Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, United States.
Department of Microbiology and Cell Science, University of Florida, Gainesville, FL, United States.
Front Immunol. 2024 Jul 22;15:1416181. doi: 10.3389/fimmu.2024.1416181. eCollection 2024.
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.
几种影响视网膜和视神经的致盲性疾病是由炎症失调和氧化应激引起或导致的。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，尽管它们的症状不同，但减少氧化应激和抑制炎症的治疗方法可能具有治疗作用。炎症细胞因子的产生及其活性受一类称为细胞因子信号转导抑制因子（SOCS）的蛋白质调节。SOCS1 和 SOCS3 已知可通过采用 Janus 激酶和转录激活因子（JAK/STAT）、Toll 样受体（TLR）、核因子κB 轻链增强子的激活 B 细胞（NF-κB）、丝裂原激活蛋白激酶（MAPK）和富含 N 端富含亮氨酸重复序列的pyrin 域 3（NLRP3）的途径来抑制信号。我们从 SOCS1 和 SOCS3 的激酶抑制区开发了细胞穿透肽（分别表示为 R9-SOCS1-KIR 和 R9-SOCS3-KIR），并在视网膜色素上皮（RPE）细胞和巨噬细胞系中进行了测试。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 细胞均被抑制，同时抑制其他炎症标志物。我们还观察到氧化剂减少，同时神经保护和抗氧化效应物增加。此外，治疗可防止 RPE 细胞中缝隙连接蛋白的丢失和随后的跨上皮电阻下降。当通过滴眼剂在小鼠模型中进行测试时，它们显示出对自身免疫性葡萄膜炎的保护作用，无论是预防还是治疗。通过滴眼剂给予的内毒素诱导的葡萄膜炎小鼠也受到保护。R9-SOCS3-KIR 对通过 STAT3 起作用的途径特别有效，例如介导导致黄斑变性的 IL-6 和 VEGF-A 的反应。滴眼剂给予 R9-SOCS3-KIR 刺激抗氧化效应物的产生，并减少模拟 AMD 中 RPE 损伤的氧化应激小鼠模型中的临床症状。由于这些肽抑制多种致病刺激，并且可以局部递送至角膜，因此它们是葡萄膜炎、黄斑变性、糖尿病性视网膜病变和青光眼治疗的有吸引力的候选药物。
