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

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

Objective: Suppressors of cytokine signaling (SOCS) are implicated in etiology of diabetes, obesity and metabolic-syndrome. Here, we show that some SOCS members are induced while others are constitutively expressed in retina and have examined 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: (i) experimental uveitis model; (ii) SOCS1-transgenic rats; (iii) insulin-deficient diabetic rats; (iv) retinal cells depleted of SOCS6 or over-expressing SOCS1/SOCS3; (v) 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 PI3K/AKT signaling in retina, is validated in retina-specific SOCS1-transgenic rats and retinal cells over-expressing SOCS1/SOCS3. We further show that 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 maybe a common physiologic response of neuroretinal cells to cellular-stress.

Conclusion: 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, CNTF, LIF, insulin, that are essential for retinal cell survival.

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