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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The </span>neuropeptide<span> alpha-melanocyte stimulating hormone (α-MSH) normally circulates in the aqueous humour of the </span></span>anterior chamber and the vitreous fluid, secreted by iris and ciliary epithelium, and </span>retinal pigment epithelium (RPE). α-MSH plays an important role in maintaining </span>ocular immune privilege by helping the development of suppressor </span>immune cells and by activating regulatory T-cells. α-MSH functions by binding to and activating </span>melanocortin receptors<span><span><span><span> (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 </span>corneal endothelium and potentially enhancing </span>corneal graft<span><span> survival, regulating aqueous tear secretion with implications for dry </span>eye disease, facilitating retinal </span></span>homeostasis </span></span><em>via</em><span><span><span> maintaining blood-retinal barriers, providing neuroprotection<span> in the retina, and controlling abnormal new vessel growth in the choroid<span> and retina. The role of melanocortin signalling in uveal melanocyte </span></span></span>melanogenesis however remains unclear compared to its established role in skin melanogenesis. The early application of a melanocortin agonist to downregulate systemic inflammation used </span>adrenocorticotropic hormone<span><span><span><span><span><span> (ACTH)-based repository cortisone<span> 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 </span></span>MC1R, </span>MC3R, </span>MC4R and/or </span>MC5R<span>, but not adrenal gland MC2R<span>, 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 </span></span></span>uveitis<span> and dry eye disease, and translational applications in promoting ocular homeostasis, for example, in corneal transplantation and diabetic retinopathy.</span></span></span></p></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":"95 ","pages":"Article 101187"},"PeriodicalIF":18.6000,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"The multifunctional human ocular melanocortin system\",\"authors\":\"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\",\"doi\":\"10.1016/j.preteyeres.2023.101187\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p><span><span><span><span><span><span><span>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 </span>neuropeptide<span> alpha-melanocyte stimulating hormone (α-MSH) normally circulates in the aqueous humour of the </span></span>anterior chamber and the vitreous fluid, secreted by iris and ciliary epithelium, and </span>retinal pigment epithelium (RPE). α-MSH plays an important role in maintaining </span>ocular immune privilege by helping the development of suppressor </span>immune cells and by activating regulatory T-cells. α-MSH functions by binding to and activating </span>melanocortin receptors<span><span><span><span> (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 </span>corneal endothelium and potentially enhancing </span>corneal graft<span><span> survival, regulating aqueous tear secretion with implications for dry </span>eye disease, facilitating retinal </span></span>homeostasis </span></span><em>via</em><span><span><span> maintaining blood-retinal barriers, providing neuroprotection<span> in the retina, and controlling abnormal new vessel growth in the choroid<span> and retina. The role of melanocortin signalling in uveal melanocyte </span></span></span>melanogenesis however remains unclear compared to its established role in skin melanogenesis. The early application of a melanocortin agonist to downregulate systemic inflammation used </span>adrenocorticotropic hormone<span><span><span><span><span><span> (ACTH)-based repository cortisone<span> 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 </span></span>MC1R, </span>MC3R, </span>MC4R and/or </span>MC5R<span>, but not adrenal gland MC2R<span>, 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 </span></span></span>uveitis<span> and dry eye disease, and translational applications in promoting ocular homeostasis, for example, in corneal transplantation and diabetic retinopathy.</span></span></span></p></div>\",\"PeriodicalId\":21159,\"journal\":{\"name\":\"Progress in Retinal and Eye Research\",\"volume\":\"95 \",\"pages\":\"Article 101187\"},\"PeriodicalIF\":18.6000,\"publicationDate\":\"2023-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Progress in Retinal and Eye Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1350946223000265\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"OPHTHALMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Progress in Retinal and Eye Research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1350946223000265","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
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.
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.