Fractalkine-CX3CR1 signaling is critical for progesterone-mediated neuroprotection in the retina.
Fractalkine-CX3CR1 signaling is critical for progesterone-mediated neuroprotection in the retina.
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DOI：
10.1038/srep43067
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发表时间：
2017-02-20
影响因子：
4.6
通讯作者：
Cotter TG
中科院分区：
文献类型：
--
作者：
Roche SL;Wyse-Jackson AC;Ruiz-Lopez AM;Byrne AM;Cotter TG
视网膜色素变性（RP）包括一组导致感光细胞丧失和失明的视网膜疾病。我们先前已经在RP的rd 10小鼠模型中显示，rd 10小胶质细胞驱动存活神经元的变性。炔诺孕酮，一种孕酮类似物，可以使存活的神经元免受潜在的小胶质细胞损伤。在目前的研究中，我们希望进一步研究这种神经保护作用。我们对fractalkine-CX 3CR 1信号传导的作用特别感兴趣，该信号传导此前已被证明介导感光器-小胶质细胞串扰并促进rd 10视网膜的存活。炔诺孕酮上调rd 10视网膜中的fractalkine-CX 3CR 1信号传导，与感光细胞存活一致。我们发现，诺孕酮处理的光感受器样细胞，661 Ws，和C57外植体调制rd 10小胶质细胞的活动在共培养，导致增加感光细胞的生存。当在661 W细胞中敲低fractalkine并且在rd 10外植体中减少fractalkine的释放时，对炔诺孕酮的神经保护作用的评估证实了fractalkine-CX 3CR 1信号传导在炔诺孕酮介导的神经保护中的关键作用。为了进一步了解fractalkine在神经保护中的作用，我们评估了fractalkine处理的rd 10小胶质细胞和外植体中40种细胞因子的释放。在这两种情况下，用fractalkine治疗减少了多种促炎细胞因子。这些发现进一步加深了我们对Norgestrel的神经保护特性的理解，能够通过光感受器间接调节有害的小胶质细胞活性，从而增加神经保护。
Retinitis pigmentosa (RP) encompasses a group of retinal diseases resulting in photoreceptor loss and blindness. We have previously shown in the rd10 mouse model of RP, that rd10 microglia drive degeneration of viable neurons. Norgestrel, a progesterone analogue, primes viable neurons against potential microglial damage. In the current study we wished to investigate this neuroprotective effect further. We were particularly interested in the role of fractalkine-CX3CR1 signaling, previously shown to mediate photoreceptor-microglia crosstalk and promote survival in the rd10 retina. Norgestrel upregulates fractalkine-CX3CR1 signaling in the rd10 retina, coinciding with photoreceptor survival. We show that Norgestrel-treated photoreceptor-like cells, 661Ws, and C57 explants modulate rd10 microglial activity in co-culture, resulting in increased photoreceptor survival. Assessment of Norgestrel’s neuroprotective effects when fractalkine was knocked-down in 661 W cells and release of fractalkine was reduced in rd10 explants confirms a crucial role for fractalkine-CX3CR1 signaling in Norgestrel-mediated neuroprotection. To further understand the role of fractalkine in neuroprotection, we assessed the release of 40 cytokines in fractalkine-treated rd10 microglia and explants. In both cases, treatment with fractalkine reduced a variety of pro-inflammatory cytokines. These findings further our understanding of Norgestrel’s neuroprotective properties, capable of modulating harmful microglial activity indirectly through photoreceptors, leading to increased neuroprotection.