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Chang He, Chengrong Yu, Lin Sun, Rashid M Mahdi, Justine Yeung, CHRALES E EGWUAGU; SOCS1-Mimetic Eye-drops inhibit ocular inflammation and protect against ocular pathology during Experimental Autoimmune Uveitis (EAU). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3098.
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© ARVO (1962-2015); The Authors (2016-present)
Suppressor of cytokine signaling 1 (SOCS1) inhibits inflammation by targeting JAK kinases and activated cytokine receptors for degradation in the proteasome, thereby terminating STAT signals activated by pro-inflammatory cytokines. Enhancing SOCS1 activity has therefore been considered as a potential therapeutic approach to mitigate pathology in inflammatory and autoimmune diseases. However, a major impediment to the therapeutic use of SOCS1 is its relatively short half-life. Consequently there is significant interest in developing strategies to efficiently deliver exogenous SOCS1 into cells. In this study, we have synthesized a 16 amino acids lipophilic SOCS1 peptide (SOC1-KIR) that penetrates cell membrane, interacts with JAK auto-phosphorylation loop and inhibits its kinase activity. We investigated whether topical administration of SOCS1-KIR can be used as therapy for uveitis.
We induced EAU in C57/BL6 mice by immunization with interphotoreceptor retinoid-binding protein in complete Freund's adjuvant. Mice received 10µg SOCS1-KIR (diluted in PBS to 5µl/eye) as eye drops, every day beginning Day 0 until Day 12. Disease severity was assessed by fundoscopy, optical coherence tomography, histological examination, and electroretinogram. The development of inflammation or production of inflammatory molecules was assessed by flow cytometry and mRNA analysis of cells in the draining lymph nodes and retina.
Treatment with SOCS1-KIR eye drops efficiently suppressed EAU and protected mice from ocular pathology by inhibiting lymphocyte proliferation and limiting infiltration of inflammatory cells into the eye. In line with our in vivo results, analyses of lymphocytes isolated from the lymph nodes and spleen of the mice show that treatment with the SOCS1-KIR inhibited the expression of chemokine receptors and integrins, which mediate lymphocyte trafficking. Importantly, SOCS1-KIR had no effect on systemic immune response.
Local administration of SOCS1-KIR peptide inhibited the development of uveitis in the mouse EAU model by suppressing the expansion of pathogenic cells that mediate uveitis and their recruitment into the retina. SOCS1-KIR is nontoxic, suggesting that topical administration of SOCS1-Mimetics can be exploited as a non-invasive treatment for human uveitis.
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