Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy

Abstract

Age-related ocular diseases are the leading cause of blindness in developed countries and constitute a sizable socioeconomic burden worldwide. Age-related macular degeneration (AMD) and Fuchs endothelial corneal dystrophy (FECD) are some of the most common age-related diseases of the retina and cornea, respectively. AMD is characterized by a breakdown of the retinal pigment epithelial monolayer, which maintains retinal homeostasis, leading to retinal degeneration, while FECD is characterized by degeneration of the corneal endothelial monolayer, which maintains corneal hydration status, leading to corneal edema. Both AMD and FECD pathogenesis are characterized by disorganized local extracellular matrix (ECM) and toxic protein deposits, with both processes linked to aberrant protease activity. Granzyme B (GrB) is a serine protease traditionally known for immune-mediated initiation of apoptosis; however, it is now recognized that GrB is expressed by a variety of immune and non-immune cells and aberrant extracellular localization of GrB substantially contributes to various age-related pathologies through dysregulated cleavage of ECM, tight junction, and adherens junction proteins. Despite growing recognition of GrB involvement in multiple age-related pathologies, its role in AMD and FECD remains poorly understood. This review summarizes the pathophysiology of, and similarities between AMD and FECD, outlines the current knowledge of the role of GrB in AMD and FECD, as well as hypothesizes putative contributions of GrB to AMD and FECD pathogenesis and highlights the therapeutic potential of pharmacologically inhibiting GrB as an adjunctive treatment for AMD and FECD.

Granzyme B degrades extracellular matrix and promotes inflammation and choroidal neovascularization

“…The major risk factor for AMD is aging, and our data here as well as our earlier studies support an age-related accumulation of extracellular GzmB in the outer retina and choroid of older nonhuman primates and older human eyes; these findings confirm that the immunoreactivity for GzmB increases with age, thereby an important potential age-related factor in the pathogenesis of AMD [15,23]. The localization of GzmB in RPE cells near drusen sites, a hallmark of AMD, further supports this concept [42].…”

“…Consistent with our earlier work, it has been shown that in skin aging and non-ocular pathologies (including cardiovascular disease, congestive obstructive pulmonary disease, and rheumatoid arthritis), GzmB is associated with promoting pathophysiology through ECM-degradation, epithelial barrier disruption, promotion of inflammation and/or angiogenesis (for review, see Dubchak et al [23]). Our initial work suggested that GzmB may contribute to AMD, particularly through an ECM remodelling mechanism, as many of GzmB's substrates are present in the ECM of BrM and choroid [15].…”

“…GzmB is present in RPE and choroidal mast cells in mouse, human and, as revealed in this study, non-human primate [15,23]. Using a mouse choroidal sprouting assay, exogenous application of GzmB promoted choroidal angiogenesis and inflammation, through ECM remodelling, pro-inflammatory and pro-angiogenesis pathways.…”

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

“…Pharmacologically inhibiting extracellular GzmB could be an effective approach to address the pathologic ECM remodeling and the subsequent angiogenic activity observed in the outer retina in nAMD ( 172 ). We have shown that both pharmacological inhibition of GzmB and genetic deletion of GzmB can be effective against CNV ex vivo and in vivo , respectively.…”