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Suppressors of Cytokine-Signaling Proteins Induce Insulin Resistance in the Retina and Promote Survival of Retinal Cells

¹ Molecular Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland
² Department of Biomedical Engineering, Harvard College, Harvard University, Cambridge, Massachusetts
³ Department of Biomedical Engineering, Pritzker Institute of Biomedical Science and Engineering, Illinois Institute of Technology, Chicago, Illinois

Corresponding author: Dr. Charles E. Egwuagu, Molecular Immunology Section, Laboratory of Immunology, National Institutes of Health, Building 10, Rm. 10N116, 10 Center Dr., Bethesda, MD 20892-1857. E-mail: egwuaguc{at}nei.nih.gov

Abbreviations: EAU, experimental autoimmune uveitis; FOXO, forkhead transcription factor; GFP, green fluorescent protein; HIF, hypoxia-inducible factor; IFN, interferon; IL, interleukin; IRBP, interphotoreceptor retinoid binding protein; IRS, insulin receptor substrate; NIH, National Institutes of Health; PI3K, phosphatidylinositol 3-kinase; pSTAT, phosphorylated STAT; qRT-PCR, quantitative RT-PCR; RPA, ribonuclease protection assay; RGC, retinal ganglion cell; RPE, retinal pigment epithelium; siRNA, small interfering RNA; SOCS, suppressors of cytokine signaling; STAT, signal transducer and activator of transcription; STZ, streptozotocin; VEGF, vascular endothelial growth factor

OBJECTIVE—Suppressors of cytokine signaling (SOCS) are implicated in the etiology of diabetes, obesity, and metabolic syndrome. Here, we show that some SOCS members are induced, while others are constitutively expressed, in retina and examine whether persistent elevation of SOCS levels in retina by chronic inflammation or cellular stress predisposes to developing insulin resistance in retina, a condition implicated in diabetic retinopathy.

RESEARCH DESIGN AND METHODS—SOCS-mediated insulin resistance and neuroprotection in retina were investigated in 1) an experimental uveitis model, 2) SOCS1 transgenic rats, 3) insulin-deficient diabetic rats, 4) retinal cells depleted of SOCS6 or overexpressing SOCS1/SOCS3, and 5) oxidative stress and light-induced retinal degeneration models.

RESULTS—We show that constitutive expression of SOCS6 protein in retinal neurons may improve glucose metabolism, while elevated SOCS1/SOCS3 expression during uveitis induces insulin resistance in neuroretina. SOCS-mediated insulin resistance, as indicated by its inhibition of basally active phosphoinositide 3-kinase/AKT signaling in retina, is validated in retina-specific SOCS1 transgenic rats and retinal cells overexpressing SOCS1/SOCS3. We further show that the SOCS3 level is elevated in retina by oxidative stress, metabolic stress of insulin-deficient diabetes, or light-induced retinal damage and protects ganglion cells from apoptosis, suggesting that upregulation of SOCS3 may be a common physiologic response of neuroretinal cells to cellular stress.

CONCLUSIONS—Our data suggest two-sided roles of SOCS proteins in retina. Whereas SOCS proteins may improve glucose metabolism, mitigate deleterious effects of inflammation, and promote neuroprotection, persistent SOCS3 expression caused by chronic inflammation or cellular stress can induce insulin resistance and inhibit neurotrophic factors, such as ciliary neurotrophic factor, leukemia inhibitory factor, and insulin, that are essential for retinal cell survival.

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