Abstract
Using mice expressing green fluorescent protein (GFP) from a transgenic CD11c promoter we found that a controlled optic nerve crush (ONC) injury attracted GFPhi retinal myeloid cells to the dying retinal ganglion cells and their axons. However, the origin of these retinal myeloid cells was uncertain. In this study we use transgenic mice in conjunction with ONC, partial and full optic nerve transection (ONT), and parabiosis to determine the origin of injury induced retinal myeloid cells. Analysis of parabiotic mice and fate mapping showed that responding retinal myeloid cells were not derived from circulating macrophages and that GFPhi myeloid cells could be derived from GFPlo microglia. Comparison of optic nerve to retina following an ONC showed a much greater concentration of GFPhi cells and GFPlo microglia in the optic nerve. Optic nerve injury also induced Ki67+ cells in the optic nerve but not in the retina. Comparison of the retinal myeloid cell response after full versus partial ONT revealed fewer GFPhi cells and GFPlo microglia in the retina following a full ONT despite it being a more severe injury, suggesting that full transection of the optic nerve can block the migration of responding myeloid cells to the retina. Our results suggest that the optic nerve can be a reservoir for activated microglia and other retinal myeloid cells in the retina following optic nerve injury.
Highlights
Microglia are the major population of immune cells in quiescent retina and are important for maintenance of retinal homeostasis [53]
While acknowledging the observations that retinal microglial proliferation post-ablation may account for a major part of the retinal repopulation response [23, 24, 71], we found evidence that optic nerve was a source of retinal myeloid cells following optic nerve injury in an already fully-populated retina
Microglia and the GFPhi cells were readily distinguished by flow cytometry of retinas gated on CD45medCD11b+Ly6G− cells from CX3CR1YFP-creER:CD11cGFP double transgenic mice (Fig. 1c)
Summary
Microglia are the major population of immune cells in quiescent retina and are important for maintenance of retinal homeostasis [53]. Since dendritic cells are the classic “professional” APC and express CD11c, we tested the CD11cGFP reporter mice [27] in our search for retinal. GFP reporter expression in retina revealed a population of microglia-like cells (CD45medCD11bhiIba1+F4/ 80+Ly6CloCX3CR1hi) that expressed GFP (GFPhi cells) from the transgenic CD11c promoter [33, 62]. We found by in vitro and in vivo studies that GFP expression in these retinal cells correlated with APC function [17, 18, 46]. Our studies of the APC function of these GFPhi retinal myeloid cells in CD11cGFP reporter mice showed that an optic nerve crush (ONC) injury to the axons of retinal ganglion cells (RGC) generated large numbers of retinal GFPhi myeloid cells [33]
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