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.

眼睛的免疫特权涉及物理屏障、免疫调节和分泌蛋白，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-黑素细胞刺激激素（α-MSH）通常在前房房水和玻璃体液中循环，由虹膜和睫状上皮以及视网膜色素上皮（RPE）分泌。α-MSH 通过帮助抑制性免疫细胞的发育和激活调节性 T 细胞，在维持眼部免疫特权中发挥重要作用。α-MSH 通过结合并激活黑皮质素受体（MC1R 至 MC5R）和受体辅助蛋白 (MRAP) 发挥作用，这些受体辅助蛋白与拮抗剂（也称为黑皮质素系统）协同工作。除了控制免疫反应和炎症，人们越来越认识到广泛的生物功能是由眼组织内的黑皮质素系统协调的。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，维持角膜上皮完整性，保护角膜内皮并潜在提高角膜移植物的存活率，调节泪液分泌（对干眼病有影响），促进视网膜稳态通过维持血视网膜屏障，提供视网膜神经保护，并控制脉络膜和视网膜异常新血管生长。然而，与其在皮肤黑素生成中的既定作用相比，黑皮质素信号传导在葡萄膜黑素细胞黑素生成中的作用仍不清楚。早期应用黑皮质素激动剂下调全身炎症时使用的是基于促肾上腺皮质激素 (ACTH) 的可的松注射液 (RCI)，但与肾上腺皮质类固醇产生增加相关的不良副作用，包括高血压、水肿和体重增加，影响了临床吸收。与 ACTH 相比，针对 MC1R、MC3R、MC4R 和/或 MC5R（而非肾上腺 MC2R）的黑皮质素肽可诱导最少的皮质类固醇产生，且不良全身反应也更少。合成 MCR 特异性靶向肽的药理学进展为治疗眼部（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皮质素系统不同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作用。我们还回顾了黑皮质素受体靶向肽作为非类固醇替代品治疗非传染性葡萄膜炎和干眼病等炎症性眼病的新优势和多功能性，以及在促进眼内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。