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Kaitryn Ronning, Sarah J Karlen, Marie Burns; Monocyte-derived macrophages take up residence in the retina following widespread photoreceptor degeneration. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2245.
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During retinal degeneration, microglia undergo dramatic changes in gene expression and morphology to clear debris and dying cells. Additionally, monocytes from the periphery can infiltrate the retina to join the microglia in the immune response to degeneration. After cell loss is complete a population of resident macrophages re-tile the retina but it remains unclear (1) whether these cells return to a normal “resting” microglial state and (2) whether monocyte-derived macrophages that had infiltrated remain in the retina as part of this population.
We used in vivo retinal imaging, immunohistochemistry (IHC), flow cytometry, and single-cell mRNA sequencing (scRNAseq) to investigate retinal macrophages before, immediately after, and several weeks after cell loss in a light-inducible model of photoreceptor degeneration (Arr1-/- mice, 0 through 20 days of light exposure). All mice were handled according to ARVO, NIH, and UC Davis IACUC guidelines.
In vivo retinal imaging and IHC revealed that ramified macrophages re-tile the inner retina following the completion of photoreceptor loss. Many macrophages exhibited a normal “resting” microglial morphology, although the degree of complexity varied more than that of cells in the healthy retina. ScRNAseq showed that the population of CD45+CD11b+ cells remained transcriptionally heterogeneous, even as homeostasis was re-established. To clearly distinguish between microglial and monocyte-derived macrophage subpopulations, we used a fluorescent lineage tracing paradigm (Arr1-/- Ai9KI/KI Cx3cr1+/YFP-CreER). These fate mapping experiments confirmed that monocyte-derived macrophages take up long-term residence, assume a ramified microglia-like morphology, and comprise approximately half of the population of immune cells in the retina after degeneration.
After photoreceptor degeneration is complete, the remaining inner retina contains a heterogeneous population of ramified macrophages that includes both microglia and monocyte-derived macrophages. These monocyte-derived macrophages adopt a microglia-like phenotype, including gene expression similar to mildly activated microglia and a ramified morphology, persisting for several weeks after recovery and accounting for a substantial portion of the re-established, long-lived resident macrophage population in the retina.
This is a 2021 ARVO Annual Meeting abstract.
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