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F. Sennlaub, C. Feumi, W. Raoul, M. Houssier, F. Behar-Cohen, C. Combadiere; Drusen Observed in CX3CR1 Knockout Animals Consist of Lipid Bloated Subretinal Microglial Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):12.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in the CX3CR1 gene have recently been associated with human AMD. In Age related Macular Degneration, microglial cells acummulate subretinally. We here studied CX3CR1 expression in AMD sections and its influence on fundoscopic appearance and microglia in senescent mice and using CX3CR1 knockout and CX3CR1-KinGFP animals
AMD sections, CX3CR1 -/-, CX3CR1 +/GFP and CX3CR1 GFP/GFP mice were used in this study. Fundoscopie, immunohistochemistry on flatmounts and sections and Electron microscopy (EM) was performed on these animals. Antibodies used were CX3CR1 and CD18 in AMD and GFP, 5D4, CD11, F4/80 and Rho4D2 on mice sections and flatmounts.
CX3CR1 is expressed in all retinal microglial cells in humans and mice (GFP staining in CX3CR1 +/GFP and CX3CR1 in humans). In AMD CX3CR1 positive bloated subretinal microglial cells are abundantly present. CX3CR1-/- animals present a progressive accumulation of subretinal microglial cells (GFP, 5D4, F4/80, CD11b positive) with age. Senescent CX3CR1-/- animals show multiple ‘Drusen’ in fundoscopy. These ‘Drusen’are visible on RPE/choroidal flatmounts (after dissection of the retina). The anatomical equivalent of these ‘Drusen’ were identified as white bloated microglial cells with Rhodopsin positive intracellular inclusions. EM revealed important intracellular lipid accumulations and ROS remnants within subretinal microglial cells.
Our data demonstrates important accumulation of SrMCs in senescent CX3CR1-/- animals. The resulting prolonged presence of MCs in the subretinal space leads to OS phagocytosis by SrMCs, and subsequent intracellular lipid accumulation in the SrMCs. Surprisingly, these subretinal microglial "foam cells" were at the origin of Drusen appearance in mice. Similarly, CX3CR1-positive bloated SrMC were found in AMD, suggesting that Drusen observed in AMD might in part be constituted of subretinal microglial "foam cells".
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