Activated microglia-derived macrophage-like cells exacerbate brain edema after ischemic stroke correlate with astrocytic expression of aquaporin-4 and interleukin-1 alpha release
Activated microglia-derived macrophage-like cells exacerbate brain edema after ischemic stroke correlate with astrocytic expression of aquaporin-4 and interleukin-1 alpha release
复制标题
DOI：
10.1016/j.neuint.2020.104848
复制
发表时间：
2020-11-01
影响因子：
4.2
通讯作者：
Matsumoto, Hiroshi
中科院分区：
文献类型：
--
作者：
Murata, Yukie;Sugimoto, Kana;Matsumoto, Hiroshi
脑梗塞后的脑水肿影响活动能力和死亡率。这一过程背后的机制仍有待阐明。动物研究表明，中风后星形胶质细胞中水通道蛋白 4 (AQP4) 的表达增加，其缺失可显着减轻脑肿胀。最近，据报道，两种细胞，常驻小胶质细胞衍生的巨噬细胞样细胞（MG-M Phi）和骨髓衍生的巨噬细胞（BM-M Phi），在缺血核心积聚并刺激邻近的星形胶质细胞。因此，我们假设这些细胞在 AQP4 的表达中起着至关重要的作用，并最终导致脑水肿加剧。为了验证这一假设，我们使用短暂大脑中动脉闭塞的大鼠模型和大鼠星形胶质细胞原代培养物研究了 MG- 或 BM-M Phi 在脑水肿中的作用。再灌注后 3-7 天 (dpr) 的梗死周围组织以及 5 和 7 dpr 的核心组织中 AQP4 表达显着增加，与 Iba1、Il1a、Tnf 和 C1qa mRNA 的表达同步。白介素 (IL)-1 α 处理或与 MG- 和 BM-M Phi 共培养可增加星形胶质细胞中 AQP4 的表达，而 I 型 IL-1 受体拮抗剂可减少这些影响。此外，加重的动物在7天后缺血核心中表现出Aqp4和Il1a mRNA的高表达，这导致脑水肿加剧。 MG-M Phi 特征基因在加重大鼠的缺血核心中高表达，而 BM-M Phi 特征基因弱表达。这些发现表明，MG-M Phi 产生的 IL-1 α 会诱导梗死周围和缺血核心组织中星形胶质细胞 AQP4 的表达，从而加剧脑水肿。因此，调节MG-M Phi可能会阻止脑水肿的恶化。
Brain edema following brain infarction affects mobility and mortality. The mechanisms underlying this process remain to be elucidated. Animal studies have shown that aquaporin-4 (AQP4) expression in astrocytes increases after stroke, and its deletion significantly reduces brain swelling. Recently, two kinds of cells, resident microgliaderived macrophage-like cells (MG-M Phi) and bone marrow-derived macrophages (BM-M Phi), have been reported to accumulate in the ischemic core and stimulate adjacent astrocytes. Therefore, we hypothesized that these cells play crucial roles in the expression of AQP4 and ultimately lead to exacerbated brain edema. To verify this hypothesis, we investigated the role of MG- or BM-M Phi in brain edema using a rat model of transient middle cerebral artery occlusion and rat astrocyte primary cultures. AQP4 expression significantly increased in the periinfarct tissue at 3-7 days post-reperfusion (dpr) and in the core tissue at 5 and 7 dpr, which synchronized with the expression of Iba1, Il1a, Tnf, and C1qa mRNA. Interleukin (IL)-1 alpha treatment or coculture with MG- and BM-M Phi increased AQP4 expression in astrocytes, while an IL-1 receptor type I antagonist reduced these effects. Furthermore, aggravated animals exhibited high expression of Aqp4 and Il1a mRNA in the ischemic core at 7 dpr, which led to the exacerbation of brain edema. MG-M Phi signature genes were highly expressed in the ischemic core in aggravated rats, while BM-M Phi signature genes were weakly expressed. These findings suggest that IL-1 alpha produced by MG-M Phi induces astrocytic AQP4 expression in the peri-infarct and ischemic core tissues, thereby exacerbating brain edema. Therefore, the regulation of MG-M Phi may prevent the exacerbation of brain edema.