BackgroundPeroxiredoxin 2 (Prx2), an intracellular protein that regulates redox reactions, released from red blood cells is involved in inflammatory brain injury after intracerebral hemorrhage (ICH). Toll‐like receptor 4 (TLR4) may be crucial in this process. This study investigated the role of the Prx2‐TLR4 inflammatory axis in brain injury following experimental ICH in mice.MethodsFirst, C57BL/6 mice received an intracaudate injection of autologous arterial blood or saline and their brains were harvested on day 1 to measure Prx2 levels. Second, mice received an intracaudate injection of either recombinant mouse Prx2 or saline. Third, the mice were co‐injected with autologous arterial blood and conoidin A, a Prx2 inhibitor, or vehicle. Fourth, the mice received a Prx2 injection and were treated with TAK‐242, a TLR4 antagonist, or saline (intraperitoneally). Behavioral tests, magnetic resonance imaging, western blot, immunohistochemistry/immunofluorescence staining, and RNA sequencing (RNA‐seq) were performed.ResultsBrain Prx2 levels were elevated after autologous arterial blood injection. Intracaudate injection of Prx2 caused brain swelling, microglial activation, neutrophil infiltration, neuronal death, and neurological deficits. Co‐injection of conoidin A attenuated autologous arterial blood‐induced brain injury. TLR4 was expressed on the surface of microglia/macrophages and neutrophils and participated in Prx2‐induced inflammation. TAK‐242 treatment attenuated Prx2‐induced inflammation and neurological deficits.ConclusionsPrx2 can cause brain injury following ICH through the TLR4 pathway, revealing the Prx2‐TLR4 inflammatory axis as a potential therapeutic target.

中文翻译：

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脑出血引起的小鼠脑损伤：过氧化还原蛋白 2-Toll 样受体 4 炎症轴的作用

背景过氧化还原蛋白 2 (Prx2) 是一种调节氧化还原反应的细胞内蛋白，由红细胞释放，参与脑出血 (ICH) 后的炎症性脑损伤。 Toll 样受体 4 (TLR4) 可能在此过程中至关重要。本研究调查了 Prx2-TLR4 炎症轴在小鼠实验性 ICH 后脑损伤中的作用。方法首先，C57BL/6 小鼠接受自体动脉血或盐水尾状注射，并在第一天收获其大脑以测量 Prx2 水平。其次，小鼠尾状核注射重组小鼠 Prx2 或盐水。第三，给小鼠联合注射自体动脉血和 Conoidin A（一种 Prx2 抑制剂）或媒介物。第四，小鼠接受 Prx2 注射，并接受 TAK-242（一种 TLR4 拮抗剂）或盐水（腹膜内注射）治疗。进行了行为测试、磁共振成像、蛋白质印迹、免疫组织化学/免疫荧光染色和 RNA 测序 (RNA-seq)。结果自体动脉血注射后脑 Prx​​2 水平升高。尾皮质内注射 Prx2 会导致脑肿胀、小胶质细胞激活、中性粒细胞浸润、神经元死亡和神经功能缺损。联合注射Conoidin A 可减轻自体动脉血引起的脑损伤。 TLR4 在小胶质细胞/巨噬细胞和中性粒细胞表面表达，参与 Prx2 诱导的炎症。 TAK-242治疗减轻了Prx2诱导的炎症和神经功能缺损。结论Prx2可以通过TLR4途径引起ICH后的脑损伤，揭示Prx2-TLR4炎症轴作为潜在的治疗靶点。