The retinal environment induces microglia-like properties in recruited myeloid cells

Abstract

Background Microglia are essential to the development of the CNS and its homeostasis. Our prior findings suggested a niche model to describe the behaviors of retinal microglia. Here, we ask whether new myeloid cells recruited to the retina are constrained to resemble endogenous microglia morphologically and functionally. Methods Use of CD11c DTR/GFP transgenic mouse allowed identification of two niches of retinal microglia distinguished by being GFP lo or GFP hi . We also used transgenic mice in which CX3CR1 + cells expressed YFP and were depletable following tamoxifen-induced expression of diphtheria toxin subunit A. We employed several ablation and injury stimulation protocols to examine the origin and fate of myeloid cells repopulating the retina. Analysis of retinal myeloid cells was done by microscopy, flow cytometry, and qRT-PCR. Results We found that the origin of new GFP hi and GFP lo myeloid cells in the retina of CD11c DTR/GFP mice, whether recruited or local, depended on the ablation and stimulation protocols. Regardless of origin, new GFP lo and GFP hi retinal myeloid cells were CD45 med CD11b + Ly6G − Ly6C lo Iba1 + F4/80 + , similar to endogenous microglia. Following tamoxifen-induced diphtheria toxin ablation, myeloid cell repopulation differed in the retina compared to the brain and optic nerve. Stimulation of replacement GFP hi cells was substantially attenuated in repopulating retinas after tamoxifen-induced diphtheria toxin ablation compared to control or radiation-ablated mice. In radiation bone marrow chimeric mice, replacement GFP hi myeloid cells from the circulation were slow to repopulate the retina unless stimulated by an optic nerve crush injury. However, once stimulated, recruited GFP hi cells were found to concentrate on injured retinal ganglion cells and were morphologically similar to GFP hi cells in non-ablated control CD11c DTR/GFP mice. Conclusions The results support the idea that GFP hi cells in the CD11c DTR/GFP mouse, whether recruited or from resident microglia, mark a unique niche of activated retinal myeloid cells. We conclude that the retinal environment has a potent influence on the function, morphology, and proliferative capacity of new myeloid cells regardless of their origin, compelling them to be equivalent to the endogenous microglia. Electronic supplementary materi...

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