多功能人眼黑素皮质素系统

IF 18.6 1区 医学 Q1 OPHTHALMOLOGY Progress in Retinal and Eye Research Pub Date : 2023-07-01 DOI:10.1016/j.preteyeres.2023.101187
Chieh-Lin (Stanley) Wu , Adrian V. Cioanca , Maria C. Gelmi , Li Wen , Nick Di Girolamo , Ling Zhu , Riccardo Natoli , R Max Conway , Constantinos Petsoglou , Martine J. Jager , Peter J. McCluskey , Michele C. Madigan
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引用次数: 1

摘要

眼睛的免疫特权包括物理屏障、免疫调节和分泌的蛋白质,它们共同限制了眼内免疫反应和炎症的破坏性影响。神经肽α-促黑素细胞激素(α-MSH)通常在前房房水和玻璃体液中循环,由虹膜、睫状体上皮和视网膜色素上皮(RPE)分泌。α-MSH通过促进抑制性免疫细胞的发育和激活调节性t细胞,在维持眼免疫特权中发挥重要作用。α-MSH通过结合和激活黑素皮质素受体(MC1R至MC5R)和受体辅助蛋白(MRAPs)发挥作用,受体辅助蛋白与拮抗剂协同作用,也称为黑素皮质素系统。除了控制免疫反应和炎症外,越来越多的生物学功能被认为是由眼部组织内的黑素皮质素系统协调的。这包括通过限制角膜(淋巴)血管生成来维持角膜透明度和免疫特权,维持角膜上皮的完整性,保护角膜内皮并可能提高角膜移植物的存活率,调节与干眼病相关的泪液分泌,通过维持血液-视网膜屏障促进视网膜稳态,在视网膜中提供神经保护,控制脉络膜和视网膜中异常的新血管生长。然而,黑素皮质素信号传导在葡萄膜黑素细胞黑素形成中的作用与其在皮肤黑素形成中的作用相比仍不清楚。黑素皮质激素激动剂的早期应用是使用促肾上腺皮质激素(ACTH)为基础的库可的松注射(RCI)来下调全身炎症,但与肾上腺皮质类固醇生成增加相关的高血压、水肿和体重增加等不良副作用影响了临床应用。与ACTH相比,靶向MC1R、MC3R、MC4R和/或MC5R(而非肾上腺MC2R)的黑素皮质素肽诱导的皮质类固醇生成量最少,且全身不良反应较少。合成mcr特异性靶向肽的药理进展为治疗眼部(和全身)炎症性疾病提供了进一步的机会。根据这些观察结果以及对黑素皮质素系统的多种生物学作用的新的临床和药理学兴趣,本综述强调了该系统在人眼组织中的生理和疾病相关参与。我们还回顾了黑素皮质素受体靶向肽作为炎性眼病(如非感染性葡萄膜炎和干眼病)的非甾体替代品的新益处和多功能性,以及在促进眼部稳态方面的转化应用,例如在角膜移植和糖尿病视网膜病变中的应用。
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The multifunctional human ocular melanocortin system

Immune privilege in the eye involves physical barriers, immune regulation and secreted proteins that together limit the damaging effects of intraocular immune responses and inflammation. The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) normally circulates in the aqueous humour of the anterior chamber and the vitreous fluid, secreted by iris and ciliary epithelium, and retinal pigment epithelium (RPE). α-MSH plays an important role in maintaining ocular immune privilege by helping the development of suppressor immune cells and by activating regulatory T-cells. α-MSH functions by binding to and activating melanocortin receptors (MC1R to MC5R) and receptor accessory proteins (MRAPs) that work in concert with antagonists, otherwise known as the melanocortin system. As well as controlling immune responses and inflammation, a broad range of biological functions is increasingly recognised to be orchestrated by the melanocortin system within ocular tissues. This includes maintaining corneal transparency and immune privilege by limiting corneal (lymph)angiogenesis, sustaining corneal epithelial integrity, protecting corneal endothelium and potentially enhancing corneal graft survival, regulating aqueous tear secretion with implications for dry eye disease, facilitating retinal homeostasis via maintaining blood-retinal barriers, providing neuroprotection in the retina, and controlling abnormal new vessel growth in the choroid and retina. The role of melanocortin signalling in uveal melanocyte melanogenesis however remains unclear compared to its established role in skin melanogenesis. The early application of a melanocortin agonist to downregulate systemic inflammation used adrenocorticotropic hormone (ACTH)-based repository cortisone injection (RCI), but adverse side effects including hypertension, edema, and weight gain, related to increased adrenal gland corticosteroid production, impacted clinical uptake. Compared to ACTH, melanocortin peptides that target MC1R, MC3R, MC4R and/or MC5R, but not adrenal gland MC2R, induce minimal corticosteroid production with fewer adverse systemic effects. Pharmacological advances in synthesising MCR-specific targeted peptides provide further opportunities for treating ocular (and systemic) inflammatory diseases. Following from these observations and a renewed clinical and pharmacological interest in the diverse biological roles of the melanocortin system, this review highlights the physiological and disease-related involvement of this system within human eye tissues. We also review the emerging benefits and versatility of melanocortin receptor targeted peptides as non-steroidal alternatives for inflammatory eye diseases such as non-infectious uveitis and dry eye disease, and translational applications in promoting ocular homeostasis, for example, in corneal transplantation and diabetic retinopathy.

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来源期刊
CiteScore
34.10
自引率
5.10%
发文量
78
期刊介绍: Progress in Retinal and Eye Research is a Reviews-only journal. By invitation, leading experts write on basic and clinical aspects of the eye in a style appealing to molecular biologists, neuroscientists and physiologists, as well as to vision researchers and ophthalmologists. The journal covers all aspects of eye research, including topics pertaining to the retina and pigment epithelial layer, cornea, tears, lacrimal glands, aqueous humour, iris, ciliary body, trabeculum, lens, vitreous humour and diseases such as dry-eye, inflammation, keratoconus, corneal dystrophy, glaucoma and cataract.
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