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

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Proteins Induce Insulin-Resistance in the Retina and Promote Survival of Retinal Cells Diabetes Publish Ahead of Print, published online March 20, 2008 Suppressors of Cytokine Signaling (SOCS) Proteins Induce Insulin-Resistance in the Retina and Promote Survival of Retinal Cells Xuebin Liu1, Marie G. Mameza1, Yunsang Lee1, Chikezie I. Eseonu1,2 , Cheng-Rong Yu1, Jennifer J. Kang Derwent3 and Charles E. Egwuagu1* 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. Running Title: SOCS and insulin resistance in the retina Corresponding Author: Dr. Charles E. Egwuagu. Molecular Immunology Section, Laboratory of Immunology National Institutes of Health, Building 10, Room 10N116, 10 Center Drive, Bethesda, Maryland 20892-1857 [email protected] Received for publication 14 December 2007 and accepted in revised form 28 February 2008. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org. Copyright American Diabetes Association, Inc., 2008 SOCS and insulin resistance in the retina ABSTRACT 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. 2 SOCS and insulin resistance in the retina nsulin resistance and chronic of IRS2 in retina may inhibit signaling inflammation are implicated in downstream of insulin receptor, providing Ipathogenesis of diabetic retinopathy (DR), mechanistic link between inflammation, a glucose-mediated microvascular disease that insulin resistance and DR. derives in part from inability of the retina to SOCS proteins regulate intensity and adapt to metabolic stress (1-3). Clinical duration of cytokine/growth-factor signals evidence for a role of insulin-resistance as a and integrate multiple extracellular signals risk factor for DR comes from several clinical that may converge on target cells. The 8- trials including the Diabetic Control and member SOCS family proteins attenuates Complications Trial (DCCT) and the cytokine signals through interactions with EURODIAB Prospective Complications cytokine/growth-factor receptors and Study (4,5). In insulin-deficient diabetic rats, signaling proteins, leading to proteosomal progressive diminution of insulin-receptor degradation of the receptor complex (14-16). activity and marked decrease in insulin- SOCS proteins are rapidly induced in many receptor substrate (IRS) in retina precede cell types in response to cytokines (IFN-g, IL- appearance of early features of DR and 1b, IL-6) or growth factors (CNTF, LIF, FGF, neuronal cell death (6). On the other hand, insulin) and their effects are transient due to early features of DR such as vascular their short half-life (17-19). However, permeability, edema and increase in constitutive SOCS expression occurs in some inflammatory proteins are hallmarks of ocular tissues due to unabated stimulation by chronic inflammation (1). Although direct connection inflammation or cellular stress, leading to between chronic inflammation and insulin- silencing of critical cellular pathways and resistance in etiology of DR has yet to be predisposition to organ-specific disease established, studies on obesity or metabolic development. syndrome provide a paradigm for In studies on experimental autoimmune understanding roles of these disparate uveitis (EAU), a model of human uveitis, we processes in DR (7,8). In hepatocytes or showed that SOCS1 and SOCS3 are induced adipocytes, activation of insulin-receptors in retina during uveitis (13,20). Therefore, in recruits insulin-receptor-substrate (IRS) this study, we tested the hypothesis that proteins to the receptor complex, leading to SOCS proteins induced during uveitis can activation of phosphatidyl-inositol 3-kinase induce insulin-resistance and inhibit pro- (PI3K) and AKT signaling pathways, survival insulin signaling pathways in retina. increased glucose metabolism and cell growth In addition to intraocular inflammation, we (7). However, several reports have shown that found that factors that induce cellular stress induction of suppressors of cytokine signaling (hypoxia; metabolic-stress of diabetes) or (SOCS) proteins by inflammatory cytokines photoreceptor damage (high intensity) induce desensitizes insulin signaling by targeting SOCS3 expression in retina, confer partial IRS1/IRS2 for degradation, leading to protection to neuronal cells against apoptosis development of obesity, hepatic steatosis or but also desensitize insulin signaling in retina metabolic syndromes (9-11). It is therefore of cells. We show for the first time that SOCS6 note that IRS2 is essential for insulin protein is constitutively expressed in retinal signaling in retina (12) and SOCS proteins are neurons and may function to improve glucose elevated in retina during intraocular metabolism in neuroretina. Together these inflammatory disease (uveitis) (13), results suggest two-sided roles of SOCS suggesting that SOCS-mediated degradation proteins in retina: benefits of SOCS-mediated 3 SOCS and insulin resistance in the retina protective adaptive responses to established by induction of HIF-1a expression inflammation, light damage, hypoxia or (26). Observation of cells by light microscopy metabolic-stress come at a cost, as persistent after 24h of hypoxia demonstrated that they SOCS1/SOCS3 expression induced by uveitis were viable and healthy or chronic stress can induce insulin-resistance EAU Induction. We induced EAU in and trigger DR. C57BL/6 mice by active immunization with bovine interphotoreceptor retinoid-binding RESEARCH DESIGN AND METHODS protein (IRBP, 150 µg) and 300µg human Animals and induction of diabetes. C57BL/6 IRBP peptide (1–20) in complete Freund's mice were from Jackson Laboratory (Bar adjuvant (CFA) containing mycobacterium Harbor, ME). For induction of diabetes, tuberculosis strain H37RA (2.5 mg/ml) (13). overnight-fasted Sprague-Dawley rats Eyes for histology were harvested 0, 14, and (Charles River Laboratories, Wilmington, 21 days post-immunization, fixed in 10% MA) were given a single IV injection of buffered formalin. Sections were stained with streptozotocin (STZ) (55-65mg/kg; Sigma) in Hematoxylin and eosin (H&E). freshly dissolved 10mM/l sodium-citrate (pH Light treatment. Mice were dark-adapted 4.5). Diabetes was confirmed by blood overnight and then exposed to white light glucose >250mg/dl and tissues were harvested (5,000 lux) for 6-24h. Each animal was six and eight weeks after induction. housed in separate well-ventilated transparent Transgenic rat with targeted expression of plastic cage so that one animal could not hide SOCS1 using an opsin promoter element was behind another. Temperature was kept at generated and characterized as described (21). 25.0°C±1.0°C during light exposure. Mice/rats were housed in accordance with Confocal microscopy. Sections blocked in NIH guidelines on animal care. 5% normal goat serum were incubated with Rat retina organ culture, culture of human rabbit polyclonal SOCS6 antibody (Zymed, cell lines and hypoxia studies. Rat (postnatal San Francisco, CA). SOCS6-expressing cells day-2 pups) organ cultures were prepared as were detected with Alexa-488 conjugated described (22). Retina organs were stimulated goat-anti-rabbit secondary antibody with 100U/ml IFN-γ (Pepro Tech. Inc. Rocky containing DAPI (1ug/ml) (Invitrogen, Hill, NJ) and/or 10nM insulin in DMEM at Carlsbad, CA) on a Leica-SP2 laser scanning 37°C, 5% CO2. Human Müller cell line (MI0- confocal microscope (Leica Microsystems, M1) provided by G. Astrid Limb (London, Exton, PA) as described (20). UK) was
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