The Multifunctional Melanocortin System in the Human Choroid

The choroid is a vascular pigmented tissue in the eye located between the outer collagenous sclera and inner neural retina. The choroid stroma includes extracellular matrix, blood vessels, immune cells, nerves, fibroblasts, and melanocytes. As one of the most abundant cells within the choroid, melanocytes contribute significantly to the normal intraocular environment, including light absorption, antioxidant activity, free-radical scavenging, and the modulation of local inflammation and potentially angiogenesis. The biology and functions of choroid melanocytes have primarily been understood from studies of skin melanocytes, although there are biological and microenvironment differences between these types of melanocytes. In contrast to choroid melanocytes, skin melanocytes produce melanin in response to UV exposure, mediated by melanocortin ligand-receptor (α-MSH/MC1R) signalling. The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) activates melanocortin receptors (MC1R to MC5R) and receptor accessory proteins (MRAPs), forming the melanocortin system. α-MSH can also reduce UV-induced oxidative stress in skin melanocytes and potentially downregulate inflammation, facilitate DNA repair, stabilise damaged DNA and prevent cell death. The impact of UV radiation on human choroid melanocytes (HCMs) is likely minimal as <1% reaches the posterior eye. Visible light, particularly short-wavelength blue light, does reach the posterior eye and is absorbed by the choroid, and this thesis explored the effects of blue light on HCMs. In the eye, the melanocortin system is known to regulate immune responses and inflammation in regions of immune privilege - the anterior chamber and retina. α-MSH (melanocortin ligand) circulates in the aqueous humour and vitreous fluid and is secreted by the retinal pigment epithelium (RPE) and potentially by iris and ciliary body pigment epithelium. MC1R expression (gene and protein) has been established in HCMs, however the expression of other MCRs, MRAPs, and potential secretion of α-MSH within the human choroid (including HCMs), remains to be confirmed. Previous studies established immunomodulatory roles for HCMs, including Toll-like receptor expression, secretion of proinflammatory chemokines, and monocyte attraction during inflammatory stimulation. The evidence for the melanocortin system being able to downregulate melanocyte proinflammatory activity or to regulate melanogenesis is however limited. This thesis established the expression and functions of the melanocortin system (MCRs, MRAPs) in human choroid tissue and cells (HCMs and choroidal stromal cells (CSCs)) and RPE. Constitutive in vitro secretion of α-MSH by HCMs, CSCs, and RPE was confirmed, and activation of the canonical melanocortin signalling pathway (α-MSH/MCR/cAMP) was demonstrated. Melanocortin agonists provided homeostatic protection for HCMs with pro-metabolic, and anti-inflammatory effects observed, and increased melanin synthesis. Blue light exposure of HCMs decreased metabolism without inducing cell cytotoxicity or cell death, for the energy levels and exposure times tested. Notably, prolonged blue light exposure enhanced the in vitro pro-melanogenic effects of melanocortin agonists in HCMs, associated with increased expression of MITF (a key regulator of melanogenesis), MC1R, and melanin synthesis. The nonvisual opsin, Opsin3 (OPN3), expressed in skin melanocytes, was also detected in human choroid tissue and choroidal cells (HCMs and CSCs). The role(s) of OPN3 in normal human choroid including potential interactions with MC1R, OPN3-mediated melanogenesis, and control of choroidal blood flow, will be pursued in future studies. Overall, the thesis established that there is a functional melanocortin system in human choroid and HCMs, and that this can contribute to maintaining choroidal homeostasis, including anti-inflammatory effects. The potential application of melanocortin ligands as therapeutics for choroidal inflammation, including non-infectious uveitis, is currently being pursued. Further investigations of the interactions between HCMs, blood vessels, nerves and stromal cells will increase our understanding of how the normal human choroid functions and responds to pathology.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2024

Author dc:creator

• Wu, Chieh-Lin ; https://orcid.org/0000-0002-7090-7172

• Melanocyte
• Melanocortin peptides
• Melanogenesis
• α-melanocyte stimulating hormone (α-MSH)
• Inflammation
• Choroid
• Melanocortin receptors (MCRs)
• Adrenocorticotropic hormone (ACTH)
• Cytoprotection
• Uveitis
• Proopiomelanocortin (POMC)
• anzsrc-for: 3212 Ophthalmology and optometry

Statement dc:rights

• open access
• CC BY 4.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.26190/unsworks/25497

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/101793