Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective
Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective
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DOI：
10.1073/pnas.1608769114
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发表时间：
2017-05-09
影响因子：
11.1
通讯作者：
John, Simon W. M.
中科院分区：
文献类型：
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作者：
Harder, Jeffrey M.;Braine, Catherine E.;John, Simon W. M.
在青光眼的早期退行性前阶段，各种免疫反应途径发生改变；然而，早期免疫反应是否继发于或独立于神经元功能障碍尚不清楚。为了研究这种关系，我们使用了保护轴突功能障碍的Wlds等位基因。我们演示了DBA/2J。在DBA/2J型青光眼早期，小鼠会出现高眼压（IOP），但不会出现视网膜神经节细胞（RGC）功能障碍和神经胶质改变。尽管如此，DBA/2中的免疫通路仍然发生改变(J)。世界老鼠。这表明免疫变化不是继发于RGC功能障碍或神经胶质相互作用的改变，而是可能由高眼压施加的压力增加直接诱导的。IOP升高后的一个早期免疫反应是DBA/2J和DBA/2J星形胶质细胞中补体C3的上调。世界老鼠。出乎意料的是，由于其他补体成分（如C1Q）的破坏在青光眼中具有保护作用，C3缺乏显著增加了IOP升高后早期出现神经损伤和RGC丢失的DBA/2J眼的数量。缺乏c3的培养星形胶质细胞的转录谱暗示EGFR信号是c3依赖性反应的枢纽。EGFR抑制剂AG1478治疗也显著增加了同一早期时间点DBA/2J型青光眼的数量。这些发现表明C3可以防止早期青光眼损伤，这一过程可能涉及EGFR信号传导和视神经头的其他免疫反应。因此，针对补体级联的特定成分的治疗，而不是全局抑制，可能更适用于治疗人类青光眼。
Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wlds allele, which protects from axon dysfunction. We demonstrate that DBA/2J. Wlds mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2(J). Wlds mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/ 2J. Wlds mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.