Department of Neurological Surgery, Aichi Medical University Nagakute, Aichi, Japan.
High Technology Research Center, Pharmacology, Showa Pharmaceutical University, Machida, Tokyo, Japan.
PLoS One. 2020 Jun 1;15(6):e0233643. doi: 10.1371/journal.pone.0233643. eCollection 2020.
Chronic subdural hematoma (CSDH) is an angiogenic and inflammatory disease. Toll-like receptors (TLRs) transduce intracellular signals, resulting in the activation of nuclear factor κB (NF-κB), which leads to the production of inflammatory cytokines. High-mobility group box 1 (HMGB1) functions as a mediator of inflammatory responses through TLRs. In this study, we examined the expression of HMGB1 and components of the Toll-like receptor and NF-κB signaling pathways in the outer membrane of CSDH. Eight patients whose outer membrane was successfully obtained during trepanation surgery were included in this study. The expression of TLR4, myeloid differentiation factor 88 (MyD88), interleukin-1 receptor-associated kinase 4 (IRAK4), TNF receptor-associated factor 6 (TRAF6), TGFβ-activated kinase 1 (Tak1), interferon regulatory factors 3 (IRF3), IκB kinase β (IKKβ), IKKγ, IκBε, IκBα, NF-κB/p65 and β-actin was examined by Western blot analysis. The expression of TLR4, NF-κB/p65 and interleukin-6 (IL-6) was also examined by immunohistochemistry. The concentrations of HMGB1 and IL-6 in CSDH fluids were measured using ELISA kits. Above-mentioned molecules were detected in all cases. In addition, TLR4, NF-κB/p65 and IL-6 were localized in the endothelial cells of vessels within CSDH outer membranes. The concentrations of HMGB1 and IL-6 in CSDH fluids were significantly higher than that in the CSF and serum. There existed a correlation between the concentrations of HMGB1 and IL-6 in CSDH fluids. Our data suggest that HMGB1 in CSDH fluids produces the inflammatory cytokine IL-6 in endothelial cells through the Toll-like receptor and NF-κB signaling pathways. Anti-HMGB1 therapy might be a useful method to treat the growth of CSDH.
慢性硬脑膜下血肿（CSDH）是一种血管生成和炎症性疾病。Toll 样受体（TLRs）转导细胞内信号，导致核因子κB（NF-κB）的激活，从而导致炎症细胞因子的产生。高迁移率族蛋白 B1（HMGB1）通过 TLR 作为炎症反应的介质发挥作用。在这项研究中，我们检查了 CSDH 外膜中 HMGB1 及 Toll 样受体和 NF-κB 信号通路成分的表达。本研究纳入了 8 例在颅骨钻孔手术中成功获得外膜的患者。通过 Western blot 分析检查了 TLR4、髓样分化因子 88（MyD88）、白细胞介素 1 受体相关激酶 4（IRAK4）、肿瘤坏死因子受体相关因子 6（TRAF6）、TGFβ 激活激酶 1（Tak1）、干扰素调节因子 3（IRF3）、IκB 激酶β（IKKβ）、IKKγ、IκBε、IκBα、NF-κB/p65 和 β-肌动蛋白的表达。通过免疫组织化学检查了 TLR4、NF-κB/p65 和白细胞介素 6（IL-6）的表达。通过 ELISA 试剂盒测量了 CSDH 液中 HMGB1 和 IL-6 的浓度。所有病例均检测到上述分子。此外，TLR4、NF-κB/p65 和 IL-6 定位于 CSDH 外膜中血管的内皮细胞中。CSDH 液中 HMGB1 和 IL-6 的浓度明显高于 CSF 和血清中的浓度。CSDH 液中 HMGB1 和 IL-6 的浓度之间存在相关性。我们的数据表明，CSDH 液中的 HMGB1 通过 Toll 样受体和 NF-κB 信号通路在血管内皮细胞中产生炎症细胞因子 IL-6。抗 HMGB1 治疗可能是治疗 CSDH 生长的一种有用方法。
