Inhibition of Notch1 Signaling Alleviates Endotoxin-Induced Inflammation Through Modulating Retinal Microglia Polarization
Inhibition of Notch1 Signaling Alleviates Endotoxin-Induced Inflammation Through Modulating Retinal Microglia Polarization
复制标题
抑制 Notch1 信号传导通过调节视网膜小胶质细胞偏振减轻内毒素引起的炎症
DOI：
10.3389/fimmu.2019.00389
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发表时间：
2019-03-08
影响因子：
7.3
通讯作者：
Lin, Xiaofeng
中科院分区：
文献类型：
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作者：
Cheng, Zhixing;Yang, Yao;Lin, Xiaofeng
小胶质细胞是常驻免疫细胞，在各种脑和视网膜炎症性疾病中发挥重要作用。 Notch1 信号传导参与小胶质细胞极化和脑炎症反应的控制。然而，其在内毒素诱导的葡萄膜炎（EIU）中的作用仍不清楚。本研究旨在探讨Notch1信号在培养的视网膜小胶质细胞和EIU大鼠模型中对视网膜小胶质细胞极化和炎症的作用。我们发现，用 N-[N-(3, 5-二氟苯乙酰基)-1-alany1-S-苯甘氨酸叔丁酯 (DAPT) 阻断 Notch1 信号传导，可将视网膜小胶质细胞表型从促炎 M1 表型（COX2+ 和 iNOS+）转变为抗炎 M2 表型（Arg-1+），并减少促炎细胞的释放。 体内和体外的细胞因子。此外，DAPT治疗有助于防止视网膜神经节细胞凋亡，减少眼内浸润细胞，减轻视网膜功能损伤。综上所述，这些结果表明，抑制Notch1信号传导可以主要通过调节视网膜小胶质细胞的极化来减轻EIU大鼠的炎症反应。因此，Notch1信号可能是治疗眼部炎症疾病的一个有前景的治疗靶点。
Microglial cells are resident immune cells and play an important role in various cerebral and retinal inflammatory diseases. Notch1 signaling is involved in the microglia polarization and the control of cerebral inflammatory reactions. However, its role in endotoxin-induced uveitis (EIU) remains unknown. This study aimed to investigate the role of Notch1 signaling on retinal microglia polarization and inflammation in the cultured retinal microglial cells and EIU rat model. We found that Notch1 signaling blockade with N-[N-(3, 5-difluorophenacetyl)-1-alany1-S-phenyglycine t-butyl ester (DAPT) shifted retinal microglia phenotype from pro-inflammatory M1 phenotype (COX2+ and iNOS+) to anti-inflammatory M2 phenotype (Arg-1+) and reduced the release of pro-inflammatory cytokines both in vivo and in vitro. Moreover, DAPT treatment contributed to prevent retinal ganglion cells from apoptosis, reduce the intraocular infiltrating cells, and attenuate the impairment of retinal function. Taken together, these results suggest that inhibition of Notch1 signaling could alleviate the inflammatory response in EIU rat mainly through regulating the polarization of retinal microglia. Therefore, Notch1 signaling might be a promising therapeutic target in the treatment of ocular inflammatory diseases.