Macrophage origin, heterogeneity, and function during experimental choroidal neovascularization in mice

Wet age-related macular degeneration (AMD) is a common cause of vision loss from new blood vessel growth. Current treatment includes frequent eye injections that inhibit a single blood vessel growth factor. Despite this advance, 1/3 of patients still lose vision. Macrophages are immune cells that can perform many functions, and are found in new blood vessel growths from patients with wet AMD. Macrophage function is determined by their location and origin. Macrophages originate from local tissue, or two types of blood precursor cells: classical or non-classical monocytes. Classical monocyte blockade reduces experimental wet AMD, while inhibition of non-classical monocytes exacerbates experimental wet AMD. Our premise is there are macrophage subtypes, and classically-derived macrophages promote wet AMD, while non-classical macrophages block wet AMD. Our preliminary data identifies a macrophage subset that expresses blood vessel growth factors, is derived from classical monocytes, and present in patients with wet AMD. In Aim 1, we will show that this specific macrophage subtype is both necessary and sufficient for experimental wet AMD. In Aim 2, we will identify non-classical monocyte-derived macrophage subsets and demonstrate that they are sufficient to inhibit experimental wet AMD. These experiments will set the stage for new cell-based therapies that have the advantage of inhibiting multiple pathways of blood vessel growth, leading to improved vision for wet AMD patients.