IL18 does not reduce choroidal neovascularization and causes retinal dysfunction in mice

Abstract

AbstractPurpose It was reported that intravitreous administration anti‐mouse IL18 antibody increases the size of laser‐induced choroidal neovascularization (CNV) lesions in mice (Doyle et al. Nat Med 2012). IL‐18 administration was therefore proposed as a potential therapeutic for CNV, although this hypothesis was never directly tested. Here, we determined the effect of IL‐18 injection on laser CNV in mice, and also show for the first time that IL‐18 is toxic to retinal function.Methods Laser photocoagulations were performed to perforate Bruch’s membrane followed by intravitreous injections of recombinant IL‐18 (rIL‐18) or PBS, and the eyes were collected and analyzed on the day 7 after laser treatment. Laser‐induced CNV lesions stained with isolectin B4 were imaged by a confocal microscope system (Leica). Mice receiving rIL‐18 or PBS were subjected to electroretinography 7 days after sub‐retinal injection. RPE flat mounts of rIL‐18 or PBS treated wild type, Fas‐/‐, and FasL‐/‐ mice were stained for intercellular junctions.Results Average CNV volume was not different in eyes treated with recombinant IL‐18 compared to vehicle treated. Wild‐type mice receiving rIL‐18 had RPE degeneration, but the degeneration did not occur in Fas or FasL knockout mice. We also injected plasmids coding pro‐IL‐18 and mature IL‐18, and found mature IL‐18 didn't change CNV volume but caused degeneration. Wild type mice receiving rIL‐18 injections showed lower amplitude in electroretinography compared to vehicle injected eyes.Conclusion IL‐18 injections did not reduce CNV. Also, IL‐18 administration induced RPE degeneration via a Fas/Fas ligand‐dependent pathway.