Osteopontin activates retinal microglia causing retinal ganglion cells loss via p38 MAPK signaling pathway in glaucoma
Osteopontin activates retinal microglia causing retinal ganglion cells loss via p38 MAPK signaling pathway in glaucoma
复制标题
青光眼中骨桥蛋白通过 p38 MAPK 信号通路激活视网膜小胶质细胞，导致视网膜神经节细胞丢失
DOI：
10.1096/fj.202002218r
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发表时间：
2021-03-01
期刊：
影响因子：
4.8
通讯作者：
Zhong，Yisheng
中科院分区：
文献类型：
--
作者：
Yu，Huan;Zhong，Huimin;Zhong，Yisheng
小胶质细胞的激活和促炎细胞因子的释放与青光眼密切相关。然而，启动这些途径的机制仍不清楚。在这里，我们研究了促炎细胞因子——骨桥蛋白（OPN）在视网膜小胶质细胞激活过程中的作用以及青光眼的潜在机制。建立了大鼠慢性高眼压（COH）模型，表现为视网膜 OPN 水平增加和小胶质细胞激活。分离原代小胶质细胞并在压力培养系统下培养，结果显示小胶质细胞来源的 OPN 表达升高，炎症因子（TNF-α、IL-1β 和 IL-6）发生变化。 OPN 和 OPN 中和抗体 (Anti-OPN) 干预措施都是用于比较的应用系统，并与体外 OPN 敲低进行交叉引用。 JAK/STAT、NF-κB、ERK1/2 和 p38 MAPK 被认为是与小胶质细胞激活相关的主要信号通路，然后筛选它们是否可以促进 OPN 作用于小胶质细胞及其对特定抑制剂的影响。此后，使用视网膜神经节细胞（RGC）的逆行标记和闪光视觉诱发电位（F-VEP）来研究每次封锁背景下的神经元保护。结果表明，OPN 能够增强实验性青光眼中视网膜小胶质细胞的增殖和活化，这可能在青光眼性视神经病变中发挥作用，并导致最终的 RGC 损失和视力功能损害。这种作用可能是通过p38 MAPK信号通路的调节来介导的。
Microglia activation and release of pro‐inflammatory cytokines have been closely linked to glaucoma. However, the mechanisms that initiate these pathways remain unclear. Here, we investigated the role of a pro‐inflammatory cytokine––osteopontin (OPN), in retinal microglia activation process along with the underlying mechanisms in glaucoma. A rat chronic ocular hypertension (COH) model was established presenting an increase in retinal OPN level and activation of microglia. Primary microglia cells were isolated and cultured under a pressure culture system showing heightened expressions of microglia‐derived OPN with changes in inflammatory factors (TNF‐α, IL‐1β, and IL‐6). OPN and OPN neutralizing antibody (Anti‐OPN) interventions were both applied systems for comparison, and cross‐referenced with OPN knockdown in vitro. JAK/STAT, NF‐κB, ERK1/2, and p38 MAPK, recognized as the primary signaling pathways related to microglia activation, were then screened on whether they can facilitate OPN to act on microglia and their impact on specific inhibitors. Thereafter, retrograde labeling of retinal ganglion cells (RGCs) and flash visual evoked potentials (F‐VEP) were used to investigate neuron protection in context of each blockade. Results suggest that OPN is able to enhance the proliferation and activation of retinal microglia in experimental glaucoma which may play a role in the glaucomatous optic neuropathy, and contribute to the eventual RGCs loss and vision function impairment. Such effect may be mediated through the regulation of p38 MAPK signaling pathway.