Abstract:
Several blinding diseases affecting the retina and optic nerve are exacerbated by or caused by dysregulated inflammation and oxidative stress. These diseases include uveitis, age related macular degeneration, diabetic retinopathy and glaucoma. Consequently, despite their divergent symptoms, treatments that reduce oxidative stress and suppress inflammation may be therapeutic. The production of inflammatory cytokines and their activities are regulated by a class of proteins termed Suppressors of Cytokine Signaling (SOCS). SOCS1 and SOCS3 are known to dampen signaling via pathways employing Janus kinases and signal transducer and activator of transcription proteins (JAK/STAT), Toll-like Receptors (TLR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen activated kinase (MAPK) and NLR family pyrin domain containing 3 (NLRP3). We have developed cell-penetrating peptides from the kinase inhibitory region of the SOCS1 and SOCS3 (denoted as R9-SOCS1-KIR and R9-SOCS3-KIR) and tested them in retinal pigment epithelium (RPE) cells and in macrophage cell lines. SOCS-KIR peptides exhibited anti-inflammatory, anti-oxidant and anti-angiogenic properties. In cell culture, both Th1 and Th17 cells were suppressed together with the inhibition of other inflammatory markers. We also observed a decrease in oxidants and a simultaneous rise in neuroprotective and anti-oxidant effectors. In addition, treatment prevented the loss of gap junction proteins and the ensuing drop in transepithelial electrical resistance in RPE cells. When tested in mouse models by eye drop instillation, they showed protection against autoimmune uveitis, as a prophylactic as well as a therapeutic. Mice with endotoxin-induced uveitis were protected by eye drop administration as well. R9-SOCS3-KIR was particularly effective against the pathways acting through STAT3, e.g. IL-6 and VEGF-A mediated responses that lead to macular degeneration. Eye drop administration of R9-SOCS3-KIR stimulated production of antioxidant effectors and reduced clinical symptoms in mouse model of oxidative stress that replicates the RPE injury occurring in AMD. Because these peptides suppress multiple pathogenic stimuli and because they can be delivered topically to the cornea, they are attractive candidates for therapeutics for uveitis, macular degeneration, diabetic retinopathy and glaucoma.
摘要:
影响视网膜和视神经的几种致盲疾病由失调的炎症和氧化应激加剧或引起。这些疾病包括葡萄膜炎,年龄相关性黄斑变性,糖尿病性视网膜病变和青光眼。因此,尽管他们的症状不同,减少氧化应激和抑制炎症的治疗可能是治疗性的。炎性细胞因子的产生及其活性受一类称为细胞因子信号抑制因子(SOCS)的蛋白质的调节。已知SOCS1和SOCS3通过采用Janus激酶和信号转导和转录激活蛋白(JAK/STAT)的途径抑制信号传导,Toll样受体(TLR),核因子κ-活化B细胞的轻链增强子(NF-κB),丝裂原活化激酶(MAPK)和NLR家族pyrin结构域含3(NLRP3)。我们已经从SOCS1和SOCS3的激酶抑制区(表示为R9-SOCS1-KIR和R9-SOCS3-KIR)开发了细胞穿透肽,并在视网膜色素上皮(RPE)细胞和巨噬细胞中进行了测试。细胞系。SOCS-KIR肽表现出抗炎,抗氧化和抗血管生成特性。在细胞培养中,Th1和Th17细胞均受到抑制,同时抑制其他炎症标志物。我们还观察到氧化剂的减少和神经保护和抗氧化效应物的同时增加。此外,治疗可防止RPE细胞中间隙连接蛋白的丢失和随后的跨上皮电阻下降。当通过滴注滴眼液在小鼠模型中进行测试时,它们对自身免疫性葡萄膜炎有保护作用,作为预防和治疗。患有内毒素诱导的葡萄膜炎的小鼠也通过滴眼液给药进行保护。R9-SOCS3-KIR对通过STAT3起作用的途径特别有效,例如IL-6和VEGF-A介导的导致黄斑变性的应答。在复制AMD中发生的RPE损伤的氧化应激小鼠模型中,R9-SOCS3-KIR的滴眼剂给药刺激抗氧化剂效应物的产生并减少临床症状。因为这些肽抑制多种致病刺激,并且因为它们可以局部递送到角膜,他们是葡萄膜炎治疗的有吸引力的候选人,黄斑变性,糖尿病性视网膜病变和青光眼。