Prenatally-Derived Macrophages Regulate Choroidal Health And Are Depleted In Age-Related Macular Degeneration

Authors

• Seth Daniel Fortmann, University of Alabama at Birmingham

Advisor(s)

Maria Grant

Committee Member(s)

Amit Gaggar
Erik Roberson
Lawrence Sincich
Robert Welner

School

School of Optometry

Document Type

Dissertation

Department (new version)

Vision Science

Date of Award

9-9-2024

Abstract

The ocular choroid is the pigmented vascular bed that lies immediately deep to the retinal pigmented epithelium (RPE). The principal function of the choroid is to supply the photoreceptors with oxygen and nutrients and to remove waste products from the outer retina. In age-related macular degeneration (AMD), the choroid is dysfunctional as evidenced by hallmark histopathological findings including accumulation of extracellular lipid and vasodegeneration of the choriocapillaris. How and why the choroid fails in AMD remains incompletely understood. To this end, much attention has been paid to the RPE and endothelium but less is known about the contributions of other supporting cell types in the pathogenesis of AMD. This dissertation used both human donor eyes and various mouse models to investigate the role of choroidal macrophages in health and AMD. We characterized the immune system of the human choroid and identified a dense and dynamic network of lymphocytes, myeloid cells, and mast cells. Two distinct populations of choroidal macrophages, which could be differentiated on the basis of FOLR2 expression, accounted for the majority of myeloid cells. We showed that FOLR2+ choroidal macrophages predominate in the nondiseased eye and are specifically depleted in AMD. FOLR2+ choroidal macrophages express lipid-handling machinery, uptake lipoprotein particles, and contain high amounts of various lipid species. In mice, the FOLR2+ subset becomes the minority macrophage population by early adulthood and is negative for the postnatal reporter MS4A3, suggesting self-maintenance and prenatal origin. Specific depletion of FOLR2+ choroidal macrophages using a topical diphtheria model caused severe vasodegeneration of the choriocapillaris, choroidal fibrosis, and loss of vision. In the laser-induced choroidal neovascularization model, specific depletion of FOLR2+ choroidal macrophages worsened neovascularization and increased neutrophil recruitment. Our results show that FOLR2+ choroidal macrophages play an essential, homeostatic role in multiple hallmark functions known to be compromised in AMD and suggest that replenishing this population may yield clinical benefit.

ProQuest ID

https://proquest.com/docview/3101974289