Retinal Macroglial Responses in Health and Disease

Abstract

Due to their permanent and close proximity to neurons, glial cells perform essential tasks for the normal physiology of the retina. Astrocytes and Müller cells (retinal macroglia) provide physical support to neurons and supplement them with several metabolites and growth factors. Macroglia are involved in maintaining the homeostasis of extracellular ions and neurotransmitters, are essential for information processing in neural circuits, participate in retinal glucose metabolism and in removing metabolic waste products, regulate local blood flow, induce the blood-retinal barrier (BRB), play fundamental roles in local immune response, and protect neurons from oxidative damage. In response to polyetiological insults, glia cells react with a process called reactive gliosis, seeking to maintain retinal homeostasis. When malfunctioning, macroglial cells can become primary pathogenic elements. A reactive gliosis has been described in different retinal pathologies, including age-related macular degeneration (AMD), diabetes, glaucoma, retinal detachment, or retinitis pigmentosa. A better understanding of the dual, neuroprotective, or cytotoxic effect of macroglial involvement in retinal pathologies would help in treating the physiopathology of these diseases. The extensive participation of the macroglia in retinal diseases points to these cells as innovative targets for new drug therapies.

Figure 1

Retinal astrocytes. Retinal whole-mount. Immunoperoxidase ((a) and (b)). Immunofluorescence (c). Astrocytes in the normal retina of a 58-year-old man. In the ganglion cell layer of the human retina, star-shaped astrocytes form a honeycomb plexus (a). In the rat (b) and mouse (c) retina star-shaped astrocytes form a plexus distributed throughout the retina. Such plexus is denser in the rat than in the mouse retina.

Figure 2

Schematic drawing illustrating the functions of the retinal macroglia. Macroglial cells perform various essential roles for the normal physiology of the retina, maintaining a close and permanent relationship with the neurons. The scheme illustrates the links between the retinal macroglia, the neurons, and the blood-retinal barrier (from [154]).

Figure 3

Diagram summarizing the functions of activated macroglia. Under conditions of tissue stress that might represent a risk to neuronal survival, glial cells undergo reactive gliosis. The aim of acute gliosis is to protect the nervous tissue by reestablishing the extracellular medium and by supplementing neurons with factors that promote their survival (in green). An uncontrolled response (in blue), as occurs in most neurodegenerative diseases, will harm the tissue [BRB: blood-retinal barrier; ET: endothelin; GDNF: glial cell derived neurotrophic factor; GLAST: glutamate aspartate transporter; MHC: major histocompatibility complex; NO: nitric oxide; RGC: retinal ganglion cell; VEGF: vascular endothelium growth factor].

Figure 4

Retinal macroglia in the mouse retina. Retinal whole-mount. Double immunostaining for GFAP (red) and MHC-II (green) after 15 days of laser-induced ocular hypertension. (A)–(C): naïve eyes; (D)–(F): contralateral eyes; (G)–(I): OHT eyes. In contralateral eyes, MHC-II immunoreaction of astrocytes (arrow) and Müller cells (arrowhead) in (E) was increased with respect to naïve eyes (arrow) in (B). In OHT eyes, MHC-II immunoreaction of Müller cells (arrowhead) in (H) was notably upregulated in comparison with contralateral (E). In OHT eyes the Müller cells were GFAP⁺ throughout the retina and appeared as punctate structures between the astrocytes and their radiating processes (G). Fluorescence microscopy and image acquisition using the ApoTome. GFAP: glial fibrillary acidic protein; MHC: major histocompatibility complex; OHT: ocular hypertension (from Figure 10 of [19] with permission).

Figure 5

Müller cell gliosis. Schematic drawing illustrating Müller cell proliferative gliosis (a). Transmission electron microscopy of a retina from an 81-year-old patient with age-related macular degeneration (b). Immunoperoxidase anti-GFAP. Retinal whole-mount from a 90-year-old patient with age-related macular degeneration (c). (a) Müller cells reenter into the cell cycle and migrate to the subretinal space and the vitreous humor where they contribute to forming the subretinal membranes and the epiretinal membranes, respectively. (b) Epiretinal astroglial membrane formed by astrocyte and Müller cells located in the vitreous humor. The Müller cells adhere to the vitreous face of the inner limiting membrane. The inset shows the astrocyte microvilli. (c) Glial membrane at the vitreoretinal interphase showing strongly GFAP⁺ Müller cells (arrow). A: astrocyte; BM: basement membrane; M: Müller cells; v: vitreous (schematic drawing modified from [18]; (b) and (c) from Figures 8F and 12A of [47] with permission).