Coordinated Intervention of Microglial and Müller Cells in Light-Induced Retinal Degeneration

Abstract

To analyze the role of microglial and Müller cells in the formation of rings of photoreceptor degeneration caused by phototoxicity. METHODS. Two-month-old Sprague-Dawley rats were exposed to light and processed 1, 2, or 3 months later. Retinas were dissected as whole-mounts, immunodetected for microglial cells, Müller cells, and Sand L/M-cones and analyzed using fluorescence, thunder imaging, and confocal microscopy. Cone populations were automatically counted and isodensity maps constructed to document cone topography. RESULTS. Phototoxicity causes a significant progressive loss of Sand L/M-cones of up to 68% and 44%, respectively, at 3 months after light exposure (ALE). One month ALE, we observed rings of cone degeneration in the photosensitive area of the superior retina. Two and 3 months ALE, these rings had extended to the central and inferior retina. Within the rings of cone degeneration, there were degenerating cones, often activated microglial cells, and numerous radially oriented processes of Müller cells that showed increased expression of intermediate filaments. Between 1 and 3 months ALE, the rings coalesced, and at the same time the microglial cells resumed a mosaic-like distribution, and there was a decrease of Müller cell gliosis at the areas devoid of cones. CONCLUSIONS. Light-induced photoreceptor degeneration proceeds with rings of cone degeneration, as observed in inherited retinal degenerations in which cone death is secondary to rod degeneration. The spatiotemporal relationship of cone death microglial cell activation and Müller cell gliosis within the rings of cone degeneration suggests that, although both glial cells are involved in the formation of the rings, they may have coordinated actions and, while microglial cells may be more involved in photoreceptor phagocytosis, Müller cells may be more involved in cone and microglial cell migration, retinal remodeling and glial seal formation.

Bone Marrow-Derived Mononuclear Cell Transplants Decrease Retinal Gliosis in Two Animal Models of Inherited Photoreceptor Degeneration

“…This antigliotic effect was similar in both strains and with both injection techniques. Retinal gliosis is an early sign of photoreceptor degeneration [ 24 , 80 ] that may accompany intravitreal injections of substances [ 61 ] or of bone marrow mesenchymal stem cell [ 81 ] and includes microglial cell activation and migration to the outer retinal layers and hypertrophy and overexpression of GFAP in Müller cells and may have negative effects in retinal remodeling. Retinal degeneration proceeds with formation of a glial seal that can prevent the integration of the transplanted cells [ 27 , 80 ].…”

“…Retinal gliosis is an early sign of photoreceptor degeneration [ 24 , 80 ] that may accompany intravitreal injections of substances [ 61 ] or of bone marrow mesenchymal stem cell [ 81 ] and includes microglial cell activation and migration to the outer retinal layers and hypertrophy and overexpression of GFAP in Müller cells and may have negative effects in retinal remodeling. Retinal degeneration proceeds with formation of a glial seal that can prevent the integration of the transplanted cells [ 27 , 80 ]. Furthermore, retinal gliosis may affect the structure of the entire retina causing neuronal death and impeding the success of treatments designed to replace or substitute photoreceptors [ 23 , 27 , 81 ] and therefore is important to prevent it.…”

Pigment Epithelium-Derived Factor (PEDF) Fragments Prevent Mouse Cone Photoreceptor Cell Loss Induced by Focal Phototoxicity In Vivo

“…The environmental risk factors in developing the disease are not yet fully established, but, in addition to smoking, obesity or hypertension, excessive exposure to sunlight is considered a determining factor in its development, precocity and severity, particularly at early stages [ 3 ]. Therefore, taking into account this risk factor, many animal models of light-induced retinal degeneration have been developed, and serve to study the evolution of the degeneration and to test possible protective strategies [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Several of these studies have documented the effect of excessive exposure to short-wave visible light (blue light) on the retina [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Sectoral activation of glia in an inducible mouse model of autosomal dominant retinitis pigmentosa

“…Though we established correlation between Müller glia and microglia, we did not investigate the mechanisms of interaction between these cell types. However, crosstalk between Müller glia and microglia has been reported to help determine photoreceptor survival in other models 16,[37][38][39] . Müller glia are capable of providing crucial neuroprotective support to photoreceptors, for example, by secreting LIF 40 , but can also contribute to the inflammatory response via secretion of cytokines 41,42 .…”