Contribution of microglia-mediated neuroinflammation to retinal degenerative diseases

Abstract

Retinal degenerative diseases are major causes of vision loss and blindness worldwide and are characterized by chronic and progressive neuronal loss. One common feature of retinal degenerative diseases and brain neurodegenerative diseases is chronic neuroinflammation. There is growing evidence that retinal microglia, as in the brain, become activated in the course of retinal degenerative diseases, having a pivotal role in the initiation and propagation of the neurodegenerative process. A better understanding of the events elicited and mediated by retinal microglia will contribute to the clarification of disease etiology and might open new avenues for potential therapeutic interventions. This review aims at giving an overview of the roles of microglia-mediated neuroinflammation in major retinal degenerative diseases like glaucoma, age-related macular degeneration, and diabetic retinopathy.

Figure 1

Schematic representation of the major retinal cell types and their organization in the retina. The outermost part of the retina is the retinal pigment epithelium (RPE), which consists of a monolayer of cuboid, pigmented cells between the photoreceptors and the choroid. The retina is divided into three laminar layers: the outer nuclear layer (ONL), the inner nuclear layer (INL), and the ganglion cell layer (GCL). The nuclei of rod and cone photoreceptors are located in the ONL. The INL comprises the nuclei of the bipolar, horizontal, and amacrine cells. Cell bodies of the retinal ganglion cells are present in the GCL, and their axons form the nerve fiber layer (NFL), just beneath the GCL. Synapses between photoreceptors and interneurons are located in the outer plexiform layer (OPL) and interneurons synapse with RGC in the inner plexiform layer (IPL). Müller cells span all retinal layers. Microglia are mainly found in IPL and GCL, whereas astrocytes are located near the NFL.

Figure 2

Schematic representation of microglial responses in glaucoma, AMD, and diabetic retinopathy. Reactive microglial cells are found in the retina of patients and animal models of glaucoma (a), AMD (b), and diabetic retinopathy (c). (a) Glaucomatous retinas present abnormally distributed activated microglial cells in the GCL, namely, surrounding the RGC axons and soma. (b) In AMD retinas, microglial cells accumulate in the ONL and subretinal space, surrounding drusen deposits. (c) Increased vascular permeability in diabetic retinopathy is accompanied by perivascular accumulation of activated microglial cells.

Figure 3

Relationships between microglial activation and neuronal cell death. In response to changes in the environment, microglia change to a more reactive phenotype, characterized by alterations in cell morphology, gene expression and proinflammatory mediators release. The sustained release of inflammatory factors perpetuates the neuroinflammatory process further activating microglia, which release proinflammatory and neurotoxic factors, contributing to neuronal dysfunction and to pathology.