TREM2 in age-related macular degeneration: a microglia-centered perspective in the retinal myeloid landscape

Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in older adults. Advanced AMD comprises an atrophic ("dry") form characterized by retinal pigment epithelium (RPE) and photoreceptor degeneration and a neovascular ("wet") form driven by choroidal neovascularization (CNV). Beyond genetic predisposition and environmental stressors, chronic dysregulation of innate immunity is increasingly recognized as a convergent mechanism linking drusen/Bruch's membrane alterations to outer retinal cell death and pathological angiogenesis. Retinal myeloid cells-including resident microglia and, in specific disease contexts, recruited monocyte-derived macrophages-can support homeostasis by clearing lipids and cellular debris, yet may also exacerbate inflammation, matrix remodeling, and neovascularization. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia and other myeloid cells that regulates phagocytosis, lipid handling, migration, survival, immunometabolism, and inflammatory tone. Recent retinal studies suggest that TREM2-associated programs can restrain lesion expansion in outer retinal degeneration models and modulate CNV severity in experimental neovascularization; however, interpretation remains limited by disease stage, anatomical niche, and the difficulty of cleanly separating microglia from infiltrating macrophages in vivo. Here, we synthesize current evidence on retinal myeloid contributions to dry and neovascular AMD, provide an updated mechanistic framework for TREM2 signaling, and discuss therapeutic strategies and translational challenges for targeting TREM2 in AMD.