Specific depletion of resident microglia in the early stage of stroke reduces cerebral ischemic damage.
Specific depletion of resident microglia in the early stage of stroke reduces cerebral ischemic damage.
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中风早期驻留小胶质细胞的特异性消耗可减少脑缺血损伤
DOI：
10.1186/s12974-021-02127-w
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发表时间：
2021-03-23
影响因子：
9.3
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Li T;Zhao J;Xie W;Yuan W;Guo J;Pang S;Gan WB;Gómez-Nicola D;Zhang S
研究背景脑缺血可诱导脑内小胶质细胞迅速活化。反应性小胶质细胞作为关键的免疫活性细胞，在缺血性脑卒中的病理发展中起重要作用。然而，激活的小胶质细胞在缺血发展过程中的作用仍然存在争议。因此，我们的目的是研究反应性小胶质细胞在缺血性中风早期的功能。方法采用虎红光血栓形成模型诱导小鼠靶向缺血性中风。使用CX 3CR 1CreER：R26 iDTR小鼠通过胃内施用他莫昔芬（Ta）和腹膜内注射白喉毒素（DT）来特异性地消耗驻留的小胶质细胞。在缺血性卒中后第3天，进行行为测试。在此之后，小鼠脑被收集作进一步的组织学分析和炎症因子的mRNA表达的检测。ResultsThe结果表明，特定的小胶质细胞耗竭导致缺血性梗死体积的显着减少，并改善运动能力中风后3天的性能。小胶质细胞耗竭导致退化神经元和诱导型一氧化氮合酶阳性（iNOS+）细胞的密度显着减少。重要的是，耗竭小胶质细胞诱导了抗炎因子TGF-β1、Arg 1、IL-10、IL-4和Ym 1的mRNA表达水平的显著增加，以及促炎因子TNF-α、iNOS和IL-1β在卒中后3天的显著下降。导致神经功能缺损和梗塞扩大。通过在精确的时间点消除小胶质细胞来调节炎症反应可能是治疗脑缺血的有希望的治疗方法。
BackgroundIschemia can induce rapid activation of microglia in the brain. As key immunocompetent cells, reactive microglia play an important role in pathological development of ischemic stroke. However, the role of activated microglia during the development of ischemia remains controversial. Thus, we aimed to investigate the function of reactive microglia in the early stage of ischemic stroke.MethodsA Rose Bengal photothrombosis model was applied to induce targeted ischemic stroke in mice. CX3CR1CreER:R26iDTRmice were used to specifically deplete resident microglia through intragastric administration of tamoxifen (Ta) and intraperitoneal injection of diphtheria toxin (DT). At day 3 after ischemic stroke, behavioral tests were performed. After that, mouse brains were collected for further histological analysis and detection of mRNA expression of inflammatory factors.ResultsThe results showed that specific depletion of microglia resulted in a significant decrease in ischemic infarct volume and improved performance in motor ability 3 days after stroke. Microglial depletion caused a remarkable reduction in the densities of degenerating neurons and inducible nitric oxide synthase positive (iNOS+) cells. Importantly, depleting microglia induced a significant increase in the mRNA expression level of anti-inflammatory factors TGF-β1, Arg1, IL-10, IL-4, and Ym1 as well as a significant decline of pro-inflammatory factors TNF-α, iNOS, and IL-1β 3 days after stroke.ConclusionsThese results suggest that activated microglia is an important modulator of the brain’s inflammatory response in stroke, contributing to neurological deficit and infarct expansion. Modulation of the inflammatory response through the elimination of microglia at a precise time point may be a promising therapeutic approach for the treatment of cerebral ischemia.
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DOI：
10.1093/brain/awv071
发表时间：
2015-07
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Bivard A;Levi C;Krishnamurthy V;McElduff P;Miteff F;Spratt NJ;Bateman G;Donnan G;Davis S;Parsons M
通讯作者：
Parsons M
影响因子：
6.3
作者：
Denes, Adam;Vidyasagar, Rishma;Allan, Stuart M.
通讯作者：
Allan, Stuart M.
影响因子：
5.3
作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR
影响因子：
3.3
作者：
Hayashi, Y.;Tomimatsu, Y.;Nakanishi, H.
通讯作者：
Nakanishi, H.
影响因子：
4.6
作者：
Donocoff, Rachel S.;Teteloshvili, Nato;Creusot, Remi J.
通讯作者：
Creusot, Remi J.