Post-stroke DHA Treatment Protects Against Acute Ischemic Brain Injury by Skewing Macrophage Polarity Toward the M2 Phenotype
Post-stroke DHA Treatment Protects Against Acute Ischemic Brain Injury by Skewing Macrophage Polarity Toward the M2 Phenotype
复制标题
中风后 DHA 治疗通过将巨噬细胞极性偏向 M2 表型来预防急性缺血性脑损伤
DOI：
10.1007/s12975-018-0662-7
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发表时间：
2018-12-01
影响因子：
6.9
通讯作者：
Lu, Zhengqi
中科院分区：
文献类型：
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作者：
Cai, Wei;Liu, Sanxin;Lu, Zhengqi
全身性二十二碳六烯酸（DHA）已被探索为中风模型中临床可行的保护剂。然而，DHA提供神经保护的机制仍然难以捉摸。诱导短暂性大脑中动脉闭塞（tMCAO）1 h。DHA（i.p.，10 mg/kg），每天重复3天。卒中后3天评估卒中结局、全身炎症状态和小胶质细胞/巨噬细胞表型改变。通过注射氯膦酸盐脂质体诱导巨噬细胞耗竭。原代巨噬细胞培养物用于评估DHA对巨噬细胞的直接作用。我们证明，卒中后注射DHA有效地减少了脑梗死，并改善了tMCAO后3天的神经功能缺损。全身DHA治疗显著抑制免疫细胞浸润（巨噬细胞、中性粒细胞、T淋巴细胞和B淋巴细胞），并促进缺血性脑中巨噬细胞向抗炎M2表型极化。同时，全身DHA给药抑制了血液中升高的促炎因子，并在缺血性卒中后将循环巨噬细胞极性向M2表型转移。然而，DHA和溶剂处理组之间血液和脾脏中循环免疫细胞的数量是相等的。DHA的保护作用是巨噬细胞依赖性的，因为巨噬细胞耗竭消除了DHA提供的神经保护作用。体外研究证实，DHA抑制炎症刺激下巨噬细胞产生趋化因子和促炎细胞因子。这些数据表明，中风后DHA治疗以巨噬细胞依赖性方式改善急性缺血性脑损伤，并且DHA增强了巨噬细胞表型向抗炎表型的转变，以减少中风后的中枢和外周炎症。
Systemic docosahexaenoic acid (DHA) has been explored as a clinically feasible protectant in stroke models. However, the mechanism for DHA-afforded neuroprotection remains elusive. Transient middle cerebral artery occlusion (tMCAO) was induced for 1 h. DHA (i.p., 10 mg/kg) was administered immediately after reperfusion and repeated daily for 3 days. Stroke outcomes, systemic inflammatory status, and microglia/macrophage phenotypic alterations were assessed 3 days after stroke. Macrophage depletion was induced by clodronate liposomes injection. Primary macrophage cultures were used to evaluate the direct effect of DHA on macrophages. We demonstrated that post-stroke DHA injection efficiently reduced brain infarct and ameliorated neurological deficits 3 days after tMCAO. Systemic DHA treatment significantly inhibited immune cell infiltration (macrophages, neutrophils, T lymphocytes, and B lymphocytes) and promoted macrophage polarization toward an anti-inflammatory M2 phenotype in the ischemic brain. Meanwhile, systemic DHA administration inhibited the otherwise elevated pro-inflammatory factors in blood and shifted circulating macrophage polarity toward M2 phenotype after ischemic stroke. The numbers of circulating immune cells in blood and spleen, however, were equivalent between DHA- and vehicle-treated groups. The protective effects of DHA were macrophage-dependent, as macrophage depletion abolished DHA-afforded neuroprotection. In vitro studies confirmed that DHA suppressed production of chemokines and pro-inflammatory cytokines from macrophages under inflammatory stimulation. These data indicate that post-stroke DHA treatment ameliorated acute ischemic brain injury in a macrophage-dependent manner and DHA enhanced macrophage phenotypic shift toward an anti-inflammatory phenotype to reduced central and peripheral inflammation after stroke.