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. Photoreceptor degeneration is a cause of irreversible vision loss in incurable blinding retinal diseases including retinitis pigmentosa (RP) and atrophic age-related macular degeneration. We found in two separate mouse models of photoreceptor degeneration that tamoxifen, a selective estrogen receptor modulator and a drug previously linked with retinal toxicity, paradoxically provided potent neuroprotective effects. In a light-induced degeneration model, tamoxifen prevented onset of photoreceptor apoptosis and atrophy and maintained near-normal levels of electroretinographic responses. Rescue effects were correlated with decreased microglial activation and inflammatory cytokine production in the retina in vivo and a reduction of microglia-mediated toxicity to photoreceptors in vitro, indicating a microglia-mediated mechanism of rescue. Tamoxifen also rescued degeneration in a genetic (Pde6brd10) model of RP, significantly improving retinal structure, electrophysiological responses, and visual behavior. These prominent neuroprotective effects warrant the consideration of tamoxifen as a drug suitable for being repurposed to treat photoreceptor degenerative disease. Age-related macular degeneration (AMD), a leading contributor of vision loss, currently lacks comprehensive treatment. While AMD histopathology involves retinal pigment epithelium (RPE) injury associated with immune cell infiltration, the nature of immune cell responses to RPE injury remains undefined. We induced RPE injury pharmacologically and genetically in transgenic mouse models in which microglia and systemic monocytes were separately tagged, enabling a spatial and temporal dissection of the relative contributions of microglia vs. monocytes to post-injury changes. We found that myeloid cell responses to RPE injury occur in stages: (1) an early mobilization of endogenous microglia from the inner retina to the RPE layer, followed by (2) subsequent monocyte infiltration from the retinal vasculature into the inner retina that replenishes the local myeloid cell population in a CCR2-regulated manner. These altered distributions of myeloid cells post-injury were long-lived, with recruited monocytes acquiring the distribution, markers, and morphologies of neighboring endogenous microglia in a durable manner. These findings indicate the role played by infiltrating monocytes in maintaining myeloid cell homeostasis in the retina following AMD-relevant RPE injury and provide a foundation for understanding and therapeutically modulating immune aspects in retinal disease.

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National Eye Institute (NEI)
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Silverman, Sean M; Wong, Wai T (2018) Microglia in the Retina: Roles in Development, Maturity, and Disease. Annu Rev Vis Sci 4:45-77
Li, Yichao; Zhang, Yikui; Chen, Sonia et al. (2018) Light-Dependent OCT Structure Changes in Photoreceptor Degenerative rd 10 Mouse Retina. Invest Ophthalmol Vis Sci 59:1084-1094
Ma, Wenxin; Zhang, Yikui; Gao, Chun et al. (2017) Monocyte infiltration and proliferation reestablish myeloid cell homeostasis in the mouse retina following retinal pigment epithelial cell injury. Sci Rep 7:8433
Zhao, Lei; Li, Jun; Fu, Yingmei et al. (2017) Photoreceptor protection via blockade of BET epigenetic readers in a murine model of inherited retinal degeneration. J Neuroinflammation 14:14
Wang, Xu; Zhao, Lian; Zhang, Yikui et al. (2017) Tamoxifen Provides Structural and Functional Rescue in Murine Models of Photoreceptor Degeneration. J Neurosci 37:3294-3310
Zabel, Matthew K; Zhao, Lian; Zhang, Yikui et al. (2016) Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by CX3CL1-CX3CR1 signaling in a mouse model of retinitis pigmentosa. Glia 64:1479-91
Ma, Wenxin; Wong, Wai T (2016) Aging Changes in Retinal Microglia and their Relevance to Age-related Retinal Disease. Adv Exp Med Biol 854:73-8
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Indaram, Maanasa; Ma, Wenxin; Zhao, Lian et al. (2015) 7-Ketocholesterol increases retinal microglial migration, activation, and angiogenicity: a potential pathogenic mechanism underlying age-related macular degeneration. Sci Rep 5:9144
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