Abstract
Immunosenescence is considered a possible factor in the development of age-related macular degeneration and choroidal neovascularization (CNV). However, age-related changes of myeloid cells (MCs), such as microglia and macrophages, in the healthy retina or during CNV formation are ill-defined. In this study, Cx3cr1-positive MCs were isolated by fluorescence-activated cell sorting from six-week (young) and two-year-old (old) Cx3cr1GFP/+ mice, both during physiological aging and laser-induced CNV development. High-throughput RNA-sequencing was performed to define the age-dependent transcriptional differences in MCs during physiological aging and CNV development, complemented by immunohistochemical characterization and the quantification of MCs, as well as CNV size measurements. These analyses revealed that myeloid cells change their transcriptional profile during both aging and CNV development. In the steady state, senescent MCs demonstrated an upregulation of factors contributing to cell proliferation and chemotaxis, such as Cxcl13 and Cxcl14, as well as the downregulation of microglial signature genes. During CNV formation, aged myeloid cells revealed a significant upregulation of angiogenic factors such as Arg1 and Lrg1 concomitant with significantly enlarged CNV and an increased accumulation of MCs in aged mice in comparison to young mice. Future studies need to clarify whether this observation is an epiphenomenon or a causal relationship to determine the role of immunosenescence in CNV formation.
Highlights
Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly and can progress in its advanced stages to an atrophic or a neovascular form [1,2,3,4,5]
Gene Ontology enrichment analysis demonstrated that DEGs in senescent retinal myeloid cells contribute to processes associated with cell proliferation, such as cell cycle phase transition (GO:0044770; p. adj. = 0.01) and mononuclear cell proliferation (GO:0032944; p. adj. = 0.04), suggesting the enhanced proliferation of aged myeloid cells (Figure 2B)
We found a significant enrichment of DEGs in senescent myeloid cells that contributes to migration-associated processes, such as chemotaxis (GO:0006935; p. adj. = 0.004) and retinal homeostasis (GO:0001895; p. adj. = 0.04; Figure 2B)
Summary
Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly and can progress in its advanced stages to an atrophic or a neovascular form (nAMD) [1,2,3,4,5]. Though atrophic AMD proceeds slowly, nAMD is often associated with a sudden and rapid loss of central vision. This is caused by the formation of choroidal neovascularization (CNV) growing from the choroid into the subretinal space, which leads to edema, inflammation, fibrosis, and irreversible loss of vision (for a detailed review, see [6]). One-third of patients with nAMD continue to lose vision 4.0/). Despite repeated treatments [7,8], highlighting the continuous need to further explore the underlying causes and treatment options of this still-enigmatic disease.
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