Fig. 3. IL-33 therapeutic potential in early AMD.

The interleukin-33 biological function has The potential to protect against early pathogenic pathways in AMD via dual function, as a signalling molecule and nuclear factor. With diverse cellular targets, IL-33 can stimulate 1) retinal pigment epithelium (RPE) in the eye directly, increasing AMPK phosphorylation and subsequent mitochondrial metabolism⁷⁸. AMPK phosphorylation can also increase autophagy. Both will combat reactive oxygen species (ROS) production and oxidative stress. 2) IL-33 influences alternative activation of macrophages by stimulation of mast cells to release IL-13 and IL-4⁶⁸, which can promote inflammation resolution. 3) IL-33 stimulation of an alternative microglia phenotype promotes deposit clearance in Alzheimer’s disease models^59,73 and could prove beneficial against drusen. 4) IL-33 stimulated mast cells to induce changes to tight-junction proteins in RPE cells 5) and directly stimulate retinal endothelial cells reducing migration⁷¹, both important in mediating wound-healing responses. 6) Nuclear IL-33 is a key metabolic regulator in RPE cells, promoting increased mitochondrial metabolism (OXPHOS; oxidative phosphorylation)⁷⁸. The dashed line indicates indirect evidence.