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Annexin A1 protects against cerebral ischemia-reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway.
Xu, Xin; Gao, Weiwei; Li, Lei; Hao, Jiheng; Yang, Bin; Wang, Tao; Li, Long; Bai, Xuesong; Li, Fanjian; Ren, Honglei; Zhang, Meng; Zhang, Liyong; Wang, Jiyue; Wang, Dong; Zhang, Jianning; Jiao, Liqun.
Afiliação
  • Xu X; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China. xuxindoc@hotmail.com.
  • Gao W; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, 100053, China. xuxindoc@hotmail.com.
  • Li L; Department of Neurology, Tianjin Huanhu Hospital, 6 Jizhao Road, Tianjin, 300350, China. hongw1980@hotmail.com.
  • Hao J; Department of Neurosurgery & Neurology, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, China.
  • Yang B; Department of Neurosurgery, Liaocheng People's Hospital, 67 Dongchang West Road, Liaocheng, 252000, China.
  • Wang T; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China.
  • Li L; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, 100053, China.
  • Bai X; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China.
  • Li F; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, 100053, China.
  • Ren H; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China.
  • Zhang M; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, 100053, China.
  • Zhang L; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China.
  • Wang J; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, 100053, China.
  • Wang D; Department of Neurosurgery & Neurology, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, China.
  • Zhang J; Department of Neurosurgery & Neurology, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, China.
  • Jiao L; Department of Neurosurgery, Liaocheng People's Hospital, 67 Dongchang West Road, Liaocheng, 252000, China.
J Neuroinflammation ; 18(1): 119, 2021 May 22.
Article em En | MEDLINE | ID: mdl-34022892
BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury is a major cause of early complications and unfavorable outcomes after endovascular thrombectomy (EVT) therapy in patients with acute ischemic stroke (AIS). Recent studies indicate that modulating microglia/macrophage polarization and subsequent inflammatory response may be a potential adjunct therapy to recanalization. Annexin A1 (ANXA1) exerts potent anti-inflammatory and pro-resolving properties in models of cerebral I/R injury. However, whether ANXA1 modulates post-I/R-induced microglia/macrophage polarization has not yet been fully elucidated. METHODS: We retrospectively collected blood samples from AIS patients who underwent successful recanalization by EVT and analyzed ANXA1 levels longitudinally before and after EVT and correlation between ANXA1 levels and 3-month clinical outcomes. We also established a C57BL/6J mouse model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) and an in vitro model of oxygen-glucose deprivation and reoxygenation (OGD/R) in BV2 microglia and HT22 neurons to explore the role of Ac2-26, a pharmacophore N-terminal peptide of ANXA1, in regulating the I/R-induced microglia/macrophage activation and polarization. RESULTS: The baseline levels of ANXA1 pre-EVT were significantly lower in 23 AIS patients, as compared with those of healthy controls. They were significantly increased to the levels found in controls 2-3 days post-EVT. The increased post-EVT levels of ANXA1 were positively correlated with 3-month clinical outcomes. In the mouse model, we then found that Ac2-26 administered at the start of reperfusion shifted microglia/macrophage polarization toward anti-inflammatory M2-phenotype in ischemic penumbra, thus alleviating blood-brain barrier leakage and neuronal apoptosis and improving outcomes at 3 days post-tMCAO/R. The protection was abrogated when mice received Ac2-26 together with WRW4, which is a specific antagonist of formyl peptide receptor type 2/lipoxin A4 receptor (FPR2/ALX). Furthermore, the interaction between Ac2-26 and FPR2/ALX receptor activated the 5' adenosine monophosphate-activated protein kinase (AMPK) and inhibited the downstream mammalian target of rapamycin (mTOR). These in vivo findings were validated through in vitro experiments. CONCLUSIONS: Ac2-26 modulates microglial/macrophage polarization and alleviates subsequent cerebral inflammation by regulating the FPR2/ALX-dependent AMPK-mTOR pathway. It may be investigated as an adjunct strategy for clinical prevention and treatment of cerebral I/R injury after recanalization. Plasma ANXA1 may be a potential biomarker for outcomes of AIS patients receiving EVT.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Traumatismo por Reperfusão / Diferenciação Celular / Anexina A1 / Microglia / Infarto da Artéria Cerebral Média / Serina-Treonina Quinases TOR / Macrófagos Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Neuroinflammation Assunto da revista: NEUROLOGIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Traumatismo por Reperfusão / Diferenciação Celular / Anexina A1 / Microglia / Infarto da Artéria Cerebral Média / Serina-Treonina Quinases TOR / Macrófagos Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Neuroinflammation Assunto da revista: NEUROLOGIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: China