The dual functional roles of immune surveillance and tissue maintenance provided by microglia are equally important to the ocular environment. They are critical as regulators of immune health within the retina, acting as phagocytic sentinels to detect initial danger signals (DAMPs), and then rapidly activate to process both pathogens and dying cells. Equally, microglia secrete neurotrophic factors, which impact the physiology and survival of photoreceptors, contributing to the maintenance and integrity of the neuronal network and tissue function.
94 There are checkpoint regulators through ligand–receptor interactions that mediate tonic inhibitory signals maintaining the resting phenotype of resident microglia and regulate myeloid cell inflammatory and angiogenic responses. These include CD200 (expressed on neurons) and myeloid-expressing inhibitory CD200R
95 to maintain normal homeostatic control and limit immune-mediated damage and can be exploited therapeutically.
96 For example, RPE destruction in the model of laser-induced choroidal neovascular membranes (CNV) polarizes infiltrating myeloid cells toward a proangiogenic phenotype. Augmentation of the inhibitory CD200R signaling pathway or administration of Th2 cytokines could suppress macrophage activation or drive antiangiogenic function respectively.
32,97 Similarly, the CX3CR1 signaling pathway modulates cell activation and migration. With age, deficiency in the CX3CR1 receptor was considered linked to increased microglial activation, subretinal migration, and retinal degeneration,
5 supporting GWAS data that
Cx3cr1 polymorphisms are a potential risk factor for AMD. However, conflicting reports raised questions as to whether the accumulation of dysfunctional subretinal macrophages was directly attributable to retinal degeneration.
98–101 Determining genomic background differences between C57BL/6 substrains in these studies revealed the
Crb1 mutation (
rd8), now firmly recognized to impact and enhance degenerative phenotypes in ocular inflammatory models.
101,102 Thus, subsequent studies using rd8-ve transgenic strains demonstrate that deficiency of CX3CR1 (but also CCL2-CCR2) signaling pathways differentially affects the trafficking of microglia and macrophages with age in the retina but do not cause retinal degeneration per se.
103 However, Cx3CR1 signaling does play an important role in controlling retinal inflammation, as
Cx3cr1−/−mice (rd8-) are susceptible to oxidative stress-induced retinal inflammation and photoreceptor loss.
104