Suppressing NK Cells by Astragaloside IV Protects Against Acute Ischemic Stroke in Mice Via Inhibiting STAT3
Natural killer (NK) cells, a key member of innate lymphocytes, are a promising immunotherapeutic target for ischemic stroke. Astragaloside IV (ASIV) is isolated from Astragalus mongholicus Bunge (Fabaceae), a herbal medicine possessing immunomodulatory ability. This study investigated the effect of...
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.802047/full |
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| author | Shichun Li Shichun Li Baokai Dou Shi Shu Luyao Wei Shiguo Zhu Zunji Ke Zhifei Wang |
| author_facet | Shichun Li Shichun Li Baokai Dou Shi Shu Luyao Wei Shiguo Zhu Zunji Ke Zhifei Wang |
| author_sort | Shichun Li |
| collection | DOAJ |
| description | Natural killer (NK) cells, a key member of innate lymphocytes, are a promising immunotherapeutic target for ischemic stroke. Astragaloside IV (ASIV) is isolated from Astragalus mongholicus Bunge (Fabaceae), a herbal medicine possessing immunomodulatory ability. This study investigated the effect of ASIV on NK cells during the acute stage of brain ischemic injury in a mouse model of middle cerebral artery occlusion (MCAO). MCAO mice treated with ASIV had better functional outcomes, smaller brain infarction and less NK cell brain infiltration. NK cell depletion echoed the protective effect of ASIV. Notably, ASIV did not enhance the protective effect of NK cell depletion against brain ischemic injury. ASIV inhibited glial cell-derived CCL2-mediated chemotaxis to prevent post-ischemic NK cell brain recruitment. Meanwhile, ASIV also abrogated NK cell-mediated cytolytic killing of neurons subjected to oxygen-glucose deprivation and suppressed NK cell-derived IFN-γ and NKG2D expression in the ischemic brain. The inhibitory effect of ASIV on NK cell brain infiltration and activation was mimicked by cryptotanshinone, a STAT3 inhibitor. There was no additive effect when ASIV and cryptotanshinone were used together. In conclusion, ASIV inhibits post-ischemic brain infiltration and activation of NK cells through STAT3 suppression, and this inhibitory effect of ASIV on NK cells plays a key role in its protection against acute ischemic brain injury. Our findings suggest that ASIV is a promising therapeutic candidate in NK cell-based immunotherapy for the treatment of acute ischemic stroke and pave the way for potential clinical trials. |
| first_indexed | 2024-04-11T19:35:09Z |
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| id | doaj.art-71e376cd4c2c49ddb6294602312e57ee |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T19:35:09Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-71e376cd4c2c49ddb6294602312e57ee2022-12-22T04:06:52ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-02-011210.3389/fphar.2021.802047802047Suppressing NK Cells by Astragaloside IV Protects Against Acute Ischemic Stroke in Mice Via Inhibiting STAT3Shichun Li0Shichun Li1Baokai Dou2Shi Shu3Luyao Wei4Shiguo Zhu5Zunji Ke6Zhifei Wang7School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaAcademy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaAcademy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaAcademy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaNatural killer (NK) cells, a key member of innate lymphocytes, are a promising immunotherapeutic target for ischemic stroke. Astragaloside IV (ASIV) is isolated from Astragalus mongholicus Bunge (Fabaceae), a herbal medicine possessing immunomodulatory ability. This study investigated the effect of ASIV on NK cells during the acute stage of brain ischemic injury in a mouse model of middle cerebral artery occlusion (MCAO). MCAO mice treated with ASIV had better functional outcomes, smaller brain infarction and less NK cell brain infiltration. NK cell depletion echoed the protective effect of ASIV. Notably, ASIV did not enhance the protective effect of NK cell depletion against brain ischemic injury. ASIV inhibited glial cell-derived CCL2-mediated chemotaxis to prevent post-ischemic NK cell brain recruitment. Meanwhile, ASIV also abrogated NK cell-mediated cytolytic killing of neurons subjected to oxygen-glucose deprivation and suppressed NK cell-derived IFN-γ and NKG2D expression in the ischemic brain. The inhibitory effect of ASIV on NK cell brain infiltration and activation was mimicked by cryptotanshinone, a STAT3 inhibitor. There was no additive effect when ASIV and cryptotanshinone were used together. In conclusion, ASIV inhibits post-ischemic brain infiltration and activation of NK cells through STAT3 suppression, and this inhibitory effect of ASIV on NK cells plays a key role in its protection against acute ischemic brain injury. Our findings suggest that ASIV is a promising therapeutic candidate in NK cell-based immunotherapy for the treatment of acute ischemic stroke and pave the way for potential clinical trials.https://www.frontiersin.org/articles/10.3389/fphar.2021.802047/fullnatural killer cellsbrain ischemiaastragaloside IVoxygen-glucose deprivationsignal transducer and activator of transcription 3 |
| spellingShingle | Shichun Li Shichun Li Baokai Dou Shi Shu Luyao Wei Shiguo Zhu Zunji Ke Zhifei Wang Suppressing NK Cells by Astragaloside IV Protects Against Acute Ischemic Stroke in Mice Via Inhibiting STAT3 Frontiers in Pharmacology natural killer cells brain ischemia astragaloside IV oxygen-glucose deprivation signal transducer and activator of transcription 3 |
| title | Suppressing NK Cells by Astragaloside IV Protects Against Acute Ischemic Stroke in Mice Via Inhibiting STAT3 |
| title_full | Suppressing NK Cells by Astragaloside IV Protects Against Acute Ischemic Stroke in Mice Via Inhibiting STAT3 |
| title_fullStr | Suppressing NK Cells by Astragaloside IV Protects Against Acute Ischemic Stroke in Mice Via Inhibiting STAT3 |
| title_full_unstemmed | Suppressing NK Cells by Astragaloside IV Protects Against Acute Ischemic Stroke in Mice Via Inhibiting STAT3 |
| title_short | Suppressing NK Cells by Astragaloside IV Protects Against Acute Ischemic Stroke in Mice Via Inhibiting STAT3 |
| title_sort | suppressing nk cells by astragaloside iv protects against acute ischemic stroke in mice via inhibiting stat3 |
| topic | natural killer cells brain ischemia astragaloside IV oxygen-glucose deprivation signal transducer and activator of transcription 3 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.802047/full |
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