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 microglia-derived macrophage-like cells (MG-MΦ) and bone marrow-derived macrophages (BM-MΦ), 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-MΦ in brain edema using a rat model of transient middle cerebral artery occlusion and rat astrocyte primary cultures. AQP4 expression significantly increased in the peri-infarct 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)-1α treatment or coculture with MG- and BM-MΦ 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-MΦ signature genes were highly expressed in the ischemic core in aggravated rats, while BM-MΦ signature genes were weakly expressed. These findings suggest that IL-1α produced by MG-MΦ induces astrocytic AQP4 expression in the peri-infarct and ischemic core tissues, thereby exacerbating brain edema. Therefore, the regulation of MG-MΦ may prevent the exacerbation of brain edema.

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，据报道有两种细胞，驻留小胶质细胞衍生的巨噬细胞样细胞 (MG-MΦ) 和骨髓衍生的巨噬细胞 (BM-MΦ)，在缺血核心中积累并刺激邻近的星形胶质细胞。因此，我们假设这些细胞在 AQP4 的表达中起关键作用，并最终导致脑水肿加剧。为了验证这一假设，我们使用暂时性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-MΦ 在脑水肿中的作用。Iba1、Il1a、Tnf和C1qa mRNA。白细胞介素 (IL)-1α 处理或与 MG- 和 BM-MΦ 共培养增加了星形胶质细胞中 AQP4 的表达，而 IL-1 受体 I 型拮抗剂降低了这些影响。此外，加重的动物表现出Aqp4和Il1a 的高表达7 dpr 时缺血核心中的 mRNA，导致脑水肿加重。MG-MΦ特征基因在加重大鼠缺血核心高表达，而BM-MΦ特征基因弱表达。这些发现表明 MG-MΦ 产生的 IL-1α 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，MG-MΦ的调节可以防止脑水肿的恶化。