Annexin A1 protects against cerebral ischemia–reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway

Journal of Neuroinflammation

Weiwei Gao¹  Lei Li²  Jianning Zhang²  Fanjian Li²  Honglei Ren²  Dong Wang²  Jiheng Hao³  Jiyue Wang³  Liyong Zhang³  Meng Zhang³  Long Li⁴  Xin Xu⁴  Tao Wang⁴  Xuesong Bai⁴  Bin Yang⁴  Liqun Jiao⁵ 

[1] Department of Neurology, Tianjin Huanhu Hospital, 6 Jizhao Road, 300350, Tianjin, China;Department of Neurosurgery & Neurology, Tianjin Medical University General Hospital, 154 Anshan Road, 300052, Tianjin, China;Department of Neurosurgery, Liaocheng People’s Hospital, 67 Dongchang West Road, 252000, Liaocheng, China;Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, 100053, Beijing, China;China International Neuroscience Institute (China-INI), 45 Changchun Street, 100053, Beijing, China;Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, 100053, Beijing, China;China International Neuroscience Institute (China-INI), 45 Changchun Street, 100053, Beijing, China;Department of Interventional Neuroradiology, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, 100053, Beijing, China;

关键词: Cerebral ischemia-reperfusion injury;    Endovascular thrombectomy;    Neuroinflammation;    Microglial/macrophage polarization;    Annexin A1;    Formyl peptide receptor 2;   

DOI  :  10.1186/s12974-021-02174-3

来源: Springer

【 摘 要 】

BackgroundCerebral 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.MethodsWe 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.ResultsThe 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.ConclusionsAc2-26 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.

【 授权许可】

CC BY