Topical administration of a suppressor of cytokine signaling-1 (SOCS1) mimetic peptide inhibits ocular inflammation and mitigates ocular pathology during mouse uveitis.
Topical administration of a suppressor of cytokine signaling-1 (SOCS1) mimetic peptide inhibits ocular inflammation and mitigates ocular pathology during mouse uveitis.
复制标题
局部施用细胞因子信号1（SOCS1）模拟肽的抑制剂抑制眼部炎症，并减轻小鼠葡萄膜炎期间的眼病理。
DOI：
10.1016/j.jaut.2015.05.011
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发表时间：
2015-08
影响因子：
12.8
通讯作者：
Egwuagu CE
中科院分区：
文献类型：
--
作者：
He C;Yu CR;Sun L;Mahdi RM;Larkin J 3rd;Egwuagu CE
葡萄膜炎是一组潜在威胁视力的眼内炎性疾病，其病理学来源于在光轴中持续产生促炎细胞因子。虽然局部或全身性类固醇是有效的治疗方法，但其不良反应妨碍了长期使用，并促使人们寻求替代免疫抑制剂，特别是对难治性葡萄膜炎患者。在这项研究中，我们合成了一个16个氨基酸的细胞因子信号转导1肽（SOCS 1-KIR），抑制JAK/STAT信号通路，并显示它抑制和改善实验性自身免疫性葡萄膜炎（EAU），人类葡萄膜炎的小鼠模型。眼睛的眼底图像、组织学和光学相干断层扫描分析显示出对临床疾病的显著抑制，平均临床评分为0.5，而在用乱序肽处理的对照小鼠中观察到的平均临床评分为2.0。我们进一步表明，SOCS 1-KIR通过抑制致病性Th 17细胞的扩增和抑制EAU期间炎性细胞向神经视网膜的运输而赋予对眼部病理的保护。暗适应暗视和明视视网膜电图进一步揭示了SOCS 1-KIR防止视网膜功能的减退，强调了SOCS 1-KIR在葡萄膜炎中的潜在神经保护作用。重要的是，SOCS 1-KIR是无毒的，表明SOCS 1-模拟物的局部给药可用作葡萄膜炎的非侵入性治疗，并用于限制其他眼部炎性疾病（包括巩膜炎）中的精氨酸介导的病理
Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases and pathology derives from sustained production of pro-inflammatory cytokines in the optical axis. Although topical or systemic steroids are effective therapies, their adverse effects preclude prolonged usage and are impetus for seeking alternative immunosuppressive agents, particularly for patients with refractory uveitis. In this study, we synthesized a 16 amino acid membrane-penetrating lipophilic suppressor of cytokine signaling 1 peptide (SOCS1-KIR) that inhibits JAK/STAT signaling pathways and show that it suppresses and ameliorates experimental autoimmune uveitis (EAU), the mouse model of human uveitis. Fundus images, histological and optic coherence tomography analysis of eyes showed significant suppression of clinical disease, with average clinical score of 0.5 compared to 2.0 observed in control mice treated with scrambled peptide. We further show that SOCS1-KIR conferred protection from ocular pathology by inhibiting the expansion of pathogenic Th17 cells and inhibiting trafficking of inflammatory cells into the neuroretina during EAU. Dark-adapted scotopic and photopic electroretinograms further reveal that SOCS1-KIR prevented decrement of retinal function, underscoring potential neuroprotective effects of SOCS1-KIR in uveitis. Importantly, SOCS1-KIR is non-toxic, suggesting that topical administration of SOCS1-Mimetics can be exploited as a non-invasive treatment for uveitis and for limiting cytokine-mediated pathology in other ocular inflammatory diseases including scleritis