FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages
FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages
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FGF21 通过调节小胶质细胞/巨噬细胞的时空动态减轻缺血性中风后的神经炎症
DOI：
10.1186/s12974-020-01921-2
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发表时间：
2020-02
期刊：
影响因子：
--
通讯作者：
Ye Xiong
中科院分区：
文献类型：
--
作者：
Dongxue Wang;Fei Liu;Liyun Zhu;Ping Lin;Fanyi Han;Xue Wang;Xianxi Tan;Li Lin;Ye Xiong
研究背景小胶质细胞和巨噬细胞是引起神经炎症和免疫反应的主要因素，在缺血性脑损伤的发病机制中起重要作用。控制炎症反应被认为是一种有前途的治疗中风的方法。重组人成纤维细胞生长因子21（rhFGF 21）通过调节小胶质细胞和巨噬细胞呈现抗炎特性;然而，我们缺乏关于rhFGF 21在局灶性脑缺血中的炎症调节的知识。因此，我们研究了rhFGF 21是否通过靶向小胶质细胞和巨噬细胞来改善实验性脑卒中的缺血结局。方法C57 BL/6小鼠大脑中动脉闭塞（MCAO），随机分为两组，分别于再灌注后6 h开始每天腹腔注射rhFGF 21或溶媒。在MCAO后14天监测行为评估，并通过qRT-PCR分析炎性细胞因子的基因表达水平。通过流式细胞术和免疫染色检查小胶质细胞/巨噬细胞的表型变化和浸润的免疫细胞的存在。结果rhFGF 21可通过调节促炎和抗炎细胞因子的分泌，改善大鼠神经功能缺损。rhFGF 21还减弱了小胶质细胞/巨噬细胞向M1表型的极化和中风后外周免疫细胞的积累，伴随着小胶质细胞/巨噬细胞表型的时间演变和外周免疫细胞的浸润。此外，委员会认为，rhFGF 21通过抑制核因子-κ B（NF-κB）和上调过氧化物酶体增殖物激活受体-γ（PPAR-γ），抑制FGF受体1（FGFR 1）表达，从而抑制小胶质细胞M1极化和促炎细胞因子的表达。γ信号通路，使其成为治疗中风的潜在抗炎剂。
BackgroundResident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) presents anti-inflammatory properties by modulating microglia and macrophages; however, our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages.MethodsC57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 days after MCAO, and the gene expression levels of inflammatory cytokines were analyzed via qRT-PCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages.ResultsrhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment inhibited M1 polarization of microglia and pro-inflammatory cytokine expression through its actions on FGF receptor 1 (FGFR1) by suppressing nuclear factor-kappa B (NF-κB) and upregulating peroxisome proliferator-activated receptor-γ (PPAR-γ).ConclusionsrhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment.
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影响因子：
5.3
作者：
通讯作者：
--
影响因子：
16.2
作者：
Edbauer, Dieter;Neilson, Joel R.;Foster, Kelly A.;Wang, Chi-Fong;Seeburg, Daniel P.;Batterton, Matthew N.;Tada, Tomoko;Dolan, Bridget M.;Sharp, Phillip A.;Sheng, Morgan
通讯作者：
Sheng, Morgan
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1016/j.bbi.2018.07.021
发表时间：
2018-10
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Loppi S;Kolosowska N;Kärkkäinen O;Korhonen P;Huuskonen M;Grubman A;Dhungana H;Wojciechowski S;Pomeshchik Y;Giordano M;Kagechika H;White A;Auriola S;Koistinaho J;Landreth G;Hanhineva K;Kanninen K;Malm T
通讯作者：
Malm T
DOI：
10.1016/j.pnpbp.2016.07.003
发表时间：
2017-10-03
影响因子：
5.6
作者：
Anttila, Jenni E.;Whitaker, Keith W.;Wires, Emily S.;Harvey, Brandon K.;Airavaara, Mikko
通讯作者：
Airavaara, Mikko