Microglia In Diabetic Retina And Their Potential

Microglia reside in the internal plexiform layers of the retina, exhibiting small cell bodies and many long protrusions that span the nuclear layers (Karlstetter et al. , 2015). In DR patients, perivascular microglia are amplified in numbers and highly hypertrophic in the inner retinal layers.

The hypertrophic microglia assemble around cotton-wool spots of the retina and infiltrate into the optic nerve in their preproliferative form. During the onset of DR when the BRB is intact, metabolic disorders result in the accumulation of glycated-lipoproteins such as AGEs and oxidized low density lipoproteins (LDL), which are detected by the retinal microglia through surface PRRs (Chen et al. , 2013). A hyperglycemic microenvironment poses a threat to the retina, thereby inducing microglial cell activation through ROS mediated NF-kB activation, which in turn activates the release of inflammatory cytokines (Xu and Chen, 2017). Hyperglycaemia has been shown to induce the expression of Toll-like receptor-2 and 4 (TLR-2 & TLR-4), and NF-kB via ROS in human retinal endothelial cells (Rajamani and Jialal, 2014). In addition, hyperglycaemia-initiated electron transport chain dysfunction has been linked to electron leakage through complex I and III leading to increased ROS and superoxide levels (Roy et al. , 2017). Although hyperglycaemia is known to induce the pathology of DR, mounting evidence suggests that inflammatory changes and oxidative stress in the retina are involved with the pathogenesis of DR. Therefore, there is need to identify the inflammatory cytokines released by activated microglia in DR.

The activation of microglia in the diabetic retina is marked by their proliferation, migration and morphological change from ramified nature to amoeboid shape, as was observed in streptozotocin-induced diabetic rats (Zeng et al. , 2000). After the onset of diabetes in the rats, the number of microglia was increased at 4-6 months in the inner plexiform and by 14-16 months, activated microglia were noticed in the outer nuclear and photoreceptor layers (Zeng et al. , 2000). In the diabetic patients, microglia activation is evident at different stages of DR and characterised by increased proliferation and migration of the cells into the inner retinal layers and assembling around micro-aneurysms and intra-retinal haemorrhages (Altmann and Schmidt, 2018). Microglial cell activation was observed in the retina of both NPDR and PDR patients, in NPDR microglia migrated into the plexiform layers and proliferated whereas, in PDR, microglia were highly increased in number and assembled around ischemic regions (Zeng et al. , 2008).

Though the proliferation and migratory potential of the activated microglia have been demonstrated to some extent in diabetic models, there is great need to investigate the morphological and phagocytic potential of these cells in hyperglycaemic conditions. It is worth noting that microglial activation during the onset of DR is mild and the moderate activation of resident immune cells under chronic stress is a protective response in the maintenance of homeostasis (Chen and Xu, 2015). Prolonged diabetic insults in DR may override the protective immune response, and destructive chronic immunological reactivity may arise, leading to the damage of BRB. The dysregulated immune response has the potential to contribute to retinal pathologies such as DR in which inflammation is a major component (Chen and Xu, 2015).