Exploring the role of granzyme B in subretinal fibrosis of age-related macular degeneration

Abstract

Age-related macular degeneration (AMD), a prevalent and progressive degenerative disease of the macula, is the leading cause of blindness in elderly individuals in developed countries. The advanced stages include neovascular AMD (nAMD), characterized by choroidal neovascularization (CNV), leading to subretinal fibrosis and permanent vision loss. Despite the efficacy of anti-vascular endothelial growth factor (VEGF) therapy in stabilizing or improving vision in nAMD, the development of subretinal fibrosis following CNV remains a significant concern. In this review, we explore multifaceted aspects of subretinal fibrosis in nAMD, focusing on its clinical manifestations, risk factors, and underlying pathophysiology. We also outline the potential sources of myofibroblast precursors and inflammatory mechanisms underlying their recruitment and transdifferentiation. Special attention is given to the potential role of mast cells in CNV and subretinal fibrosis, with a focus on putative mast cell mediators, tryptase and granzyme B. We summarize our findings on the role of GzmB in CNV and speculate how GzmB may be involved in the pathological transition from CNV to subretinal fibrosis in nAMD. Finally, we discuss the advantages and drawbacks of animal models of subretinal fibrosis and pinpoint potential therapeutic targets for subretinal fibrosis.

Keywords: age-related macular degeneration (AMD); choroidal neovascularization; granzyme B; immunology; inflammation; mast cell; retinal pigment epithelium (RPE); subretinal fibrosis.

Figure 1

Progression of Subretinal Fibrosis in Age-Related Macular Degeneration (AMD). Normal Eye: Cross-sectional representation of a normal eye. Below, a magnified view depicts the composition of a normal retina, including resting Muller glia, photoreceptors, RPE cells, Bruch’s membrane, choriocapillaris, and choroidal mast cells. Growth factors (TGF- β, VEGF) sequestered in the Bruch’s membrane ECM are depicted. Choroidal Neovascularization (CNV): Pathological changes associated with CNV depicted in the eye cross-section include macular hemorrhage, subretinal fluid, increased retinal thickness, intraretinal cyst, and permeable neovessels. The magnified view of the retina focuses on classic choroidal neovascularization (Type 2 CNV), reactive Muller glia, and dysfunctional and dying RPE. GzmB promotes CNV, inflammation and fibrosis by mediating release of growth factors from the ECM, and fragmentation of anti-angiogenic proteins DCN and TSP-1. Subretinal Fibrosis: The eye cross-section illustrates scar tissue formation, intraretinal cyst, macular hemorrhage, and subretinal fluid. The corresponding details of the magnified retina reveal reactive Muller glia, fibrovascular membrane, dysfunctional and dying RPE, myofibroblasts, circulating fibrocytes, M2 macrophages, pericytes, endothelial cells, Labels with a star indicate potential sources of myofibroblast precursors. Increased secretion of growth factors (VEGF, TGF-β, CTGF, FGF), and mast cell proteases (tryptase, Granzyme B, chymase) are also depicted. GzmB promotes degradation of tight junction proteins, leading to EMT of RPE cells and EndMT of endothelial cells lining the choroidal vasculature. GzmB-mediated fragmentation of DCN and TSP-1 may also contribute to myofibroblast transdifferentiation.