Retinal Detachment-Induced Müller Glial Cell Swelling Activates TRPV4 Ion Channels and Triggers Photoreceptor Death at Body Temperature.
Retinal Detachment-Induced Müller Glial Cell Swelling Activates TRPV4 Ion Channels and Triggers Photoreceptor Death at Body Temperature.
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DOI：
10.1523/jneurosci.0897-18.2018
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发表时间：
2018-10-10
期刊：
影响因子：
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通讯作者：
Shibasaki K
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文献类型：
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作者：
Matsumoto H;Sugio S;Seghers F;Krizaj D;Akiyama H;Ishizaki Y;Gailly P;Shibasaki K
采用局部注射透明质酸的方法，建立了小鼠急性视网膜脱离（RD）模型，以探讨RD引发的感光细胞死亡的分子机制。我们专注于瞬时受体电位香草素4（TRPV 4）离子通道，其功能作为一个温度传感器，温度传感器，和/或mechanosensor。RD后，TRPV 4 KO小鼠中凋亡光感受器的数量相对于野生型小鼠减少了约50%，表明TRPV 4活化可能参与RD诱导的光感受器细胞死亡。此外，在Müller神经胶质细胞中表达的TRPV 4可以通过由RD诱导的这些细胞的肿胀引起的机械刺激而被激活，导致细胞因子MCP-1的释放，据报道MCP-1是RD诱导的光感受器死亡的Müller神经胶质衍生的强介体的介体。我们还发现，通过Müller神经胶质肿胀激活TRPV 4可通过体温增强。总之，我们的研究结果表明，RD通过从Müller神经胶质细胞释放TRPV 4依赖性细胞因子对感光细胞活力产生不利影响，TRPV 4是一种新的分子途径的一部分，可能会加剧RD后缺氧对感光细胞存活的影响。重要性声明确定视网膜脱离中感光细胞死亡的机制是建立预防视力丧失的治疗靶点所必需的。在这项研究中，我们发现，在Müller胶质细胞中表达的TRPV 4可以被RD诱导的这些细胞肿胀引起的机械刺激激活，导致细胞因子MCP-1的释放，据报道，MCP-1是Müller胶质细胞衍生的RD诱导的光感受器死亡的强介质的介质。我们还发现，通过Müller神经胶质肿胀激活TRPV 4可通过体温增强。因此，TRPV 4抑制可以抑制RD病理条件下的细胞死亡，并表明Müller胶质细胞中的TRPV 4可能是预防RD后感光细胞死亡的新治疗靶点。
Using region-specific injection of hyaluronic acid, we developed a mouse model of acute retinal detachment (RD) to investigate molecular mechanisms of photoreceptor cell death triggered by RD. We focused on the transient receptor potential vanilloid 4 (TRPV4) ion channel, which functions as a thermosensor, osmosensor, and/or mechanosensor. After RD, the number of apoptotic photoreceptors was reduced by ∼50% in TRPV4KO mice relative to wild-type mice, indicating the possible involvement of TRPV4 activation in RD-induced photoreceptor cell death. Furthermore, TRPV4 expressed in Müller glial cells can be activated by mechanical stimuli caused by RD-induced swelling of these cells, resulting in release of the cytokine MCP-1, which is reported as a mediator of Müller glia-derived strong mediator for RD-induced photoreceptor death. We also found that the TRPV4 activation by the Müller glial swelling was potentiated by body temperature. Together, our results suggest that RD adversely impacts photoreceptor viability via TRPV4-dependent cytokine release from Müller glial cells and that TRPV4 is part of a novel molecular pathway that could exacerbate the effects of hypoxia on photoreceptor survival after RD. SIGNIFICANCE STATEMENT Identification of the mechanisms of photoreceptor death in retinal detachment is required for establishment of therapeutic targets for preventing loss of visual acuity. In this study, we found that TRPV4 expressed in Müller glial cells can be activated by mechanical stimuli caused by RD-induced swelling of these cells, resulting in release of the cytokine MCP-1, which is reported as a mediator of Müller glia-derived strong mediator for RD-induced photoreceptor death. We also found that the TRPV4 activation by the Müller glial swelling was potentiated by body temperature. Hence, TRPV4 inhibition could suppress cell death in RD pathological conditions and suggests that TRPV4 in Müller glial cells might be a novel therapeutic target for preventing photoreceptor cell death after RD.