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Ana J. Chucair-Elliott, Gennadiy P. Moiseyev, Jiangang Wang, John D. Ash; The Visual Cycle in the Retinal Pigmented Epithelium is Regulated by Stress Response Pathways in the Retina. Invest. Ophthalmol. Vis. Sci. 2011;52(14):865.
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Leukemia inhibitory factor (LIF) is an endogenously expressed cytokine that is induced in Muller cells in response to stressed retinal neurons. We have shown that LIF protects photoreceptors through the activation of its receptor gp130 and its signaling partner STAT3. However, LIF also induces robust activation of STAT3 in the retinal pigmented epithelium (RPE), suggesting that LIF may induce protection and/or functional changes in RPE cells. In this study we aimed to determine whether activation of STAT3 by LIF alters the biological activity of RPE cells in vivo.
We generated conditional knockout mice to specifically delete STAT3 in RPE cells (RPE-cre; STAT3f/f) or gp130 in the neural retina (Chx10-cre; gp130f/f). We intravitreally injected recombinant LIF in the right eye and PBS (vehicle) in the left eye. To measure RPE dependent visual cycle we analyzed: the levels of RPE65, phosphorylated STAT3 (pSTAT3), and rhodopsin in eyecup and retina fractions; measured the isomerohydrolase activity of RPE65 in eyecups; and analyzed rod photoreceptor recovery rates from bleaching light by electroretinography (ERG).
Our conditional knockout mouse line (RPE-cre; STAT3f/f) showed efficient deletion of STAT3 in a high percentage (nearly 90%) of RPE cells. We found that RPE65 protein and isomerohydrolase activity were reduced in LIF injected eyes, which required STAT3 expression in RPE cells. Consistent with reduced isomerohydrolase activity, ERG data suggests delayed recovery of rod a-wave response following bleaching light.
Our data show intravitreal injection of LIF reduces RPE visual cycle through STAT3 activation and reduction of RPE65 protein content. Precise control of visual cycle activity in RPE is critical for photoreceptor health and function. Too much or too little 11-cis retinal is detrimental to retinal health and function. Our data demonstrate that stress responses in the retina can directly modulate RPE cells and can thus control the rate of 11-cis retinal production.
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