Abstract
Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNFα triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma.
Highlights
Glaucoma is one of the most common causes of blindness worldwide and, while there are many different forms of glaucoma that differ significantly in clinical presentation and disease progression, they all share a common endpoint which is the loss of retinal ganglion cells (RGCs) [1]
There was no significant difference in the number of RGCs between either untreated WT, WT mice given an intravitreal injection of saline, or untreated Fas Ligand (FasL) KO mice
Fas ligand is a potent pro-apoptotic molecule expressed by cytotoxic effector T and NK cells that is known for its ability to eliminate virally infected target populations, tumor cells, and autoreactive T and B cells [11]
Summary
Glaucoma is one of the most common causes of blindness worldwide and, while there are many different forms of glaucoma that differ significantly in clinical presentation and disease progression, they all share a common endpoint which is the loss of retinal ganglion cells (RGCs) [1]. Data from clinical studies and animal models of induced elevated intraocular pressure (IOP) support the hypothesis that there is an inflammatory component to glaucoma and that TNFa contributes to disease progression. Elevated levels of TNFa have been detected in the aqueous humor and retinal layers of glaucoma patients with primary open angle, normal tension, and exfoliation glaucoma [3][4]. Development of glaucoma coincided with increased levels of TNFa and TNFa-inducible genes in laser induced rodent models of elevated IOP [7][8]. In this model, TNFa did not appear to directly induce cytolysis of RGCs, it could be shown to activate microglia [7]. The direct effector mechanism responsible for microglia mediated RGC neurotoxicity is not TNFa
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