Fig. 4.

Cartoon of inflammatory processes involved in AMD pathobiology. In the subretinal space, oxidized lipids and excess HDLs can elicit an inflammatory response that includes microglial and systemic monocyte recruitment. a Initially, immune responses are heightened, representing parainflammation to maintain cell health. This includes activation of RPE, microglia, and potentially choroidal macrophages, with heightened intracellular cytokine responses (IL-18, IL-33), upregulation of autophagy, and immunometabolic regulation to maintain mitochondrial health. b Conversion from parainflammation to chronic inflammation can induce inflammasome activation by microglia, monocytes and the RPE (including IL-1b production) that contributes to subretinal drusenoid deposit formation. In the RPE, complement and the inflammasome can be activated by a number of triggers. In Bruch’s membrane, the accumulation of lipoproteins and cellular debris elicits an inflammatory response from the RPE, mast cells, and monocytes/macrophages derived from the choroid or systemic circulation to activate both complement and the inflammasome. Inflammatory debris accumulates around lipoproteins/HAP particles during drusen formation in Bruch’s membrane. CEP carboxyethyllysine, CFH complement factor H, HSPG heparan sulfate proteoglycan, Ly lysosome, MDA malondialdehyde, Mit mitochondria, mono/macro monocyte/macrophage, PR photoreceptor, ROS reactive oxygen species, SDD subretinal drusenoid deposit, TLR Toll-like receptor