IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy.
IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy.
复制标题
糖尿病视网膜病变中视网膜 Müller 细胞介导 IL-17A 对视网膜神经节细胞的损伤
DOI：
10.1038/s41419-021-04350-y
复制
发表时间：
2021-11-08
影响因子：
9
通讯作者：
Liu QH
中科院分区：
文献类型：
--
作者：
Qiu AW;Huang DR;Li B;Fang Y;Zhang WW;Liu QH
糖尿病视网膜病变（diabetic retinopathy，DR）是最常见和最严重的眼部并发症，近年来被认为是一种神经血管炎性疾病。然而，由T淋巴细胞驱动的适应性免疫炎症在DR中的作用尚未得到很好的阐明。因此，本研究旨在阐明白细胞介素（IL）-17 A，主要由T淋巴细胞产生的促炎细胞因子，在视网膜病理生理学，特别是在视网膜神经元死亡的DR过程中的作用。使用糖尿病发作12周后的Ins 2秋田（秋田）糖尿病小鼠作为DR模型。通过IL-17 A敲除（IL-17 A-KO）小鼠与秋田小鼠杂交获得IL-17 A缺陷型糖尿病小鼠。用IL-17 A处理高糖条件下原代培养的视网膜Müller细胞（RMCs）和视网膜神经节细胞（RGCs）。将IL-17受体A（IL-17 RA）基因被IL-17 RA-shRNA沉默的RMCs和RGCs的transwell共培养物在HG条件下暴露于IL-17 A，并评估共培养的RGCs的存活。糖尿病小鼠表现出视网膜微血管病变增加，RMC活化和功能障碍，以及RGC凋亡。与糖尿病小鼠相比，IL-17 A-KO糖尿病小鼠显示视网膜微血管损伤、RMC异常和RGC凋亡减少。RMCs表达IL-17 RA。IL-17 A在体外可加重HG诱导的RMC活化和功能障碍，而RMC中IL-17 RA基因沉默可消除IL-17 A的有害作用。相比之下，RGC不表达IL-17 RA，IL-17 A不进一步改变HG诱导的RGC死亡。值得注意的是，IL-17 A在完整RMC的存在下加重HG诱导的RGC死亡，但在IL-17 RA基因已被敲除的RMC的存在下不加重HG诱导的RGC死亡。这些发现证实IL-17 A积极参与DR病理生理学，特别是通过RMC介导，其促进RGC死亡。总的来说，我们提出拮抗RMCs上的IL-17 RA可以防止视网膜神经元死亡，从而减缓DR进展。
Diabetic retinopathy (DR), the most common and serious ocular complication, recently has been perceived as a neurovascular inflammatory disease. However, role of adaptive immune inflammation driven by T lymphocytes in DR is not yet well elucidated. Therefore, this study aimed to clarify the role of interleukin (IL)-17A, a proinflammatory cytokine mainly produced by T lymphocytes, in retinal pathophysiology particularly in retinal neuronal death during DR process. Ins2Akita(Akita) diabetic mice 12 weeks after the onset of diabetes were used as a DR model. IL-17A-deficient diabetic mice were obtained by hybridization of IL-17A-knockout (IL-17A-KO) mouse with Akita mouse. Primarily cultured retinal Müller cells (RMCs) and retinal ganglion cells (RGCs) were treated with IL-17A in high-glucose (HG) condition. A transwell coculture of RGCs and RMCs whose IL-17 receptor A (IL-17RA) gene had been silenced with IL-17RA-shRNA was exposed to IL-17A in HG condition and the cocultured RGCs were assessed on their survival. Diabetic mice manifested increased retinal microvascular lesions, RMC activation and dysfunction, as well as RGC apoptosis. IL-17A-KO diabetic mice showed reduced retinal microvascular impairments, RMC abnormalities, and RGC apoptosis compared with diabetic mice. RMCs expressed IL-17RA. IL-17A exacerbated HG-induced RMC activation and dysfunction in vitro and silencing IL-17RA gene in RMCs abolished the IL-17A deleterious effects. In contrast, RGCs did not express IL-17RA and IL-17A did not further alter HG-induced RGC death. Notably, IL-17A aggravated HG-induced RGC death in the presence of intact RMCs but not in the presence of RMCs in which IL-17RA gene had been knocked down. These findings establish that IL-17A is actively involved in DR pathophysiology and particularly by RMC mediation it promotes RGC death. Collectively, we propose that antagonizing IL-17RA on RMCs may prevent retinal neuronal death and thereby slow down DR progression.
登录
查看更多内容
影响因子：
15.9
作者：
Barber, AJ;Lieth, E;Gardner, TW
通讯作者：
Gardner, TW
影响因子：
3.4
作者：
Capozzi, Megan E.;Savage, Sara R.;Penn, John S.
通讯作者：
Penn, John S.
影响因子：
4.4
作者：
Martin, PM;Roon, P;Smith, SB
通讯作者：
Smith, SB
影响因子：
4.3
作者：
Lai AK;Lo AC
通讯作者：
Lo AC
影响因子：
5.1
作者：
Liu, Zhan;Huang, Yan;Peng, Yu-Ping
通讯作者：
Peng, Yu-Ping