Purchase this article with an account.
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. doi: https://doi.org/.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
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.
This PDF is available to Subscribers Only