Inflammation and retinal degenerative diseases

Abstract

Vision is an ability that depends on the precise structure and functioning of the retina. Any kind of stress or injury can disrupt the retinal architecture and leads to vision impairment, vision loss, and blindness. Immune system and immune response function maintain homeostasis in the microenvironment. Several genetic, metabolic, and environmental factors may alter retinal homeostasis, and these events may initiate various inflammatory cascades. The prolonged inflammatory state may contribute to the initiation and development of retinal disorders such as glaucoma, age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa, which pose a threat to vision. In the current review, we attempted to provide sufficient evidence on the role of inflammation in these retinal disorders. Moreover, this review paves the way to focus on therapeutic targets of the disease, which are found to be promising.

Keywords: age-related macular degeneration; diabetic retinopathy; glaucoma; retina; retinal degeneration; retinitis pigmentosa.

Figure 1

Glaucoma and BRB disruption. BRB disruption results in imbalance in ET-1 concentrations in retina and choroid with leads to increased caspase-3 levels, and retinal ganglion cell death. Increased ET-1 enhances vessel contraction and reduces ocular perfusion, resulting in ischemia. Ischemia induces oxidative stress, which further promotes Müller and retinal ganglion cell death. Ischemia also upregulate TNF-α levels, which via binding to its receptor TNFR1 or COX-2 induction promote retinal ganglion cell death. TNF-α reduces Müller cell ability to uptake glutamate, resulting in glutamate excitotoxicity. BRB: Blood-retinal-barrier; COX-2: cyclooxygenase 2; ET-1: endothelin-1; NMDA receptor: N-methyl-D-aspartate receptor; RGC: retinal ganglion cells; TNFR1: tumor necrosis factor receptor 1; TNF-α: tumor necrosis factor-alpha. Reprinted from Vohra et al. (2013) with permission.

Figure 2

Graphical presentation of retina showing interactions between endothelial cells, neurons, and glia with respect to inflammatory chemokines. The blood vessels and endothelial cells are shown in pink (9), leukocytes are shown in purple (5), muller glial cells are shown in green (7,8), microglia are shown in brown (2,3) and neurons are shown in blue (6a–c) color. The graphic also shows potassium homeostasis, glutamate metabolism and secretion of chemokines, interleukins, and trophic factors. AGEs: Advanced glycation end products; bFGF: basic fibroblast growth factor; GDNF: glial cell line-derived neurotrophic factor; ICAM-1: intercellular adhesion molecule 1; IL-1 beta: interleukin-1 beta; IL-6: interleukin 6; IL-8: interleukin 8. MCP-1: monocyte chemoattractant protein 1; NGF: nerve growth factor; NO: nitric oxide; PEDF: pigment epithelium-derived factor; TNF-alpha: tumor necrosis factor-alpha; VEGF: vascular endothelial growth factor. Reprinted from Rübsam et al. (2018).

Figure 3

Elucidation of retinal photoreceptor degeneration in human retinitis pigmentosa patients and mouse rd1 mutants. (A, B) Human and mouse ocular fundus photographs, OCT and electroretinograms are shown. (i) The ocular fundus photographs and OCT images of an adult human and C57BL/6 mouse retina is shown. (ii) The ocular fundus photographs and OCT images of an adult patient with RP and 3-month-old rd1 mouse retina is shown. The black arrow in the human fundus images and the green line in the mouse fundus images depict the location of the OCT scan across the macula. The fundus images of patient with retinitis pigmentosa, shows pigmentary changes with atrophic areas indicating degeneration of photoreceptors. The OCT images of RP patient shows marked thinning, reflecting loss of photoreceptors and degeneration. The fundus images of rd1 mouse retina shows atrophy, discoloration, and loss of blood vessels showing degenerating retina. The area in the red rectangle is magnified in the right image. (iii) Retinal functions in response to light stimulation were measured by ERG. In dark conditions (scotopic), a normal eye when exposed to dim or bright white light flash, either initiates a well-formed rod response (black wave, left panel) or a type of mixed rod/cone response (black wave, right panel). In light conditions (photopic), single light stimulation of the eye leads to a cone response (black wave, lower left panel), and rapid light stimulation results in flicker waveform (black wave, lower right panel). In RP patients and in rd1 mutant mouse, the electrophysiological responses are reduced or non-detectable (red traces). ERG: Electroretinography; OCT: optical coherence tomography; RP: retinitis pigmentosa. Reprinted from Veleri et al. (2015).