The role of microglia in diabetic retinopathy

Abstract

There is growing evidence that chronic inflammation plays a role in both the development and progression of diabetic retinopathy. There is also evidence that molecules produced as a result of hyperglycemia can activate microglia. However the exact contribution of microglia, the resident immune cells of the central nervous system, to retinal tissue damage during diabetes remains unclear. Current data suggest that dysregulated microglial responses are linked to their deleterious effects in several neurological diseases associated with chronic inflammation. As inflammatory cytokines and hyperglycemia disseminate through the diabetic retina, microglia can change to an activated state, increase in number, translocate through the retina, and themselves become the producers of inflammatory and apoptotic molecules or alternatively exert anti-inflammatory effects. In addition, microglial genetic variations may account for some of the individual differences commonly seen in patient's susceptibility to diabetic retinopathy.

Figure 1

Inflammation during diabetic retinopathy. Increased plasma levels of blood glucose, vascular endothelial growth factor (VEGF), advanced glycation end-products (AGE), reactive oxygen species (ROS), chemokine (C-C motif) ligand 2 (CCL2), interleukins 1 beta and 8 (IL-1β and IL-8), and tumor necrosis factor alpha (TNF-α) profuse through leaky capillary endothelial cell junctions by the actions of VEGF. IL-1β, AGE, ROS, and TNF-α activate microglia to produce glutamate, matrix metalloproteinases (MMPs), nitric oxide synthases (NOS), IL-1β, and TNF-α. IL-1β and TNF-α drive the production of caspase 3, which along with glutamate is neurotoxic to retinal ganglion cells. Caspases also damage capillary endothelial cells and pericytes. TNF-α leads to production of ICAM-1 and VCAM that help recruit macrophages through the capillary walls sustaining a chronic inflammatory response. COX-2 is also a product stimulated by IL-1β and TNF-α.