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Andrew W Taylor, Ambika Manhapra, David Cluckey, Tat Fong Ng; Recovery of ocular immune privilege after uveitis requires melanocortin 5 receptor expression. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1349.
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© ARVO (1962-2015); The Authors (2016-present)
The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) plays an important role in retinal immune privilege. In melanocortin 5 receptor (MC5r) knocked out mice α-MSH-therapy suppresses experimental autoimmune uveitis (EAU), but does not provide protection from retinal damage, nor is there development of regulatory immunity. This has suggested that without MC5r α-MSH cannot promote recovery of immune privilege within the eye. Therefore, we studied the role of MC5r expression on RPE suppression of macrophage activity.
Wild type and MC5r(-/-) C57BL/6 mice were immunized to induce EAU, and the retinas scored for inflammation. When the EAU score = 3 the mice were injected twice i.p. with 50µg α-MSH. Untreated EAU mice were used controls. When the uveitis score = 0 for the α-MSH-treated wild type mice the eyes were collected from all the mouse groups. The anterior segment and retina were removed from the eyes, and the RPE eyecups were cultured in serum free medium for 24 hours. The conditioned media (CM) was used to treat resting peritoneal macrophages. The treated macrophages were fed opsonized-pHrodo-bioparticles and assayed by fluorescent microscopy for phagolysosome activation. In addition, the macrophages were treated with α-MSH and assayed for phagolysosome activation.
While both wild type and MC5r(-/-) mice had the same accelerated rate of recovery from EAU only the RPE from EAU-recovered wild type mice significantly suppressed (66 ± 10 %) phagocytic activity in the macrophages. Moreover, the use of a MC5r agonist instead of α-MSH to treat the EAU mice suppressed EAU also did not promote recovery of RPE suppression (1 ± 8%) of phagolysosome activation. When MC5r(-/-) macrophages were used instead of wild type macrophages the CM of RPE from EAU recovered eyes did not suppress phagolysosome activation. Moreover, α-MSH did not suppress phagocytic activity in the MC5r(-/-) knockout macrophages.
The results demonstrate that the suppression of uveitis is through α-MSH stimulating other melanocortin receptors, such as MC1r and MC3r, and through MC5r reestablish RPE regulation of innate immune cell activity. This implies that the melanocortin system in the retina regulates immune cell activity, promotes RPE mediated immune privilege, retinal cell survival; and that MC5r needs to be expressed by both immune cells and RPE.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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