Olfactory Ensheathing Cells Grafted Into the Retina of RCS Rats Suppress Inflammation by Down-Regulating the JAK/STAT Pathway
Olfactory Ensheathing Cells Grafted Into the Retina of RCS Rats Suppress Inflammation by Down-Regulating the JAK/STAT Pathway
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移植到 RCS 大鼠视网膜的嗅鞘细胞通过下调 JAK/STAT 通路抑制炎症
DOI：
10.3389/fncel.2019.00341
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发表时间：
2019-07
影响因子：
5.3
通讯作者：
Zheng Qin Yin
中科院分区：
文献类型：
--
作者：
Jing Xie;Yijian Li;Jiaman Dai;Yan He;Dayu Sun;Chao Dai;Haiwei Xu;Zheng Qin Yin
视网膜炎症微环境在视网膜色素变性（RP）的发病和进展中起着至关重要的作用。小胶质细胞炎性细胞因子的产生导致视网膜神经元的胶质增生和凋亡，并最终导致视力丧失。使用移植的嗅鞘细胞（OECs）的基于细胞的疗法已经在许多动物模型中证明了中枢神经系统（CNS）中的退行性微环境的调节。然而，移植的OECs可以减少视网膜变性的机制还不清楚。本研究通过建立体外OEC/BV 2小胶质细胞共培养体系和体内皇家外科学院（RCS）大鼠模型，采用细胞移植、免疫组化、RT-PCR、western blot等方法，探讨OEC影响视网膜促炎和抗炎细胞因子表达以及M（IL-6）和M（Arg 1）型小胶质细胞活化极化的机制。结果发现，与LPS（Lipopolysaccharide，脂多糖）和嗅神经成纤维细胞（olfactory nerve fibroblast，ONF）共培养组相比，OEC和BV 2共培养组调节小胶质细胞释放的细胞因子向抗炎方向发展，向促炎方向发展，IL-4和IL-10表达水平升高，TNF-α和IL-6表达水平降低。在体内，移植组RCS大鼠视网膜内活化的驻留小胶质细胞/浸润的巨噬细胞明显减少，促炎细胞因子表达明显减少，移植区抗炎细胞因子表达明显增加。此外，我们发现OECs表达SOCS 3并下调JAK 2/STAT 3（Janus Kinase 2/Signal Transducer and Activator of Transcription 3）通路。第三，OEC移植减少Caspase-3的表达，保护视网膜内神经元和光感受器，从而延缓视功能的退化。总之，我们的数据表明，嗅鞘细胞延迟RP视网膜变性，至少部分通过免疫调节小胶质细胞通过JAK/STAT途径。
The inflammatory microenvironment in the retina plays a vital role in the pathogenesis and progression of retinitis pigmentosa (RP). Microglial inflammatory cytokines production leads to gliosis and apoptosis of retinal neurons, and ultimately, visual loss. Cell-based therapies using grafted olfactory ensheathing cells (OECs) have demonstrated modulation of degenerative microenvironments in the central nervous system (CNS), in a number of animal models. However, mechanisms by which grafted OECs can reduce degeneration in the retina are not well understood. In the present study, we set up an in vitro OEC/BV2 microglia co-culture system, and an in vivo royal college of surgeons (RCS) rat model, used cell transplantation, immunohistochemistry, RT-PCR, western blot to explore the mechanisms by which OECs affect expression of pro- or anti-inflammatory cytokines and polarization of M(IL-6) and M(Arg1) type microglial activation in the retina. We found that compared with the LPS (Lipopolysaccharide) and olfactory nerve fibroblast (ONF), the OEC and BV2 co-culture group modulate microglial cytokines releasing toward the anti-inflammation, and away from the pro-inflammation, which was followed by higher IL-4 and IL-10 and lower TNF-a and IL-6 in their expression levels. In vivo, the transplantation group significantly reduced activated resident microglia/infiltrated macrophage, and expression of pro-inflammatory cytokines in RCS rats retina, increased anti-inflammatory cytokines in transplantation area. Additionally, we found that OECs expressed SOCS3 and down-regulated the JAK2/STAT3 (Janus Kinase 2/Signal Transducer and Activator of Transcription 3) pathway. Thirdly, OEC transplantation reduced Caspase-3 expression, protected inner retinal neurons and photoreceptors and therefore, delayed the visual function degeneration. In conclusion, our data suggest that OECs delay retinal degeneration in RP, at least in part through immunomodulation of microglia via the JAK/STAT pathway.
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影响因子：
9.8
作者：
Greenhalgh AD;Zarruk JG;Healy LM;Baskar Jesudasan SJ;Jhelum P;Salmon CK;Formanek A;Russo MV;Antel JP;McGavern DB;McColl BW;David S
通讯作者：
David S
MANF免疫调节可促进视网膜的组织修复和再生成功。
DOI：
10.1126/science.aaf3646
发表时间：
2016-07-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Neves J;Zhu J;Sousa-Victor P;Konjikusic M;Riley R;Chew S;Qi Y;Jasper H;Lamba DA
通讯作者：
Lamba DA
rd1 小鼠视网膜变性模型中小胶质细胞极化与 M1/M2 表型变化
影响因子：
2.9
作者：
Zhou Tian;Huang Zijing;Sun Xiaowei;Zhu Xiaowei;Zhou Lingli;Li Mei;Cheng Bing;Liu Xialin;He Chang
通讯作者：
He Chang
影响因子：
--
作者：
C. Lange;M. Thiersch;M. Samardzija;C. Grimm
通讯作者：
C. Lange;M. Thiersch;M. Samardzija;C. Grimm
影响因子：
3.3
作者：
Kyger, Madison;Worley, Aneta;Adamus, Grazyna
通讯作者：
Adamus, Grazyna