Role of Microglia in the Retina in Retinal Diseases

小胶质细胞，视网膜的常驻免疫细胞，已经在人类疾病和小鼠模型中涉及光感受器变性的进展。 调节小胶质细胞活化（例如用米诺环素）的临床前研究已显示改善变性。 然而，小胶质细胞和感光细胞变性的细胞机制尚未完全了解。 光感受器变性是不可治愈的致盲性视网膜疾病（包括视网膜色素变性（RP）和萎缩性年龄相关性黄斑变性）中不可逆视力丧失的原因。我们在两个不同的小鼠感光细胞变性模型中发现，他莫昔芬，一种选择性雌激素受体调节剂和一种以前与视网膜毒性有关的药物，矛盾地提供了有效的神经保护作用。在光诱导的变性模型中，他莫昔芬防止了感光细胞凋亡和萎缩的发生，并维持了接近正常水平的视网膜电图反应。救援效果与体内视网膜中小胶质细胞活化和炎性细胞因子产生减少以及体外小胶质细胞介导的对光感受器的毒性减少相关，表明小胶质细胞介导的救援机制。他莫昔芬还挽救了RP遗传（Pde6brd10）模型中的变性，显著改善视网膜结构、电生理反应和视觉行为。这些突出的神经保护作用保证了他莫昔芬作为一种适合用于治疗光感受器退行性疾病的药物的考虑。 视网膜相关性黄斑变性（AMD）是视力丧失的主要原因，目前缺乏综合治疗。虽然AMD组织病理学涉及与免疫细胞浸润相关的视网膜色素上皮（RPE）损伤，但免疫细胞对RPE损伤的应答的性质仍不明确。我们在转基因小鼠模型中诱导RPE损伤，其中小胶质细胞和全身单核细胞分别标记，从而能够在空间和时间上解剖小胶质细胞与单核细胞对损伤后变化的相对贡献。我们发现，髓系细胞对RPE损伤的反应分阶段发生：（1）内源性小胶质细胞从内层视网膜到RPE层的早期动员，随后（2）随后单核细胞从视网膜血管系统浸润到内层视网膜中，其以CCR2调节的方式使局部髓系细胞群增殖。损伤后髓样细胞的这些改变的分布是长期存在的，招募的单核细胞以持久的方式获得邻近内源性小胶质细胞的分布、标记和形态。这些发现表明浸润单核细胞在AMD相关RPE损伤后维持视网膜中骨髓细胞稳态中所起的作用，并为理解和治疗性调节视网膜疾病中的免疫方面提供了基础。

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.