Minocycline reduces inflammatory response and cell death in a S100B retina degeneration model.
Minocycline reduces inflammatory response and cell death in a S100B retina degeneration model.
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DOI：
10.1186/s12974-020-02012-y
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发表时间：
2020-12-14
影响因子：
9.3
通讯作者：
Joachim SC
中科院分区：
文献类型：
--
作者：
Grotegut P;Perumal N;Kuehn S;Smit A;Dick HB;Grus FH;Joachim SC
先前的研究指出，玻璃体内注射S100 B在14天后引发视网膜和视神经的视网膜样变性以及小胶质细胞活化。小胶质细胞在我们的玻璃体内S100 B模型中的确切作用仍不清楚。因此，通过米诺环素抑制小胶质细胞。目的是研究小胶质细胞是否对变性过程有显着影响，或者它们是否只是这里研究的模型中的副作用。每天通过腹膜内注射使用两种不同浓度（13.5mg/kg体重、25 mg/kg体重）在大鼠中施用米诺环素。治疗开始后一天，将S100 B或PBS玻璃体内注射到每只大鼠的一只眼睛中。未处理组未接受注射。这导致总共五个组（未处理n = 14，PBS n = 14，S100 B n = 13，13.5mg/kg米诺n = 15，25 mg/kg米诺n = 15）。在第14天，进行视网膜电图测量，然后进行免疫荧光和无标记定量蛋白质组学分析。这些研究的重点是RGC的存活以及它们的轴突，小胶质细胞的反应，以及S100 B的进一步病理作用模式的鉴定。在13.5 mg/kg米诺组中通过ERG检测到最佳信号传输。抑制小胶质细胞保护视神经纤维，减少S100 B对RGCs的负面影响。然而，米诺环素治疗不能触发RGC的完全保护。此外，在视网膜和视神经中，米诺环素处理以浓度依赖性方式减少S100 B触发的小胶质细胞的数量和活性。蛋白质组学分析表明，S100 B的应用导致了许多代谢功能和细胞应激，主要是增加炎症反应，糖酵解和线粒体功能障碍，这导致了视网膜中的氧化应激。重要的是，较低剂量的米诺环素的保护能力是通过抑制视网膜中S100 B损伤引起的细胞凋亡、炎症和改变的代谢过程来阐明的。玻璃体内注射S100 B不仅导致促炎性小胶质细胞反应，而且导致线粒体和代谢功能障碍。此外，这些结果表明，过度的小胶质细胞反应可能是一个重要的退行性因素，但不是增加细胞死亡的唯一触发因素。在线版本包含补充材料，可通过10.1186/s12974-020-02012-y获得。
Previous studies noted that intravitreal injection of S100B triggered a glaucoma-like degeneration of retina and optic nerve as well as microglia activation after 14 days. The precise role of microglia in our intravitreal S100B model is still unclear. Hence, microglia were inhibited through minocycline. The aim is to investigate whether microglia have a significant influence on the degeneration process or whether they are only a side effect in the model studied here. Minocycline was applied daily in rats by intraperitoneal injection using two different concentrations (13.5 mg/kg body weight, 25 mg/kg body weight). One day after treatment start, S100B or PBS was intravitreally injected in one eye per rat. The naïve groups received no injections. This resulted in a total of five groups (naïve n = 14, PBS n = 14, S100B n = 13, 13.5 mg/kg mino n = 15, 25 mg/kg mino n = 15). At day 14, electroretinogram measurements were performed, followed by immunofluorescence and label-free quantitative proteomics analysis. The focus of these investigations was on the survival of RGCs as well as their axons, the response of the microglia, and the identification of further pathological modes of action of S100B. The best signal transmission was detected via ERG in the 13.5 mg/kg mino group. The inhibition of the microglia protected optic nerve neurofilaments and decreased the negative impact of S100B on RGCs. However, the minocycline treatment could not trigger complete protection of RGCs. Furthermore, in retina and optic nerve, the minocycline treatment reduced the number and activity of S100B-triggered microglia in a concentration-dependent manner. Proteomics analysis showed that S100B application led to numerous metabolic functions and cellular stress, mainly an increased inflammatory response, glycolysis, and mitochondrial dysfunction, which caused oxidative stress in the retina. Importantly, the protective capability of lower dose of minocycline was unraveled by suppressing the apoptotic, inflammatory, and the altered metabolic processes caused by S100B insult in the retina. Intravitreally injected S100B not only led to a pro-inflammatory microglial reaction, but also a mitochondrial and metabolic dysfunction. Also, these results suggest that an excessive microglial response may be a significant degenerative factor, but not the only trigger for increased cell death. The online version contains supplementary material available at 10.1186/s12974-020-02012-y.
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影响因子：
5.6
作者：
Fasullo M;Endres L
通讯作者：
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影响因子：
82.9
作者：
Chen, M;Ona, VO;Friedlander, RM
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4.6
作者：
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影响因子：
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作者：
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通讯作者：
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作者：
Bordone, Melina P.;Gonzalez Fleitas, Maria F.;Dorfman, Damian
通讯作者：
Dorfman, Damian