Role of interleukin 33 in neovascular age-related macular degeneration

Abstract

BackgroundAge-related macular degeneration is the leading cause of irreversible blindness in the developed world, and in its most acute form, secondary to angiogenesis in neovascular age-related macular degeneration. Inflammation has a key role in its pathogenesis, particularly in angiogenesis. We have shown that retinal pigment epithelium (RPE) produces interleukin 33 (IL33), which regulates cellular responses in the underlying choroidal stroma. To further our understanding we assessed the role of IL33 in ocular angiogenesis. MethodsHuman retinal microvascular endothelial cells and RPE-choroid explants were treated with various doses of IL33, and assayed by real-time PCR, western blot, and ELISA. Laser-induced choroidal neovascularisation was used as a model of neovascular age-related macular degeneration. Wild-type (WT), ST2–/–, and IL33–/– mice were administered four laser burns in each eye before receiving IL33 as an intravitreal injection at a range of doses. The development of neovascular lesions was assessed by optical coherence tomography and immunofluorescence 7 days after injection. FindingsIL33 treatment of human retinal microvascular endothelial cells impaired their ability to migrate, whereas IL33–ST2 signalling regulated vascular sprouting in RPE-choroidal explants. Compellingly, intravitreal IL33 significantly attenuated choroidal neovascularisation in WT mice, resulting in a 50% reduction in the volume of choroidal neovascular lesions (p=0·007). IL33 did not have an effect in angiogenesis in mice lacking ST2, the IL33 receptor. Furthermore, IL33–/– mice developed larger choroidal neovascular lesions, suggesting that choroidal neovascularisation was also regulated by endogenous IL33. InterpretationWe found that the alarmin proinflammatory cytokine IL33 can inhibit the formation of choroidal neovascularisation in mice and is ST2 dependent. IL33 could represent an immunotherapeutic-based strategy for the treatment of age-related macular degeneration. FundingNational Institute for Health Research, National Eye Research Centre.