Myeloid cells in retinal and brain degeneration

Abstract

Retinal inflammation underlies multiple prevalent ocular and neurological diseases. Similar inflammatory processes are observed in glaucomatous optic neuropathy, age-related macular degeneration, retinitis pigmentosa, posterior uveitis, Alzheimer's disease, and Parkinson's disease. In particular, human and animal studies have demonstrated the important role microglia/macrophages play in initiating and maintaining a pro-inflammatory environment in degenerative processes impacting vision. On the other hand, microglia have also been shown to have a protective role in multiple central nervous system diseases. Identifying the mechanisms underlying cell dysfunction and death is the first step toward developing novel therapeutics for these diseases impacting the central nervous system. In addition to reviewing recent key studies defining important mediators of retinal inflammation, with an emphasis on translational studies that bridge this research from bench to bedside, we also highlight a promising therapeutic class of medications, the glucagon-like peptide-1 receptor agonists. Finally, we propose areas where additional research is necessary to identify mechanisms that can be modulated to shift the balance from a neurotoxic to a neuroprotective retinal environment.

Keywords: Alzheimer’s disease; Parkinson’s disease; age-related macular degeneration; glaucoma; inflammation; macrophages; microglia; monocytes; retina; retinitis pigmentosa.

Figure 1.

Anatomy of the Eye

Figure 2.. Resting and Activated Myeloid Cells in the Retina and Optic Nerve

In the resting state, microglia have a dendritic morphology and localize to the ganglion cell layer (GCL), inner plexiform layer (IPL), and outer plexiform layer (OPL), and macrophages are largely absent in the retina. Following activation, microglia take on an enlarged, amoeboid shape and migrate to the subretinal space above the RPE. Within the retina, activated microglia release pro-inflammatory cytokines, including interleukin-1α (IL-1α), tumor necrosis factor α (TNF-α), complement component 1q (C1q), reactive oxygen species (ROS), and nitric oxide (NO), and are associated with the death of both retinal ganglion cells and photoreceptors. Recruited macrophages have been shown to infiltrate the retina via the optic nerve.

Figure 3.. Glucagon-Like Peptide-1 Receptor (GLP-1R) Agonists Decrease Retinal Inflammation

Elevated intraocular pressure (IOP) increases production of the pro-inflammatory cytokines interleukin-1α (IL-1α), tumor necrosis factor α (TNF-α), and complement component 1q (C1q) by activated microglia and recruited macrophages. These cytokines activate neurotoxic astrocytes, and results in retinal ganglion cell (RGC) death. Our lab has shown that the GLP-1R agonist NLY01 inhibits activation of microglia, macrophages, and astrocytes, and prevents RGC death in eyes with microbead-induced IOP elevation. However, the mechanism behind NLY01-induced RGC rescue, including the cell types mediating its protective effects as well as the relative contribution of macrophages versus microglia, has not been examined.