The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration

Abstract

Diabetic retinopathy is a common complication of diabetes mellitus, which appears in one third of all diabetic patients and is a prominent cause of vision loss. First discovered as a microvascular disease, intensive research in the field identified inflammation and neurodegeneration to be part of diabetic retinopathy. Microglia, the resident monocytes of the retina, are activated due to a complex interplay between the different cell types of the retina and diverse pathological pathways. The trigger for developing diabetic retinopathy is diabetes-induced hyperglycemia, accompanied by leukostasis and vascular leakages. Transcriptional changes in activated microglia, mediated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and extracellular signal–regulated kinase (ERK) signaling pathways, results in release of various pro-inflammatory mediators, including cytokines, chemokines, caspases and glutamate. Activated microglia additionally increased proliferation and migration. Among other consequences, these changes in microglia severely affected retinal neurons, causing increased apoptosis and subsequent thinning of the nerve fiber layer, resulting in visual loss. New potential therapeutics need to interfere with these diabetic complications even before changes in the retina are diagnosed, to prevent neuronal apoptosis and blindness in patients.

Homocysteine Induces Inflammation in Retina and Brain

“…Microglia activation and the release of inflammatory cytokines have been reported to initiate BRB breakdown in DR [56], ocular autoimmunity [57], and retinal degenerative diseases [58]. Consistent with the established role of microglia in the induction of inflammation, our data showed evidence of microglia activation in both the inner and outer retina as well as brain hippocampus, as shown by microglia morphological transformation to an amoeboid shape with larger cell bodies and shorter thicker processes, suggesting enhanced immunoreactivity, increased phagocytic activity, and the production of pro-inflammatory mediators [59]. Given the known involvement of both inflammation and Hcy in DR, AMD, and AD, it is important to understand the role of HHcy in CNS inflammation.…”

Neurodegeneration in diabetic retinopathy: does it really matter?

“…However, during the progression of diabetic retinopathy, the M1 response is maintained whereas the M2 response declines and the classical proinflammatory signalling pathways are chronically activated [53]. In fact, a shift from pro-survival to pro-neurotoxicity occurs, and transcriptional changes in activated microglia, mediated via the NFκB and extracellular signal-regulated kinase (ERK) signalling pathways, result in the release of various proinflammatory cytokines, chemokines, caspases and glutamate [54]. These molecular mediators contribute to disruption of the BRB and NVU impairment, and to neuronal death.…”

The Oxidative Stress and Mitochondrial Dysfunction during the Pathogenesis of Diabetic Retinopathy

“…Polyol pathway activation represents one of the processes observed under the hyperglycemia-induced oxidative stress conditions during DR pathogenesis, and this pathway is known as the sorbitol-aldose reductase pathway as well [ 22 , 23 ]. Here, glucose is reduced to sorbitol and subsequently oxidized to fructose, with the help of two enzymes: aldose reductase, which converts glucose into sorbitol, and sorbitol dehydrogenase, which oxidize sorbitol into fructose [ 22 ].…”