Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8521, Japan.
Laboratory for Pharmacotherapy and Experimental Neurology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa 769-2193, Japan.
Cells. 2021 Mar 24;10(4):718. doi: 10.3390/cells10040718.
Microglia are activated after ischemic stroke and induce neuroinflammation. The expression of the aryl hydrocarbon receptor (AhR) has recently been reported to elicit cytokine expression. We previously reported that microglial activation mediates ischemic edema progression. Thus, the purpose of this study was to examine the role of AhR in inflammation and edema after ischemia using a mouse middle cerebral artery occlusion (MCAO) model. MCAO upregulated AhR expression in microglia during ischemia. MCAO increased the expression of tumor necrosis factor α (TNFα) and then induced edema progression, and worsened the modified neurological severity scores, with these being suppressed by administration of an AhR antagonist, CH223191. In THP-1 macrophages, the NADPH oxidase (NOX) subunit p47phox was significantly increased by AhR ligands, especially under inflammatory conditions. Suppression of NOX activity by apocynin or elimination of superoxide by superoxide dismutase decreased TNFα expression, which was induced by the AhR ligand. AhR ligands also elicited p47phox expression in mouse primary microglia. Thus, p47phox may be important in oxidative stress and subsequent inflammation. In MCAO model mice, P47phox expression was upregulated in microglia by ischemia. Lipid peroxidation induced by MCAO was suppressed by CH223191. Taken together, these findings suggest that AhR in the microglia is involved in neuroinflammation and subsequent edema, after MCAO via p47phox expression upregulation and oxidative stress.
小胶质细胞在缺血性中风后被激活，并引发神经炎症。最近有报道称，芳香烃受体 (AhR) 的表达可引发细胞因子表达。我们之前报道过小胶质细胞的激活介导了缺血性水肿的进展。因此，本研究旨在使用小鼠大脑中动脉闭塞 (MCAO) 模型，研究 AhR 在缺血后炎症和水肿中的作用。MCAO 在缺血期间上调小胶质细胞中的 AhR 表达。MCAO 增加了肿瘤坏死因子 α (TNFα) 的表达，进而诱导水肿进展，并使改良神经严重程度评分恶化，而用 AhR 拮抗剂 CH223191 处理可抑制这些变化。在 THP-1 巨噬细胞中，AhR 配体特别在炎症条件下显著增加 NADPH 氧化酶 (NOX) 亚基 p47phox 的表达。apocynin 抑制 NOX 活性或超氧化物歧化酶消除超氧阴离子可降低 TNFα 的表达，而 AhR 配体可诱导 TNFα 的表达。AhR 配体也可在小鼠原代小胶质细胞中诱导 p47phox 的表达。因此，p47phox 在氧化应激和随后的炎症中可能很重要。在 MCAO 模型小鼠中，缺血可上调小胶质细胞中的 p47phox 表达。MCAO 引起的脂质过氧化反应可被 CH223191 抑制。综上所述，这些发现表明，MCAO 后，通过上调 p47phox 表达和氧化应激，小胶质细胞中的 AhR 参与了神经炎症和随后的水肿。
