- 期刊
芳香烴受體：免疫反應的環境感測器在缺血性腦中風的角色
The Aryl Hydrocarbon Receptor: An Environmental Sensor for Immune Response in Acute Ischemic Stroke
摘要
芳香烴受體（Aryl hydrocarbon receptor, AhR）又稱戴奧辛受體（dioxin receptor），為一種依賴配體活化的轉錄因子，可以被環境污染物如戴奧辛、或是飲食中色胺酸（tryptophan）及其代謝物等配體活化，然後從細胞質移入細胞核去控制基因的轉錄表達，參與代謝異生素、調控免疫反應和細胞複製分化。過去研究顯示AhR活化可能引發多發性硬化症和神經膠質瘤，使微小膠細胞、星狀膠細胞和巨噬細胞活化，在炎症和癌症起決定性作用。但AhR在急性缺血性中風的角色，如對神經發炎與神經細胞新生的作用機制仍屬未知。我們研究發現在急性缺血性中風的小鼠模型中，AhR會活化調控星狀膠細胞與神經幹細胞增生，藥物抑制AhR或在神經幹細胞條件式基因剔除AhR（conditional knockout for AhR in nestin-expressing neural stem/progenitor cells），會改善中風後上肢動作和記憶功能，並且有抗發炎和促進神經新生的治療潛力，這個結果提供缺血性中風一個新觀點，即在急性期抑制AhR可調控梗塞周圍的膠細胞活化及內生性神經幹細胞增生並影響預後。
關鍵字
無資料並列摘要
The aryl hydrocarbon receptor (AHR), also known as dioxin receptor, is a ligand-dependent transcription factor activated by environmental agonists like dioxins and dietary tryptophan metabolites. AHR activation leads to its translocation to the nucleus and control of the downstream gene transcription for xenobiotic metabolism, immune response and cell cycle regulation. Emerging evidence suggests that AHR activation may involve in multiple sclerosis and glioblastoma. The AHR signaling mediates reactivation of astrocytes, microglia and macrophages in inflammatory diseases and tumor formation. However, it is unknown whether AHR activation plays a role in post-stroke neuroinflammation and neurogenesis. We found that AHR activation following acute ischemic stroke mediates astrogliosis and neurogenesis, utilizing a mouse middle cerebral artery occlusion model in wild-type and neural cell-specific conditional knockout of AHR. Both AHR inhibition and neural cell-specific gene deletion significantly decreased infarct volume, and improved sensorimotor and nonspatial working memory functions in acute stroke mice. These results provide a new perspective on AHR-mediated ischemic brain injury. AHR inhibition in acute stroke may potentially benefit functional outcomes likely through reducing proinflammatory gliosis and preserving endogenous neurogenesis.