GlyCAM1 negatively regulates monocyte entry into the optic nerve head and contributes to radiation-based protection in glaucoma.
GlyCAM1 negatively regulates monocyte entry into the optic nerve head and contributes to radiation-based protection in glaucoma.
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DOI：
10.1186/s12974-017-0868-8
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发表时间：
2017-04-26
影响因子：
9.3
通讯作者：
John SWM
中科院分区：
文献类型：
--
作者：
Williams PA;Braine CE;Foxworth NE;Cochran KE;John SWM
我们以前报道了一个深刻的长期神经保护后，一个单一的放射治疗的DBA/2 J小鼠模型的青光眼。这种神经保护作用防止单核细胞样免疫细胞在青光眼期间进入视神经乳头。在辐射处理的小鼠中进行的基因表达研究表明Glycam 1参与了这种保护作用。Glycam 1编码L-选择素的蛋白聚糖配体，是调节免疫细胞进入眼睛的极好候选者。在这里，我们实验测试的假设，辐射诱导的Glycam 1的过度表达是神经保护的关键组成部分。我们在DBA/2 J背景上产生Glycam 1的无效等位基因。评估了Glycam 1的基因和蛋白表达、单核细胞进入视神经乳头、视网膜神经节细胞死亡和视神经轴突丢失。放射治疗有效地抑制单核细胞进入视神经乳头，并防止视网膜神经节细胞死亡和轴突损失。携带Glycam 1无效等位基因的DBA/2 J小鼠在放射治疗后显示单核细胞进入增加和视网膜神经节细胞死亡和轴突损失增加，但大多数视神经仍然受到放射治疗的保护。虽然GlyCAM 1是一种L-选择素配体，但其在免疫中的作用尚未完全确定。目前的研究表明GlyCAM 1在辐射介导的保护中发挥部分作用。此外，我们的结果清楚地表明，GlyCAM 1水平调节免疫细胞从脉管系统进入神经组织。由于Glycam 1缺乏对细胞进入的影响比对神经变性的影响更深远，因此需要进一步的实验来精确定义单核细胞进入在DBA/2 J青光眼中的作用。然而，GlyCAM 1作为外渗的负调节因子的功能可能会导致一系列涉及炎症的常见疾病的新治疗策略。本文的在线版本（doi：10.1186/s12974-017-0868-8）包含补充材料，可供授权用户使用。
We previously reported a profound long-term neuroprotection subsequent to a single radiation-therapy in the DBA/2J mouse model of glaucoma. This neuroprotection prevents entry of monocyte-like immune cells into the optic nerve head during glaucoma. Gene expression studies in radiation-treated mice implicated Glycam1 in this protection. Glycam1 encodes a proteoglycan ligand for L-selectin and is an excellent candidate to modulate immune cell entry into the eye. Here, we experimentally test the hypothesis that radiation-induced over-expression of Glycam1 is a key component of the neuroprotection. We generated a null allele of Glycam1 on a DBA/2J background. Gene and protein expression of Glycam1, monocyte entry into the optic nerve head, retinal ganglion cell death, and axon loss in the optic nerve were assessed. Radiation therapy potently inhibits monocyte entry into the optic nerve head and prevents retinal ganglion cell death and axon loss. DBA/2J mice carrying a null allele of Glycam1 show increased monocyte entry and increased retinal ganglion cell death and axon loss following radiation therapy, but the majority of optic nerves were still protected by radiation therapy. Although GlyCAM1 is an L-selectin ligand, its roles in immunity are not yet fully defined. The current study demonstrates a partial role for GlyCAM1 in radiation-mediated protection. Furthermore, our results clearly show that GlyCAM1 levels modulate immune cell entry from the vasculature into neural tissues. As Glycam1 deficiency has a more profound effect on cell entry than on neurodegeneration, further experiments are needed to precisely define the role of monocyte entry in DBA/2J glaucoma. Nevertheless, GlyCAM1’s function as a negative regulator of extravasation may lead to novel therapeutic strategies for an array of common conditions involving inflammation. The online version of this article (doi:10.1186/s12974-017-0868-8) contains supplementary material, which is available to authorized users.