Fang Mei, Xia Fan, Teng Bang, Xia Wanting, Yang Yunfei, Wang Jiayan, Tao Chuanyuan, Hu Xin
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China.
West China School of Medicine, Sichuan University, Chengdu 610041, China.
Exp Neurol. 2025 Apr;386:115173. doi: 10.1016/j.expneurol.2025.115173. Epub 2025 Jan 31.
Previous studies have demonstrated the potent anti-inflammatory effects of RvE1 in various diseases, and recent research has shown that it can also promote macrophage phagocytosis. Given that hematoma clearance is crucial for intracerebral hemorrhage (ICH) treatment, while neuroinflammation significantly influences secondary injury, we hypothesize that RvE1/ChemR23 activation, by modulating the polarization of macrophages/microglia, promotes hematoma resolution and alleviates neuroinflammatory responses after ICH.
A total of 125 WT C57BL/6 and 67 ChemR23 male mice were used. Western blot and immunofluorescence staining assessed the temporal and spatial expression of ChemR23 after ICH. T2WI, T2*WI and behavioral tests were obtained to assess the protective effect of the RvE1/ChemR23 pathway in ICH. Additionally, co-staining of M1 (iNOS) or M2 polarization (Arg-1) markers with Iba-1 was used to explore the polarization status of macrophages/microglia in the perihematomal region. Finally, Akt phosphorylation was validated as a downstream mediator of the RvE1/ChemR23 pathway using an Akt inhibitor.
ChemR23 is mainly expressed in activated microglia and infiltrating macrophages, with expression peaking 5-7 days post-ICH. Activation of the RvE1/ChemR23 pathway promotes hematoma resolution, reduces brain edema, and improves neurological deficits in ICH. These effects are likely mediated by promoting M2 polarization of macrophages/microglia after ICH. Furthermore, the use of an Akt inhibitor can counteract the protective effects of RvE1 in ICH.
Our study provides the first evidence of the protective role of RvE1/ChemR23 signaling in ICH. This pathway might offer novel therapeutic targets for the clinical management of ICH.
先前的研究已证明RvE1在多种疾病中具有强大的抗炎作用，最近的研究表明它还能促进巨噬细胞吞噬作用。鉴于血肿清除对脑出血（ICH）治疗至关重要，而神经炎症会显著影响继发性损伤，我们推测RvE1/化学感受器23（ChemR23）激活通过调节巨噬细胞/小胶质细胞极化，促进血肿溶解并减轻脑出血后的神经炎症反应。
总共使用了125只野生型C57BL/6雄性小鼠和67只ChemR23雄性小鼠。采用蛋白质免疫印迹法和免疫荧光染色评估脑出血后ChemR23的时空表达。通过T2加权成像（T2WI）、T2加权成像（T2WI）和行为测试来评估RvE1/ChemR23通路对脑出血的保护作用。此外，用M1（诱导型一氧化氮合酶，iNOS）或M2极化（精氨酸酶-1，Arg-1）标志物与离子钙结合衔接分子1（Iba-1）共染色，以探究血肿周围区域巨噬细胞/小胶质细胞的极化状态。最后，使用Akt抑制剂验证Akt磷酸化作为RvE1/ChemR23通路的下游介质。
ChemR23主要表达于活化的小胶质细胞和浸润的巨噬细胞中，在脑出血后5-7天表达达到峰值。RvE1/ChemR23通路的激活促进血肿溶解，减轻脑水肿，并改善脑出血后的神经功能缺损。这些作用可能是通过促进脑出血后巨噬细胞/小胶质细胞的M2极化介导的。此外，使用Akt抑制剂可抵消RvE1对脑出血的保护作用。
我们的研究首次证明了RvE1/ChemR23信号在脑出血中的保护作用。该通路可能为脑出血的临床治疗提供新的治疗靶点。
