Microglial‐induced Müller cell gliosis is attenuated by progesterone in a mouse model of retinitis pigmentosa
Microglial‐induced Müller cell gliosis is attenuated by progesterone in a mouse model of retinitis pigmentosa
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DOI：
10.1002/glia.23243
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发表时间：
2018-02
期刊：
影响因子：
6.2
通讯作者：
S. L. Roche;Ana M. Ruiz-Lopez;Jennifer N. Moloney;A. Byrne;T. Cotter
中科院分区：
文献类型：
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作者：
S. L. Roche;Ana M. Ruiz-Lopez;Jennifer N. Moloney;A. Byrne;T. Cotter
炔诺孕酮，一种孕酮类似物，在视网膜色素变性小鼠模型中显示出神经保护作用。神经保护部分通过Norgestrels抗炎特性实现，减轻有害的小胶质细胞活性。神经胶质增生是许多视网膜神经退行性疾病的特征，包括视网膜色素变性。Müller胶质细胞是视网膜中发现的一种大胶质细胞，是神经胶质增生的主要贡献者，其特征在于胶质细胞酸性蛋白（GFAP）的上调。小胶质细胞-Müller胶质细胞串扰与神经胶质增生的发生有关。在rd 10视网膜中，在光感受器损失开始之前观察到小胶质细胞活性增加和胶质化事件。我们假设，炔诺孕酮对有害的小胶质细胞活性的抑制作用将因此影响神经胶质增生。在目前的研究中，我们探讨了小胶质细胞-Müller胶质细胞串扰在rd 10视网膜变性和Norgestrel介导的神经保护中的作用。在rd 10视网膜中的炔诺孕酮神经保护作用与小胶质细胞活性和Müller细胞胶质增生的显著降低一致。使用Müller胶质细胞系rMC-1和分离的小胶质细胞，我们表明rd 10小胶质细胞刺激rMC-1细胞中GFAP的产生。炔诺孕酮通过直接作用于小胶质细胞和Müller胶质细胞来减弱神经胶质增生。炔诺孕酮减少了小胶质细胞释放有害刺激，如干扰素-γ，否则可能会向Müller胶质细胞发出信号并刺激神经胶质增生。我们认为，炔诺孕酮也直接靶向Müller细胞神经胶质增生，通过限制pSTAT 3的可用性，pSTAT 3是GFAP的一种已知转录因子。这些发现突出了Norgestrels在患病视网膜中的神经保护作用的一个重要方面，即对抗Müller细胞神经胶质增生。
Norgestrel, a progesterone analogue, has demonstrated neuroprotective effects in a mouse model of retinitis pigmentosa. Neuroprotection is achieved in part through Norgestrels anti‐inflammatory properties, alleviating detrimental microglial activity. Gliosis is a feature of many neurodegenerative diseases of the retina, including retinitis pigmentosa. Müller glia, a type of macroglia found in the retina, are major contributors of gliosis, characterized by the upregulation of glial fibrillary acidic protein (GFAP). Microglia‐Müller glia crosstalk has been implicated in the initiation of gliosis. In the rd10 retina, increased microglial activity and gliotic events are observed prior to the onset of photoreceptor loss. We hypothesized that Norgestrels dampening effects on harmful microglial activity would consequently impact on gliosis. In the current study, we explore the role of microglia‐Müller glia crosstalk in degeneration and Norgestrel‐mediated neuroprotection in the rd10 retina. Norgestrels neuroprotective effects in the rd10 retina coincide with significant decreases in both microglial activity and Müller cell gliosis. Using a Müller glial cell line, rMC‐1, and isolated microglia, we show that rd10 microglia stimulate GFAP production in rMC‐1 cells. Norgestrel attenuates gliosis through direct actions on both microglia and Müller glia. Norgestrel reduces the release of harmful stimuli from microglia, such as interferon‐γ, which might otherwise signal to Müller glia and stimulate gliosis. We propose that Norgestrel also targets Müller cell gliosis directly, by limiting the availability of pSTAT3, a known transcription factor for GFAP. These findings highlight an important aspect to Norgestrels neuroprotective effects in the diseased retina, in combating Müller cell gliosis.