoreceptors through the activation of the receptor gp130 and its signaling partner STAT3. However, LIF also induces robust activation of STAT3 in the retinal pigmented epithelium (RPE). It is possible that this activation alters the biological activity of the RPE and/or is important for the protection of the RPE against damage. In support, studies suggest a role of STAT3 in the stressed RPE. Here, we studied whether the activation of STAT3 by LIF in the RPE induces functional changes and/or protection in RPE cells in vivo.
We generated conditional knockout mice to specifically delete STAT3 in RPE cells (RPE-cre; STAT3f/f), gp130 in the neural retina (Chx10-cre; gp130f/f), and gp130 in both retina and RPE (RPE-cre/chx10-cre; gp130 f/f). To evaluate the visual cycle function after intravitreal injection of LIF, we analyzed the expression levels of visual cycle genes and proteins, isomerohydrolase activity of RPE65, levels of rhodopsin protein, and the rates of dark adaptation and rhodopsin regeneration. To evaluate the role of STAT3 in the protection of RPE, we injected mice with sodium iodate (NaIO3), and evaluated RPE genes and proteins, survival of RPE, ERG function and retinal morphology.
We found that RPE65 protein and isomerohydrolase activity were reduced and recovery of bleachable rhodopsin was delayed in LIF-injected eyes. In mice with functional gp130/STAT3 signaling in the retina, rhodopsin protein was also reduced by LIF. However, the effect of LIF on RPE65 required a functional gp130/STAT3 cascade intrinsic to RPE. NaIO3 injections caused downregulation of RPE genes and proteins and dose-dependent death of RPE. The lack of STAT3 specifically in RPE, made the RPE dramatically susceptible to NaIO3- induced death as measured by morphology and ERG function.
The effect of LIF on RPE65 required a functional gp130/STAT3 cascade intrinsic to RPE. Our data demonstrate LIF can simultaneously affect both RPE and photoreceptors to reduce the generation and utilization of 11-cis retinal. Our data suggests that this cascade is essential to protect RPE cells under stress.
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