Department of Internal Neurology, No.215 Hospital of Shaanxi Nuclear Industry, Xianyang 712000, China.
Department of Internal Neurology, No.215 Hospital of Shaanxi Nuclear Industry, Xianyang 712000, China.
Biochem Biophys Res Commun. 2018 Dec 9;507(1-4):43-50. doi: 10.1016/j.bbrc.2018.10.141. Epub 2018 Nov 16.
Intracerebral hemorrhage (ICH) is reported as a common and often fatal type of stroke accompanied with high morbidity and mortality, and it frequently results in long-lasting neurological dysfunctions. However, the pathogenesis that contributes to ICH has not been fully understood. Rnf112, also known as Znf179, is a member of the RING finger protein family. The expression of Rnf112 is abundant in the brain and is modulated during brain progression and development. The study aimed to explore the role of Rnf112 in brain injury after ICH, as well as the underlying molecular mechanisms. The results indicated that ICH led to a significant decrease in Rnf112, which was confirmed in oxyhemoglobin (oxyHb)-incubated astrocytes and microglial cells. Moreover, the Rnf112 knockout (Rnf112) mice and wild type (WT) mice induced by ICH were further employed. Compared to the WT/ICH group, Rnf112 mice exhibited accelerated brain injury, as evidenced by the increased brain water contents and neurological deficit scores (NDS). In comparison to WT/ICH group, a remarkable up-regulation in the release of pro-inflammatory cytokines, including tumor necrotic factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β, was observed in perihematoma tissues of Rnf112 mice on day 3 post-ICH. The process was along with promoted glial fibrillary acidic protein (GFAP) and Iba1 expression and reduced NeuN levels. Furthermore, ICH-induced increases in toll-like receptor (TLR)-4 and myeloid differentiation primary response protein (MyD88) expression were exacerbated by the loss of Rnf112. The phosphorylated expression of IKKα, inhibitor of NF-κB (IκBα) and nuclear factor-kappa B (NF-κB) induced by ICH in perihematoma tissues of mice was markedly enhanced in Rnf112 mice. Rnf112 repression-induced inflammatory response was verified in lipopolysaccharide (LPS)-incubated glial cells. In contrast, over-expressing Rnf112 markedly attenuated ICH-induced brain injury by restraining inflammation via inactivating TLR-4/NF-κB pathway. In summary, our findings suggested that Rnf112 expression was highly involved in the progression of ICH, and targeting Rnf112 signaling might be a promising therapeutic strategy against ICH development.
脑出血 (ICH) 是一种常见且常致命的中风类型，伴有高发病率和死亡率，并经常导致持久的神经功能障碍。然而，导致 ICH 的发病机制尚未完全了解。Rnf112，也称为 Znf179，是 RING 指蛋白家族的成员。Rnf112 在大脑中的表达丰富，并在大脑发育过程中进行调节。该研究旨在探讨 Rnf112 在 ICH 后脑损伤中的作用以及潜在的分子机制。结果表明，ICH 导致 Rnf112 显著减少，这在氧合血红蛋白 (oxyHb) 孵育的星形胶质细胞和小胶质细胞中得到证实。此外，还进一步使用了 ICH 诱导的 Rnf112 敲除 (Rnf112) 小鼠和野生型 (WT) 小鼠。与 WT/ICH 组相比，Rnf112 小鼠的脑损伤加速，表现为脑含水量和神经功能缺损评分 (NDS) 增加。与 WT/ICH 组相比，ICH 后第 3 天，Rnf112 小鼠的血肿周围组织中促炎细胞因子（包括肿瘤坏死因子-α (TNF-α)、白细胞介素-6 (IL-6) 和白细胞介素-1β）的释放明显上调。胶质纤维酸性蛋白 (GFAP) 和 Iba1 表达增加，NeuN 水平降低。此外，ICH 诱导的 Toll 样受体 (TLR)-4 和髓样分化初级反应蛋白 (MyD88) 表达增加在 Rnf112 缺失时加剧。ICH 在小鼠血肿周围组织中诱导的 IKKα、NF-κB 抑制蛋白 (IκBα) 和核因子-κB (NF-κB) 的磷酸化表达在 Rnf112 小鼠中明显增强。在脂多糖 (LPS) 孵育的神经胶质细胞中验证了 Rnf112 抑制诱导的炎症反应。相反，过表达 Rnf112 通过抑制 TLR-4/NF-κB 通路显著减轻 ICH 引起的脑损伤，从而抑制炎症反应。总之，我们的研究结果表明，Rnf112 的表达高度参与了 ICH 的进展，针对 Rnf112 信号可能是一种有前途的治疗 ICH 发展的策略。
