Inflammation in diabetic retinopathy: possible roles in pathogenesis and potential implications for therapy

Abstract

Diabetic retinopathy, characterized as a microangiopathy and neurodegenerative disease, is the leading cause of visual impairment in diabetic patients. Many clinical features observed in diabetic retinopathy, such as capillary occlusion, acellular capillaries and retinal non-perfusion, aggregate retinal ischemia and represent relatively late events in diabetic retinopathy. In fact, retinal microvascular injury is an early event in diabetic retinopathy involving multiple biochemical alterations, and is manifested by changes to the retinal neurovascular unit and its cellular components. Currently, intravitreal anti-vascular endothelial growth factor therapy is the first-line treatment for diabetic macular edema, and benefits the patient by decreasing the edema and improving visual acuity. However, a significant proportion of patients respond poorly to anti-vascular endothelial growth factor treatments, indicating that factors other than vascular endothelial growth factor are involved in the pathogenesis of diabetic macular edema. Accumulating evidence confirms that low-grade inflammation plays a critical role in the pathogenesis and development of diabetic retinopathy as multiple inflammatory factors, such as interleukin-1β, monocyte chemotactic protein-1 and tumor necrosis factor -α, are increased in the vitreous and retina of diabetic retinopathy patients. These inflammatory factors, together with growth factors such as vascular endothelial growth factor, contribute to blood-retinal barrier breakdown, vascular damage and neuroinflammation, as well as pathological angiogenesis in diabetic retinopathy, complicated by diabetic macular edema and proliferative diabetic retinopathy. In addition, retinal cell types including microglia, Müller glia, astrocytes, retinal pigment epithelial cells, and others are activated, to secrete inflammatory mediators, aggravating cell apoptosis and subsequent vascular leakage. New therapies, targeting these inflammatory molecules or related signaling pathways, have the potential to inhibit retinal inflammation and prevent diabetic retinopathy progression. Here, we review the relevant literature to date, summarize the inflammatory mechanisms underlying the pathogenesis of diabetic retinopathy, and propose inflammation-based treatments for diabetic retinopathy and diabetic macular edema.

Keywords: Müller cells; anti-inflammation therapy; anti-vascular endothelial growth factor; diabetic retinopathy; hyperreflectivity foci; inflammation; inflammatory cells; inflammatory cytokines; leukostasis; microglia.

Figure 1

mRNA transcriptomes analysis in diabetic patient retinas. (A) Volcano plot of differentially expressed genes (DEGs) in the diabetic patient compared with those of healthy controls from the Gene Expression Omnibus (GEO) dataset. Red and blue indicate up-regulated and down-regulated genes, respectively. (B) The heatmap shows the top 50 genes from DEGs of diabetic retinas. The red and blue represents up- and down-regulated genes respectively. (C) Differentially expressed genes of diabetic retinas were enriched by gene ontology (GO) analysis including biological process, molecular function, and cellular component. (D) Kyoto encyclopedia of genes and genomes (KEGG) pathways enrichment for up-regulated genes. (E) Functional annotation of significantly expressed gene using Metascape. Orange denotes the enrichment terms color coded by p-values and an interactive network of the enrichment terms color coded by cluster ID. The retina gene profiles (GSE160306) were downloaded from Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) and modified from our unpublished data.

Figure 2

Representative images showing the relationship between blood vessels (IB4, green) and microglia (IBA-1, red) in deep capillary plexus of the retinal flatmounts in normal control (N) and 8-week diabetic (D8w) rat retinas. In normal controls, the microglia show ramified morphology and are distributed evenly in retina; while they became activated in diabetic group, showing characteristic amoeboid morphology and close proximity to retinal capillaries. N: Normal control group; D8w: 8-week diabetes group. Scale bars: 50 μm. Modified from our unpublished data.

Figure 3

Representative optical coherence tomography angiography (OCTA) images showing the subtypes of diabetes macular edema (DME) with hyperreflective foci (HRF). (A) Diffuse macular edema, (B) cystoid macular edema, (C) DME with subretinal fluid (DME-SRF), and (D) mixed type. The HRF are indicated by arrowheads. Modified from our unpublished data.