Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma.
Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma.
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DOI：
10.3389/fnins.2016.00526
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发表时间：
2016
影响因子：
4.3
通讯作者：
Vetter ML
中科院分区：
文献类型：
--
作者：
Breen KT;Anderson SR;Steele MR;Calkins DJ;Bosco A;Vetter ML
青光眼的神经变性导致视网膜神经节细胞(RGC)的衰退和丢失，并与小胶质细胞和巨噬细胞等髓系细胞的激活有关。趋化因子Fractalkine(FKN或Cx3cl1)介导神经元到髓系细胞的通讯。通过其受体CX3CR1传递的信号与多种神经退行性疾病有关，但对神经元病理的影响是不同的。由于尚不清楚FKN介导的串扰如何影响青光眼患者的RGC变性，我们在慢性小鼠模型DBA/2J中进行了评估。我们分析了CX3CR1缺陷的DBA/2J亚株，并与标准DBA/2J小鼠的RGC变性和髓系细胞反应进行了比较。我们发现，FKN信号的丢失加剧了轴突运输功能障碍，这是神经变性的早期事件，随着轴突蛋白磷酸化神经丝的胞体聚集，RGC显著增加，参与轴突运输的基因Kif1b和ATP8A2的视网膜表达减少。Brn3阳性视网膜节细胞的丢失没有变化，近端视神经的损伤程度也没有变化，这表明Fractalkine信号的丢失主要影响轴突运输。由于CX3CR1在髓系细胞中特异表达，我们评估了视网膜小胶质细胞数量和激活的变化，基因表达的变化，以及巨噬细胞浸润的程度。我们发现，Fractalkine信号的丢失导致了视网膜内的先天免疫变化，包括外周巨噬细胞的浸润增加和髓系细胞中一氧化氮合酶-2(NOS-2)的表达上调，这有助于NO的产生，并可以促进轴突运输缺陷。相反，驻留的视网膜小胶质细胞在数量、形态或髓系激活标记离子钙结合适配器分子1(IBA1)的表达上似乎没有变化。促炎基因白介素1β(IL1β)也没有明显增加。我们的结论是，Fractalkine信号的丢失导致视网膜节细胞轴突运输功能障碍的选择性恶化，这与髓系细胞中Nos-2表达增强有关。我们的发现表明，不同的机制可能导致青光眼RGC下降的不同方面，在小胶质细胞和/或巨噬细胞中CX3CR1丢失后，轴突运输选择性地改变。
Neurodegeneration in glaucoma results in decline and loss of retinal ganglion cells (RGCs), and is associated with activation of myeloid cells such as microglia and macrophages. The chemokine fractalkine (FKN or Cx3cl1) mediates communication from neurons to myeloid cells. Signaling through its receptor Cx3cr1 has been implicated in multiple neurodegenerative diseases, but the effects on neuronal pathology are variable. Since it is unknown how FKN-mediated crosstalk influences RGC degeneration in glaucoma, we assessed this in a chronic mouse model, DBA/2J. We analyzed a DBA/2J substrain deficient in Cx3cr1, and compared compartmentalized RGC degeneration and myeloid cell responses to those in standard DBA/2J mice. We found that loss of FKN signaling exacerbates axon transport dysfunction, an early event in neurodegeneration, with a significant increase in RGCs with somal accumulation of the axonal protein phosphorylated neurofilament, and reduced retinal expression of genes involved in axon transport, Kif1b, and Atp8a2. There was no change in the loss of Brn3-positive RGCs, and no difference in the extent of damage to the proximal optic nerve, suggesting that the loss of fractalkine signaling primarily affects axon transport. Since Cx3cr1 is specifically expressed in myeloid cells, we assessed changes in retinal microglial number and activation, changes in gene expression, and the extent of macrophage infiltration. We found that loss of fractalkine signaling led to innate immune changes within the retina, including increased infiltration of peripheral macrophages and upregulated nitric oxide synthase-2 (Nos-2) expression in myeloid cells, which contributes to the production of NO and can promote axon transport deficits. In contrast, resident retinal microglia appeared unchanged either in number, morphology, or expression of the myeloid activation marker ionized calcium binding adaptor molecule 1 (Iba1). There was also no significant increase in the proinflammatory gene interleukin 1 beta (Il1β). We conclude that loss of fractalkine signaling causes a selective worsening of axon transport dysfunction in RGCs, which is linked to enhanced Nos-2 expression in myeloid cells. Our findings suggest that distinct mechanisms may contribute to different aspects of RGC decline in glaucoma, with axonal transport selectively altered after loss of Cx3cr1 in microglia and/or macrophages.
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影响因子：
4.4
作者：
Banitt, Michael R.;Ventura, Lori M.;Porciatti, Vittorio
通讯作者：
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