- 學位論文
芳香烴受體在微小膠細胞活化過程中所扮演的角色
Roles of Aryl Hydrocarbon Receptor in Microglial Activation
摘要
芳香烴受體 (aryl hydrocarbon receptor, AhR) 是一種經由配體活化的轉錄因子，參與調控體內對於存在於環境污染物以及生物體內芳香碳氫化合物的代謝作用。近來研究指出，在巨噬細胞中，芳香烴受體能負調控脂多醣 （LPS） 所誘導的發炎反應。而微小膠細胞 (microglia) 是中樞神經系統中主要的免疫細胞，負責清除環境中的有害物以及受損的組織。本論文研究旨在探討 AhR 如何調控因發炎性及興奮性毒性刺激誘導，所造成的 microglia 活化。研究結果中發現給予 AhR 的外生性配體-3-methylcholanthrene (3-MC) 能夠降低 LPS 誘導的 inducible nitric oxide synthases (iNOS) mRNA 表現，但對於興奮性刺激 glutamate 所誘導的 iNOS2 表現則沒有顯著影響。此外， 3-MC 亦會抑制 LPS 以及 glutamate 所誘導的iNOS表現，且以小干擾核醣核酸 (siRNA) 專一性的降低 AhR 表現，會造成 microglia 對 LPS 所誘發的 iNOS表現反應增加並減少3-MC 抑制 LPS 以及 glutamate 所誘導之 iNOS表現的程度。另一方面，我們發現 LPS 及 glutamate 會抑制 AhR mRNA 的表現，增加 AhR 蛋白質的表現。更進一步地，我們發現 LPS 在沒有 AhR 配體的存在下，即可活化 AhR ，並且促使 AhR 累積在 microglia 的細胞核中，進而抑制 AhR mRNA 的表現。這些結果不僅顯示 LPS 以及 glutamate 所誘導的 microglia 過度活化，能夠透過 AhR 而抑制，更指出這些刺激來源能夠透過改變 microglia 的 AhR 表現量，進而影響其對於中樞神經系統發炎反應的調控過程。
並列摘要
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates xenobiotic responses to a variety of aromatic hydrocarbons present in the environmental pollutant or in the internal organism. Recent, studies show that AhR negatively regulates the lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Microglia are the major resident immune cells of the CNS and survey the microenvironment for noxious agents or injurious processes. Therefore, we aim to investigate how AhR regulates the activation of microglia upon inflammatory and excitotoxic glutamate insults. We found that treatment with an AhR exogenous ligands 3-methylcholanthrene (3-MC) down-regulates LPS-induced, but not glutmate-induced inducible nitric oxide synthases (iNOS) mRNA expression, whereas the protein levels of LPS- and glutamate-induced iNOS were both suppressed by 3-MC. Furthermore, we found that the AhR mRNA expression was obviously decreased by both LPS and glutamate treatment, but the AhR protein levels were increased by LPS and glutamate treatment. Moreover, we found that LPS activates and accumulates AhR in the nucleus of microglia. These results not only suggest that AhR downregulates the LPS- and glutamate-induced over-activation of microglia, but also indicate that these insults could change the setting of the microglial AhR level for the regulation of subsequent inflammatory processes in the central nervous system.