Melanocortin receptor agonists suppress experimental autoimmune uveitis.
Melanocortin receptor agonists suppress experimental autoimmune uveitis.
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DOI：
10.1016/j.exer.2022.108986
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发表时间：
2022-05
影响因子：
3.4
通讯作者：
Taylor, Andrew W.
中科院分区：
文献类型：
--
作者：
Ng, Tat Fong;Dawit, Kaleb;Taylor, Andrew W.
关键词：
黑皮质素系统在免疫活动的调节中起着至关重要的作用。眼睛的抗炎微环境依赖于黑皮质素-神经肽α-黑素细胞刺激激素（α-MSH）的表达。此外，黑皮质素系统可能在视网膜变性条件下的发育和视网膜细胞存活中起作用。我们发现用α-MSH治疗实验性自身免疫性葡萄膜炎（EAU）可抑制视网膜炎症。此外，黑皮质素系统的这种增强促进了免疫耐受和视网膜结构的保护。α-MSH治疗的益处似乎取决于不同的黑皮质素受体。因此，我们用具有不同黑皮质素受体靶点的α-MSH类似物治疗EAU小鼠。这种方法证明了黑皮质素受体抑制炎症，保护视网膜结构，并诱导免疫耐受性葡萄膜炎。在EAU的慢性阶段，给小鼠注射两次50 μg α-MSH或α-MSH类似物，间隔1天。α-MSH类似物是一种泛激动剂PL 8331、PL 8177（仅有效的MC 1 r激动剂）、PL 5000（无MC 5 r功能活性的泛激动剂）、MT-II（与PL 5000相同）和PG 901（MC 5 r激动剂，但也是MC 3r和MC 4 r的拮抗剂）。测量临床EAU评分，直至α-MSH处理小鼠消退，此时收集眼睛进行组织学检查，并收集脾细胞进行视网膜抗原刺激的细胞因子产生。用α-MSH或PL 8331处理观察到EAU的显著抑制。这伴随着视网膜结构的显著保留。在用PL 8177处理的EAU小鼠中观察到类似的效果，除了EAU的抑制是暂时的。在用PL 5000、MTII或PG 901处理的EAU小鼠中，没有对EAU的抑制，整个视网膜和外核层厚度显著损失。用α-MSH、PL 8331、PL 8177或PL 5000处理的EAU小鼠的视网膜抗原刺激的脾T细胞诱导IL-10，显著抑制IL-17，但用MT-II或PG 901处理的EAU小鼠则没有。我们以前的研究表明黑皮质素系统在维持眼免疫赦免中的重要性，α-MSH治疗加速EAU的恢复并诱导视网膜抗原特异性调节免疫。我们目前的结果表明，这种活动是围绕MC 1 r和MC 5 r。此外，结果表明，靶向MC 1 r和MC 5 r一起抑制葡萄膜炎的治疗潜力诱导调节性免疫，并可能维持正常的视网膜结构。
The melanocortin system plays an essential role in the regulation of immune activity. The anti-inflammatory microenvironment of the eye is dependent on the expression of the melanocortin-neuropeptide alpha-melanocyte stimulating hormone (α-MSH). In addition, the melanocortin system may have a role in the development and retinal cell survival under conditions of retinal degeneration. We have found that treating experimental autoimmune uveitis (EAU) with α-MSH suppresses retinal inflammation. Also, this augmentation of the melanocortin system promotes immune tolerance and protection of the retinal structure. The benefit of α-MSH-therapy appears to be dependent on different melanocortin receptors. Therefore, we treated EAU mice with α-MSH-analogs with different melanocortin-receptor targets. This approach demonstrated which melanocortin-receptors suppress inflammation, preserve retinal structure, and induce immune tolerance in uveitis. At the chronic stage of EAU the mice were injected twice 1 day apart with 50 μg of α-MSH or an α-MSH-analog. The α-MSH-analogs were a pan-agonist PL8331, PL8177 (potent MC1r-only agonist), PL5000 (a pan-agonist with no MC5r functional activity), MT-II (same as PL5000) and PG901 (MC5r agonist, but also an antagonist to MC3r, and MC4r). Clinical EAU scores were measured until resolution in the α-MSH-treated mice, when the eyes were collected for histology, and spleen cells collected for retinal-antigen-stimulated cytokine production. Significant suppression of EAU was seen with α-MSH or PL8331 treatment. This was accompanied with significant preservation of retinal structure. A similar effect was seen in EAU-mice that were treated with PL8177, except the suppression of EAU was temporary. In EAU mice treated with PL5000, MTII, or PG901, there was no suppression of EAU with a significant loss in whole retina and outer-nuclear layer thickness. There was significant suppression of IL-17 with induction of IL-10 by retinal-antigen stimulated spleen T cells from EAU mice treated with α-MSH, PL8331, PL8177, or PL5000, but not from EAU mice treated with MT-II, or PG901. Our previous studies show the melanocortin system's importance in maintaining ocular immune privilege and that α-MSH-treatment accelerates recovery and induces retinal-antigen-specific regulatory immunity in EAU. Our current results show that this activity is centered around MC1r and MC5r. In addition, the results suggest that a therapeutic potential to target MC1r and MC5r together to suppress uveitis induces regulatory immunity with potentially maintaining a normal retinal structure.
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DOI：
10.1152/ajpregu.1999.276.5.r1289
发表时间：
1999-05-01
影响因子：
2.8
作者：
Taherzadeh, S;Sharma, S;Lipton, JM
通讯作者：
Lipton, JM
影响因子：
5.6
作者：
Spana, Carl;Taylor, Andrew W.;Dodd, John
通讯作者：
Dodd, John
影响因子：
5.5
作者：
Li, Dayu;Taylor, Andrew W.
通讯作者：
Taylor, Andrew W.
影响因子：
3.3
作者：
Clemson CM;Yost J;Taylor AW
通讯作者：
Taylor AW
影响因子：
5.5
作者：
Lee, Darren J.;Taylor, Andrew W.
通讯作者：
Taylor, Andrew W.