Blocking the interaction between interleukin-17A and endoplasmic reticulum stress in macrophage attenuates retinal neovascularization in oxygen-induced retinopathy.
Blocking the interaction between interleukin-17A and endoplasmic reticulum stress in macrophage attenuates retinal neovascularization in oxygen-induced retinopathy.
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阻断巨噬细胞中白细胞介素- 17a与内质网应激的相互作用可减弱氧诱导视网膜病变中视网膜新生血管的形成。
DOI：
10.1186/s13578-021-00593-6
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发表时间：
2021-05-01
影响因子：
7.5
通讯作者：
Shen X
中科院分区：
文献类型：
--
作者：
Wang Y;Gao S;Gao S;Li N;Xie B;Shen X
新生血管是导致视力丧失的主要原因，通常与糖尿病视网膜病变(DR)和早产儿视网膜病变(ROP)有关。白介素17A(IL-17A)和内质网(ER)应激都被证明在缺血性视网膜病变中发挥促血管生成作用。然而，低氧条件下视网膜新生血管(RNV)中IL-17A与内质网应激的关系及其机制尚不清楚。本研究建立了氧源性视网膜病变(OIR)小鼠模型，并进行了玻璃体腔注射。检测视网膜和原代培养的骨髓巨噬细胞(BMDM)在常氧和低氧条件下IL-17A和ER应激标志物的变化。采用Western blotting、Real-Time RT-PCR、免疫荧光分析等方法，探讨IL-17A与内质网应激在RNV中的作用和关系及其可能的机制。与正常对照组相比，IL-17A和ER应激标记物在体内和体外低氧条件下均显著升高。中和或敲除IL-17A可减轻内质网应激。内质网应激抑制剂4-苯基丁酸酯(4-PBA)可抑制IL-17A的产生，提示IL-17A与内质网应激之间存在正反馈循环。抑制IL-17A或内质网应激可减少OIR视网膜中无灌注区和新生血管的面积。由于TXNIP/NLRP3通路的激活被证实参与了缺氧性视网膜病变视网膜血管通透性的增加，我们观察到在低氧条件下，TXNIP/NLRP3通路介导了IL-17A与内质网应激的相互作用。在低氧条件下，IL-17A和内质网应激的相互作用通过调节TXNIP/NLRP3信号通路参与巨噬细胞RNV的发生。该反馈环可能成为治疗缺血性视网膜病变的一种创新的、多元的药物治疗靶点。网上版载有补充材料，可在10.1186/s13578-021-00593-6查阅。
Neovascularization is a leading cause of visual loss typically associated with diabetic retinopathy (DR) and retinopathy of prematurity (ROP). Interleukin-17A (IL-17A) and endoplasmic reticulum (ER) stress both have been demonstrated to play a proangiogenic role in ischemic retinopathies. However, the relationship between IL-17A and ER stress in retinal neovascularization (RNV) under hypoxic conditions and its underlying mechanisms remain unclear. In this study, oxygen-induced retinopathy (OIR) mice model was established and intravitreal injections were conducted. Changes of IL-17A and ER stress markers in retinas and cultured primary bone marrow derived macrophage (BMDM) under normoxic or hypoxic conditions were detected. Western blotting, Real-Time RT-PCR, Immunofluorescence assays were conducted to explore the roles and relationship of IL-17A and ER stress in RNV, as well as its underlying mechanisms. Compared to that in normal controls, IL-17A and ER stress markers were all remarkably increased under hypoxic conditions both in vivo and in vitro. Neutralization or knock out of IL-17A decreased ER stress. ER stress inhibitor 4-phenylbutyrate (4-PBA), attenuated the production of IL-17A, suggesting a positive feedback loop between IL-17A and ER stress. Inhibition of IL-17A or ER stress decreased areas of nonperfusion and neovascularization in OIR retinas. As TXNIP/NLRP3 pathway activation has been demonstrated to be involved in increased retinal vascular permeability of ischemic retinopathy, we observed that TXNIP/NLRP3 pathway mediated in the interaction between IL-17A and ER stress under hypoxic conditions. The interplay between IL-17A and ER stress contributes to RNV in macrophages via modulation of TXNIP/NLRP3 signaling pathway under hypoxic conditions. The feedback loops may become an innovative and multiple pharmacological therapeutic target for ischemic retinopathy. The online version contains supplementary material available at 10.1186/s13578-021-00593-6.
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影响因子：
29
作者：
Lerner AG;Upton JP;Praveen PV;Ghosh R;Nakagawa Y;Igbaria A;Shen S;Nguyen V;Backes BJ;Heiman M;Heintz N;Greengard P;Hui S;Tang Q;Trusina A;Oakes SA;Papa FR
通讯作者：
Papa FR
影响因子：
32.4
作者：
Bronner DN;Abuaita BH;Chen X;Fitzgerald KA;Nuñez G;He Y;Yin XM;O'Riordan MX
通讯作者：
O'Riordan MX
影响因子：
4.3
作者：
Li, Nan;Wang, Xue-Ming;Zhao, Ya-Jiao
通讯作者：
Zhao, Ya-Jiao
影响因子：
8
作者：
Gyongyosi, B.;Cho, Y.;Szabo, G.
通讯作者：
Szabo, G.
内质网应激与视网膜炎症和糖尿病性视网膜病有关。
影响因子：
3.5
作者：
Li, Jingming;Wang, Joshua J.;Yu, Qiang;Wang, Min;Zhang, Sarah X.
通讯作者：
Zhang, Sarah X.