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Heterogeneity of mononuclear phagocytes during photoreceptor degeneration


The healthy central nervous system (CNS) contains resident macrophages, known as microglia, which constantly survey their environment, support neuronal function, and activate in response to neuronal disruption and loss. In response to damage and disease, monocytes can breach blood-CNS barriers, extravasate from the vasculature, and invade the neural parenchyma. These monocytes can then transform into monocyte-derived macrophages, which have traditionally been difficult to distinguish from microglia, due to similar morphologies and expression of common markers. However, recent technical advances have made it easier to identify these cell types as well as distinct subpopulations of these cells. In this dissertation, I investigate microglial and monocytic cells in the retina, predominantly in a model of rapid, inducible photoreceptor degeneration, the Arr1-/- mouse. I find that monocytes rapidly invade the retina during degeneration, and then transform into microglia-like macrophages. These monocyte-derived macrophages are strongly pro-inflammatory during degeneration, and then later adopt a more resting microglia-like phenotype and take up residence alongside bona fide microglia after degeneration has ceased. Using single-cell mRNA sequencing during and after photoreceptor loss, I find that there are also distinct subpopulations of these mononuclear phagocytes. Microglia are particularly heterogeneous during photoreceptor loss, and there are also distinct subpopulations of monocytes and monocyte-derived macrophages. Differences between these subpopulations include differences in cell division, antigen presentation, inflammatory cytokines, and other macrophage activation genes. Finally, I find that these mononuclear phagocytes remain able to respond to further retinal injury following photoreceptor degeneration, although monocyte-derived macrophages appear to be less responsive than the resident microglia. Altogether, I find that there is a complex immune response during photoreceptor degeneration, and that the retinal immune state remains changed even well after photoreceptor loss is complete.

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