Figure 3.

Geographic atrophy: (1) Progressive accumulation of oxidative byproducts (CEP, MDA) and (2) chronic overactivated complement pathway chronically activate microglia (3), which secrete neuraminidase and desialylate photoreceptors and RPE cells. (4) This loss of sialylation prevents restoration of homeostasis. (5) Chronically overactivated phagocytosis and inflammation recruits peripheral blood macrophages by upregulation of the fucosyltransferase FUT5 that produces Lewis X glycosylation on monocytes to bind E-selectin and (6) localize monocytes to sites of inflammation (7), allowing for diapedesis of the monocyte across the blood–retinal barrier. (8) These monocytes polarize to M1 macrophages when they enter the retina and are not able to clear substances like lipofuscin and other undegradable substances. (9) The macrophages form multinucleated giant cells because they phagocytose structures that are undegradable. (10) Since there is no sialic acid or polysialic acid to polarize to the healing M2c state, the macrophages are unchecked and result in elimination (11) first of the RPE cells then the (12) photoreceptors. The unchecked macrophages are the main determinant of growth of geographic atrophy.