Microglia Contribution to the Regulation of the Retinal and Choroidal Vasculature in Age-Related Macular Degeneration

Abstract

The retina is a highly metabolically active tissue with high-level consumption of nutrients and oxygen. This high metabolic demand requires a properly developed and maintained vascular system. The retina is nourished by two systems: the central retinal artery that supplies the inner retina and the choriocapillaris that supplies the outer retina and retinal pigment epithelium (RPE). Pathological neovascularization, characterized by endothelial cell proliferation and new vessel formation, is a common hallmark in several retinal degenerative diseases, including age-related macular degeneration (AMD). A limited number of studies have suggested that microglia, the resident immune cells of the retina, have an important role not only in the pathology but also in the formation and physiology of the retinal vascular system. Here, we review the current knowledge on microglial interaction with the retinal vascular system under physiological and pathological conditions. To do so, we first highlight the role of microglial cells in the formation and maintenance of the retinal vasculature system. Thereafter, we discuss the molecular signaling mechanisms through which microglial cells contribute to the alterations in retinal and choroidal vasculatures and to the neovascularization in AMD.

Keywords: age-related macular degeneration (AMD); angiogenesis; choroid; inflammation; microglia; neogenesis; retina; retinal vasculature.

Figure 1

Contribution of microglial cells to vascular development in the retina. (A) The activation of the MAS receptor is involved in the recruitment of microglia and vascular growth in the developing retina by activating the Notch signaling pathway. (A’) Microglial cells secrete CD95L that binds to its receptor CD95 on endothelial cells. The phosphorylation of the death domain by Src-family kinase results in the activation of PI3K signaling pathways, leading to the activation of AKT or ERK (A’’).

Figure 2

The role of microglial cells in choroidal neovascularization (CNV). Microglial AGE receptor (RAGE) activation by RAGE ligands (AGEs, S100B and HMGB1) leads to the release of inflammatory cytokines (IL-1β, TNFα, IL-6 and TGFβ) and production of ROS, ultimately leading to CNV (A); VEGF secreted by RPE can activate microglial VEGFR1 and VEGFR2, which may play a role in the early and late stages of CNV (B). Moreover, proangiogenic cytokines and growth factors like VEGF and PGF produced by microglia contribute to CNV (B); interaction of CX3CR1 with its ligand CX3CL1 may play a role in regulating microglia accumulation in the subretinal space, retinal degeneration and ultimately to CNV (C).