Targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia/macrophages and promotes long-term recovery after ischemic stroke.
Targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia/macrophages and promotes long-term recovery after ischemic stroke.
复制标题
DOI：
10.1186/s12974-023-02860-4
复制
发表时间：
2023-07-29
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
脑小胶质细胞和巨噬细胞（Mi/MΦ）可在缺血性卒中后转变为有害或有利的表型。确定调节静息Mi/MΦ转化的关键分子有助于开发缺血性卒中的创新疗法。转录因子信号转导激活因子1 （STAT1）已被发现有助于缺血性卒中后急性神经元死亡（在最初24小时内），但其对Mi/MΦ的影响以及对长期卒中结局的影响尚未确定。我们产生了由Cx3cr1CreER驱动的他莫昔芬诱导的STAT1 Mi/MΦ-specific敲除（mKO）小鼠。用流式细胞术和RNA测序技术检测短暂性大脑中动脉闭塞（MCAO）致缺血性脑卒中后脑组织中STAT1的表达。在MCAO后3-5天检测STAT1 mKO对神经元细胞死亡、Mi/MΦ表型和脑炎症谱的影响。在MCAO后的5周内，通过各种神经行为测试和免疫组织化学评估神经功能缺损和灰质和白质的完整性。STAT1在MCAO后亚急性期（3天）在Mi/MΦ中被激活。MCAO后24小时，Mi/MΦ中STAT1的选择性缺失没有改变神经元细胞死亡或梗死面积，但MCAO后Mi/MΦ高迁移率组盒1的释放减弱，Mi/MΦ 3d产生精氨酸酶1的增加，表明Mi/MΦ的消炎反应增强。因此，STAT1 mKO小鼠在MCAO后亚急性期减轻了脑炎症，长期减少了白质损伤。重要的是，STAT1 mKO足以改善雄性和雌性小鼠MCAO后至少5周的功能恢复。Mi/MΦ-targeted STAT1 KO不能立即提供神经保护，但可以增强Mi/MΦ的消炎作用，从而促进中风后的长期功能恢复。因此，STAT1是一个有希望的治疗靶点，可以利用有益的Mi/MΦ反应并改善缺血性卒中后的长期预后。在线版本包含补充材料，可在10.1186/s12974-023-02860-4获得。
Brain microglia and macrophages (Mi/MΦ) can shift to a harmful or advantageous phenotype following an ischemic stroke. Identification of key molecules that regulate the transformation of resting Mi/MΦ could aid in the development of innovative therapies for ischemic stroke. The transcription factor signal transducer and activator of transduction 1 (STAT1) has been found to contribute to acute neuronal death (in the first 24 h) following ischemic stroke, but its effects on Mi/MΦ and influence on long-term stroke outcomes have yet to be determined. We generated mice with tamoxifen-induced, Mi/MΦ-specific knockout (mKO) of STAT1 driven by Cx3cr1CreER. Expression of STAT1 was examined in the brain by flow cytometry and RNA sequencing after ischemic stroke induced by transient middle cerebral artery occlusion (MCAO). The impact of STAT1 mKO on neuronal cell death, Mi/MΦ phenotype, and brain inflammation profiles were examined 3–5 days after MCAO. Neurological deficits and the integrity of gray and white matter were assessed for 5 weeks after MCAO by various neurobehavioral tests and immunohistochemistry. STAT1 was activated in Mi/MΦ at the subacute stage (3 days) after MCAO. Selective deletion of STAT1 in Mi/MΦ did not alter neuronal cell death or infarct size at 24 h after MCAO, but attenuated Mi/MΦ release of high mobility group box 1 and increased arginase 1-producing Mi/MΦ 3d after MCAO, suggesting boosted inflammation-resolving responses of Mi/MΦ. As a result, STAT1 mKO mice had mitigated brain inflammation at the subacute stage after MCAO and less white matter injury in the long term. Importantly, STAT1 mKO was sufficient to improve functional recovery for at least 5 weeks after MCAO in both male and female mice. Mi/MΦ-targeted STAT1 KO does not provide immediate neuroprotection but augments inflammation-resolving actions of Mi/MΦ, thereby facilitating long-term functional recovery after stroke. STAT1 is, therefore, a promising therapeutic target to harness beneficial Mi/MΦ responses and improve long-term outcomes after ischemic stroke. The online version contains supplementary material available at 10.1186/s12974-023-02860-4.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
8
作者：
Cai, Wei;Dai, Xuejiao;Chen, Jun
通讯作者：
Chen, Jun
影响因子：
8.3
作者：
Alkayed, NJ;Murphy, SJ;Hurn, PD
通讯作者：
Hurn, PD
影响因子：
4.4
作者：
Lee, CK;Smith, E;Levy, DE
通讯作者：
Levy, DE
影响因子：
8.3
作者：
Fisher M;Feuerstein G;Howells DW;Hurn PD;Kent TA;Savitz SI;Lo EH;STAIR Group
通讯作者：
STAIR Group