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A role for choroidal mast cell degranulation in geographic atrophy

Gerard Lutty

Presenter:

Gerard A. Lutty, Ph.D., Imran Bhutto, M.D., Ph.D., Shuntaro Ogura, M.D., Ph.D.

Authors:

Affiliation:

Wilmer Ophthalmological Institute

Johns Hopkins Hospital

Baltimore, MD 21287 USA

Purpose: Mast cells (MCs) are the initial responders of innate immunity and their degranulation contribute to various etiologies. While the abundance of MCs in the choroid implies their fundamental importance in the eye, little has been known about the significance of MCs and their degranulation. The cause of geographic atrophy (GA), a progressive dry form of age-related macular degeneration, is elusive and there is currently no therapy for this blinding disorder. We have previously demonstrated that MC number and number of degranulated MCs are significantly elevated in human GA (Bhutto et al, Brit. J. Ophthamol 2016). Furthermore, using immunohistochemistry, MC tryptase was present in Bruchs membrane and choroidal stroma in GA (McLeod et al, IOVS 2017). The purpose of this study was to investigate the effects of inducing choroidal mast cell degranulation on RPE cell viability and retinal and choroidal integrity.
Methods: Compound 48/80, a snake venom like compound, was incorporated in a slow release hydrogel that was injected subconjunctivally in Sprague Dawley rats. Degranulation of MCs was assessed with nonspecific esterase or toluidine blue staining of choroid. RPE integrity was evaluated in flat mount eyecups labeled for RPE65. Cross sections through optic nerve were used to determine retinal and choroid thickness.
Results: Slow releasing compound 48/80 induced choroidal MC degranulation that peaked at 14 days post injection. Continuous choroidal MC stimulation and activation in a slow release fashion caused retinal pigment epithelium (RPE) degeneration occurred at 4- 6 weeks post-implantation, followed by significant retinal and choroidal thinning at 8-10 weeks, all characteristic phenotypes of GA. Genetic manipulation of MCs (48/80 in a cKit K/O animal), pharmacological intervention targeting MC degranulation with oral ketotifen fumarate or inhibition of MC-derived tryptase with oral APC 366 prevented all of GA-like phenotypes in the rat model.
Conclusions: Our results demonstrate the fundamental role of choroidal MC involvement in GA disease etiology, and the results provide new opportunities for understating the GA pathology and identifying novel therapies for GA targeting MCs.

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