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B. R. Ksander, C. G. Hackett, E. F. Abernathy, A. Marshak-Rothstein, K. Lee, D. F. Chen, M. S. Gregory; The Form of Fas Ligand Determines Whether Retinal Ganglion Cells Survive or Die During Glaucoma. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5925.
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© ARVO (1962-2015); The Authors (2016-present)
All forms of glaucoma result in a loss of retinal ganglion cells (RGCs). While data indicates RGC apoptosis occurs during glaucoma, the exact molecular mechanisms of cell death are unclear. Fas Ligand (FasL) is produced primarily by microglia and astrocytes in the retina and triggers apoptosis of Fas+ cells. However, FasL can exist in two forms that have opposite functions: membrane (mFasL) is pro-apoptotic and can be cleaved to produce soluble (sFasL) that is anti-apoptotic. We hypothesize the extent of RGC loss during glaucoma is determined, in part, by whether the microenvironment activates microglia and/or astrocytes to express either mFasL (triggers death of Fas+ RGC), or sFasL (protects RGC from apoptosis).
mFasL-only knock-in mice (ΔCS.1) were constructed by mutating the cleavage site in the FasL gene. ΔCS.1 mice only express mFasL and no sFasL. RGC loss was triggered by an intravitreal injection of TNF- (1ng), a known mediator of RGC death in glaucoma. Eyes were enucleated and whole mounts or sections were prepared from retina and optic nerve. RGC were stained with anti-β-tubulin and counted. Immunohistochemical analysis: Fas and FasL, microglia (Iba), astrocytes (anti-GFAP), nerve fibers (SMI32 ab), and myelin (anti-MBP). Mice used: wild-type, ΔCS.1, FasL KO, and ΔCS.1 x lpr.
Groups of WT, ΔCS.1, FasL KO, and ΔCS.1 x lpr mice received intravitreal TNF-, or saline treatment. WT, but not FasL KO mice displayed a significant loss of RGCs beginning at 4 wks, indicating FasL is required for RGC death. By contrast, ΔCS.1 mice displayed an early rapid loss of RGCs (30%) at 1 wk. The accelerated loss of RGCs did not occur in TNF- treated ΔCS.1 x lpr mice that lacked Fas. TNF- treated ΔCS.1 mice at 1 wk displayed within the retina activated microglia and a loss of nerve fibers; within the optic nerve there were: activated astrocytes, demyelination of axons, and a loss of nerve fibers.
Mice that expressed mFasL in the absence of sFasL are highly susceptible to glaucoma. These data imply that the ratio of membrane to soluble FasL on microglia and/or astrocytes determines whether RGCs survive. This may, in part, explain the seemingly contradictory data that immunity can be either neuroprotective, or neurotoxic during glaucoma.
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