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

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Abstract

Purpose

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.

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