Abstract
Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-induced cell death of Fas-positive photoreceptors following a retinal detachment. However, as FasL exists in membrane-bound (mFasL) and soluble (sFasL) forms, and is expressed on resident microglia and infiltrating monocyte/macrophages, the current study examined the relative contribution of mFasL and sFasL to photoreceptor cell death after induction of experimental retinal detachment in wild-type, knockout (FasL−/−), and mFasL-only knock-in (ΔCS) mice. Retinal detachment in FasL−/− mice resulted in a significant reduction of photoreceptor cell death. In contrast, ΔCS mice displayed significantly more apoptotic photoreceptor cell death. Photoreceptor loss in ΔCS mice was inhibited by a subretinal injection of recombinant sFasL. Thus, Fas/FasL-triggered cell death accounts for a significant amount of photoreceptor cell loss following the retinal detachment. The function of FasL was dependent upon the form of FasL expressed: mFasL triggered photoreceptor cell death, whereas sFasL protected the retina, indicating that enzyme-mediated cleavage of FasL determines, in part, the extent of vision loss following the retinal detachment. Moreover, it also indicates that treatment with sFasL could significantly reduce photoreceptor cell loss in patients with retinal detachment.
Highlights
Fas ligand (FasL) exists as a trimer in the cell membrane, whereas the Fas receptor (FasR or Fas) is expressed as a monomer
We previously demonstrated that the number of TUNEL-positive cells peaked on day 1.23 we analyzed TUNEL-positive cell density in outer nuclear layer (ONL) at 0.5, 1, 3, 5, and 7 days after retinal detachment
BALB/c FasL − / − mice displayed significantly higher ONL/ inner nuclear layer (INL) ratios as compared with BALB/c WT mice 7 days after retinal detachment (WT: 1.30 ± 0.06 and FasL − / − : 1.51 ± 0.04; *Po0.05; Figure 1c), suggesting that photoreceptor cell death was prevented in FasL-deficient mice
Summary
Fas ligand (FasL) exists as a trimer in the cell membrane, whereas the Fas receptor (FasR or Fas) is expressed as a monomer. The function of Fas/FasL in photoreceptor death was examined by our group in a rat model of retinal detachment,[5] as well as other groups who observed a significant decrease in photoreceptor apoptosis in FasLgld and Faslpr mutant mice.[6,20] these data demonstrate clearly that this pathway contributes to photoreceptor cell loss in detached retinas, these studies did not examine the contribution of the different forms of FasL (mFasL and sFasL) These previous studies used FasLgld and Faslpr mutant mice, which have specific point mutations in FasL and Fas (gld and lpr mutations, respectively) that reduce but do not block completely Fas/FasL signaling;[21] the overall contribution of FasL in photoreceptor cell death is not completely known
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