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Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death.

Gregory MS, Hackett CG, Abernathy EF, Lee KS, Saff RR, Hohlbaum AM, Moody KS, Hobson MW, Jones A, Kolovou P, Karray S, Giani A, John SW, Chen DF, Marshak-Rothstein A, Ksander BR - PLoS ONE (2011)

Bottom Line: 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.By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, The Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.

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.

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The loss of retinal ganglion cell nerve fibers is accelerated in ΔCS mice.WT, ΔCS, or ΔCS×lpr mice were either untreated, or received intravitreal TNFα. Seven days later the nerve fibers in retinal whole mounts were stained with SMi32 (anti-neurofilament antibody) and examined by confocal microscopy. (A) untreated WT retina, (B) untreated ΔCS retina, (C) WT+TNFα treated retina, (D and E) ΔCS+TNFα treated retina, (F) ΔCS×lpr+TNFα treated retina. Asterisks mark the optic nerve head, Red = SMi32, and blue = nuclear stain. The pictures presented are representative of individual mice (N = 10 for each group).
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pone-0017659-g003: The loss of retinal ganglion cell nerve fibers is accelerated in ΔCS mice.WT, ΔCS, or ΔCS×lpr mice were either untreated, or received intravitreal TNFα. Seven days later the nerve fibers in retinal whole mounts were stained with SMi32 (anti-neurofilament antibody) and examined by confocal microscopy. (A) untreated WT retina, (B) untreated ΔCS retina, (C) WT+TNFα treated retina, (D and E) ΔCS+TNFα treated retina, (F) ΔCS×lpr+TNFα treated retina. Asterisks mark the optic nerve head, Red = SMi32, and blue = nuclear stain. The pictures presented are representative of individual mice (N = 10 for each group).

Mentions: Glaucoma is characterized not only by the loss of RGCs, but also by the loss of the their axons. The axonal loss is often visualized clinically as slit-like or wedge-shape defects in the retinal nerve fiber layer. To evaluate the effect of FasL triggered RGC death on axonal integrity, we examined the nerve fiber layer of WT and ΔCS mice in retinal whole mounts (see diagram in Figure 1A). There was no significant difference between the nerve fiber layers of WT and ΔCS mice that were either uninjected (Figure 3 A, B), or administered an intravitreal injection of saline (data not shown). Moreover, WT mice treated with TNFα displayed a normal nerve fiber layer one week after treatment that was not significantly different from the untreated controls (Figure 3C). By contrast, at 1 week after treatment, the TNFα-treated ΔCS mice displayed a significant loss of nerve fibers (Figure 3D), with some mice displaying very few intact axons (Figure 3E). Axonal loss in the TNFα treated ΔCS mice was abrogated in B6/129ΔCS/ΔCS lpr/lpr mice that lacked a functional Fas receptor (Figure 3F). These data demonstrate that ΔCS mice exhibit accelerated loss of both the soma and axon in response to TNFα.


Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death.

Gregory MS, Hackett CG, Abernathy EF, Lee KS, Saff RR, Hohlbaum AM, Moody KS, Hobson MW, Jones A, Kolovou P, Karray S, Giani A, John SW, Chen DF, Marshak-Rothstein A, Ksander BR - PLoS ONE (2011)

The loss of retinal ganglion cell nerve fibers is accelerated in ΔCS mice.WT, ΔCS, or ΔCS×lpr mice were either untreated, or received intravitreal TNFα. Seven days later the nerve fibers in retinal whole mounts were stained with SMi32 (anti-neurofilament antibody) and examined by confocal microscopy. (A) untreated WT retina, (B) untreated ΔCS retina, (C) WT+TNFα treated retina, (D and E) ΔCS+TNFα treated retina, (F) ΔCS×lpr+TNFα treated retina. Asterisks mark the optic nerve head, Red = SMi32, and blue = nuclear stain. The pictures presented are representative of individual mice (N = 10 for each group).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3066205&req=5

pone-0017659-g003: The loss of retinal ganglion cell nerve fibers is accelerated in ΔCS mice.WT, ΔCS, or ΔCS×lpr mice were either untreated, or received intravitreal TNFα. Seven days later the nerve fibers in retinal whole mounts were stained with SMi32 (anti-neurofilament antibody) and examined by confocal microscopy. (A) untreated WT retina, (B) untreated ΔCS retina, (C) WT+TNFα treated retina, (D and E) ΔCS+TNFα treated retina, (F) ΔCS×lpr+TNFα treated retina. Asterisks mark the optic nerve head, Red = SMi32, and blue = nuclear stain. The pictures presented are representative of individual mice (N = 10 for each group).
Mentions: Glaucoma is characterized not only by the loss of RGCs, but also by the loss of the their axons. The axonal loss is often visualized clinically as slit-like or wedge-shape defects in the retinal nerve fiber layer. To evaluate the effect of FasL triggered RGC death on axonal integrity, we examined the nerve fiber layer of WT and ΔCS mice in retinal whole mounts (see diagram in Figure 1A). There was no significant difference between the nerve fiber layers of WT and ΔCS mice that were either uninjected (Figure 3 A, B), or administered an intravitreal injection of saline (data not shown). Moreover, WT mice treated with TNFα displayed a normal nerve fiber layer one week after treatment that was not significantly different from the untreated controls (Figure 3C). By contrast, at 1 week after treatment, the TNFα-treated ΔCS mice displayed a significant loss of nerve fibers (Figure 3D), with some mice displaying very few intact axons (Figure 3E). Axonal loss in the TNFα treated ΔCS mice was abrogated in B6/129ΔCS/ΔCS lpr/lpr mice that lacked a functional Fas receptor (Figure 3F). These data demonstrate that ΔCS mice exhibit accelerated loss of both the soma and axon in response to TNFα.

Bottom Line: 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.By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, The Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.

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.

Show MeSH
Related in: MedlinePlus