Targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia/macrophages and promotes long-term recovery after ischemic stroke
Abstract Background 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 t...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02860-4 |
| _version_ | 1797769398213148672 |
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| author | Wenxuan Han Hongjian Pu Sicheng Li Yaan Liu Yongfang Zhao Mingyue Xu Caixia Chen Yun Wu Tuo Yang Qing Ye Hong Wang R. Anne Stetler Jun Chen Yejie Shi |
| author_facet | Wenxuan Han Hongjian Pu Sicheng Li Yaan Liu Yongfang Zhao Mingyue Xu Caixia Chen Yun Wu Tuo Yang Qing Ye Hong Wang R. Anne Stetler Jun Chen Yejie Shi |
| author_sort | Wenxuan Han |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
| first_indexed | 2024-03-12T21:08:28Z |
| format | Article |
| id | doaj.art-dc076fe749a948e4ac99b110a32d025e |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-12T21:08:28Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-dc076fe749a948e4ac99b110a32d025e2023-07-30T11:21:07ZengBMCJournal of Neuroinflammation1742-20942023-07-0120112110.1186/s12974-023-02860-4Targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia/macrophages and promotes long-term recovery after ischemic strokeWenxuan Han0Hongjian Pu1Sicheng Li2Yaan Liu3Yongfang Zhao4Mingyue Xu5Caixia Chen6Yun Wu7Tuo Yang8Qing Ye9Hong Wang10R. Anne Stetler11Jun Chen12Yejie Shi13Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghPittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghPittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghPittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghPittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghPittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghPittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghPittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghPittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghPittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghDepartment of Biostatistics, University of PittsburghPittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghPittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghPittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of PittsburghAbstract Background 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. Methods 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. Results 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. Conclusions 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.https://doi.org/10.1186/s12974-023-02860-4Behavior testConditional gene knockoutNeuroinflammationSTAT1White matter injury |
| spellingShingle | Wenxuan Han Hongjian Pu Sicheng Li Yaan Liu Yongfang Zhao Mingyue Xu Caixia Chen Yun Wu Tuo Yang Qing Ye Hong Wang R. Anne Stetler Jun Chen Yejie Shi Targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia/macrophages and promotes long-term recovery after ischemic stroke Journal of Neuroinflammation Behavior test Conditional gene knockout Neuroinflammation STAT1 White matter injury |
| title | Targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia/macrophages and promotes long-term recovery after ischemic stroke |
| title_full | Targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia/macrophages and promotes long-term recovery after ischemic stroke |
| title_fullStr | Targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia/macrophages and promotes long-term recovery after ischemic stroke |
| title_full_unstemmed | Targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia/macrophages and promotes long-term recovery after ischemic stroke |
| title_short | Targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia/macrophages and promotes long-term recovery after ischemic stroke |
| title_sort | targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia macrophages and promotes long term recovery after ischemic stroke |
| topic | Behavior test Conditional gene knockout Neuroinflammation STAT1 White matter injury |
| url | https://doi.org/10.1186/s12974-023-02860-4 |
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