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Hidetaka Matsumoto, Yusuke Murakami, Dimosthenis Mantopoulos, George Trichonas, Joan Miller, Meredith Gregory-Ksander, Bruce Ksander, Demetrios Vavvas; Membrane-bound Fas ligand has a critical role in photoreceptor cell death in an experimental model of retinal detachment. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2851.
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The Fas signaling pathway plays a key role in photoreceptor cell death after retinal detachment (RD). The membrane-bound Fas ligand (mFasL) can be cleaved from the cell surface by metalloproteinases to produce a truncated soluble product (sFasL), derived from the extracellular domain. In this study, we investigated the role of mFasL in a mouse model of RD using ΔCS mice, a line in which FasL metalloproteinase cleavage sites have been mutated and thus only mFasL and no sFasL is expressed.
RDs were created to B6129SF2/J and ΔCS mice by subretinal injection of sodium hyaluronate. TUNEL staining was used to evaluate photoreceptor cell death at 12 hours, day 1, 2, and 3 after induction of RD. Photoreceptor cell loss was evaluated at day 5 by measuring the outer nuclear layer (ONL) thickness. Levels of Fas downstream proteins, inflammatory cytokine secretion, and macrophage/microglia infiltration were evaluated at day 1 by Western blot analysis, ELISA and immunohistochemistry, respectively.
ΔCS mice showed significantly higher TUNEL-positive cell density in the ONL at 12 hours (P=0.002) and day1 (P=0.017), while both groups showed a peak of TUNEL positivity at day 1. ONL thickness was significantly decreased in the ΔCS group (P=0.009). Western blot analysis showed significantly higher levels of cleaved caspase- 8 and 3 in the ΔCS mice, however, cleaved caspase- 9 was almost the same in both groups. Furthermore, interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 were significantly higher in the ΔCS group (P<0.001 and P=0.001, respectively). In addition, the macrophages/microglia detected in that same group were significantly more (P=0.045).
These findings demonstrate that mFasL plays a critical role in the photoreceptor cell death after RD, suggesting that FasL cleavage is an important mechanism for limiting the neurotoxic effect of FasL in the retina.
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