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Dale S. Gregerson, Thien N. Sam, Neal D. Heuss, Scott W. McPherson; Enhanced Survival Of Injured Retinal Ganglion Cells By Depletion Of Dendritic Cells. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3496. doi: https://doi.org/.
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We previously reported that injury of retinal ganglion cells (RGC) by an optic nerve crush (ONC) led to the close association of dendritic cells (DC) with RGC axons in the nerve fiber layer. The DC dominated this response, raising the question of whether their response to RGC injury was protective, harmful, or unrelated to the survival of RGC. The role of the DC, and the potential contributions of other immune system activities, was examined.
Unilateral ONCs were done in several strains of B6 transgenic mice to examine different activities of the immune system for effects on RGC survival post-injury. These strains included CD11c-DTR/GFP mice whose DC express the diphtheria toxin receptor (DTR) and GFP. The DC of this strain can be locally depleted with diphtheria toxin (DTx). Other strains included mice deficient in MHC Class I, MHC Class II, or Fas. Wild type mice were used as controls. All mice were compared to uninjured mice, as well as the contralateral retinas. An ONC protocol limited in severity was used in all mice to increase the baseline survival of RGC. RGC were identified by their uptake of Fluorogold injected into the superior colliculus at 4 wks post-ONC. Retinal wholemounts were made 1 wk after Fluorogold injection, using Vectashield with propidium iodide to stain nuclei. Injection of DTx, or saline, was done into the anterior chamber in 1 microL containing 5 ng DTx.
Normal, unmanipulated retinas from all mice, wt and transgenic, contained similar numbers of RGC. Ipsilateral retinas from ONC-crushed eyes of wt mice showed that the survival of RGC was 40.4%. The RGC counts in the contralateral retinas were unchanged. MHC class I-deficient mice showed a reduced survival of 25.9% of RGC post-ONC (Pvalue <0.05). The CD11c-DTR/GFP mice, when treated with saline in the ipsilateral eye after the ONC, were not different from controls (35.3%). However, when treated with DTx, the RGC survived at a higher rate (54.8% if DTx-treated versus 35.3% if saline treated; Pvalue <0.05).
Activation of innate immunity by an optic nerve crush leads to an influx of myeloid cells into the retina and optic nerve including DC, macrophages and granulocytes. Depletion of a portion of these cells, the DC in CD11c-DTR/GFP mice, gave a higher RGC survival at 4 wks post-ONC. Use of a limited ONC to increase RGC survival in control mice (approximately 40%) may have provided a larger window of opportunity to detect differences in survival due to activities of the immune system.
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