Role of Microglia in the Retina in Retinal Diseases

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Microglia, the resident immune cell of the retina, have been implicated in the progress of photoreceptor degeneration in human disease and in mouse models. Preclinical studies modulating microglial activation (e.g. with minocycline) have been shown to ameliorate degeneration. However, the cellular mechanisms underlying microglia and photoreceptor degeneration are not fully understood. Eyes from the rd10 mouse strain were harvested during early- (postnatal (P) 18), mid- (P25), and late- (P60) phases of rod degeneration, fixed, embedded in agarose, and sectioned into 100 micrometer-thick vibratome sections. Sections were stained with DAPI and primary antibodies to Iba1, rhodopsin, and cone opsin, and apoptotic cells were marked using a TUNEL assay. The inferior mid-peripheral retinal region was imaged using confocal microscopy following cell staining. In the rd10 mouse at P18, the outer nuclear layer (ONL) was of normal thickness and contained only a few isolated TUNEL+ cells. Iba1+ microglia were found only in the inner retina and demonstrated ramified morphologies. At P25, numerous microglia migrated into the ONL, which at this point demonstrated significant thinning with multiple nuclei showing TUNEL positivity. Microglia located in the ONL possessed large, deramified, amoeboid morphologies, and were observed to phagocytose multiple rhodopsin-positive rod photoreceptors. Interestingly, the majority of these phagocytosed rods were negative for TUNEL staining; conversely most TUNEL+ nuclei in the ONL were not phagocytosed by microglia. Microglial phagocytosis also spared cone-opsin labeled cone photoreceptors. At P60, the ONL was reduced to a single layer of cone photoreceptors and contained microglia that had reverted back to a ramified, non-amoeboid morphology, without evidence of significant ongoing cone phagocytosis. Amoeboid microglia migrating into the ONL during retinal degeneration appear capable of specifically phaogocytosing rods during the period of rod degeneration. Microglial phagocytosis may constitute an apoptosis-independent mechanism that contributes to overall photoreceptor cell death. Inhibition of microglial phagocytosis may delay overall rod degeneration and prolong the survival of photoreceptors in retinal degenerations.