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Aryl hydrocarbon receptor mediates both proinflammatory and anti‐inflammatory effects in lipopolysaccharide‐activated microglia
Author(s) -
Lee YiHsuan,
Lin ChunHua,
Hsu PeiChien,
Sun YuYo,
Huang YuJie,
Zhuo JiunHorng,
Wang ChenYu,
Gan YuLing,
Hung ChiaChi,
Kuan ChiaYi,
Shie FengShiun
Publication year - 2015
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22805
Subject(s) - aryl hydrocarbon receptor , microglia , neuroinflammation , proinflammatory cytokine , lipopolysaccharide , tumor necrosis factor alpha , biology , microbiology and biotechnology , nitric oxide synthase , nitric oxide , neurotoxicity , inflammation , immunology , chemistry , endocrinology , transcription factor , biochemistry , gene , organic chemistry , toxicity
The aryl hydrocarbon receptor (AhR) regulates peripheral immunity; but its role in microglia‐mediated neuroinflammation in the brain remains unknown. Here, we demonstrate that AhR mediates both anti‐inflammatory and proinflammatory effects in lipopolysaccharide (LPS)‐activated microglia. Activation of AhR by its ligands, formylindolo[3,2‐b]carbazole (FICZ) or 3‐methylcholanthrene (3MC), attenuated LPS‐induced microglial immune responses. AhR also showed proinflammatory effects, as evidenced by the findings that genetic silence of AhR ameliorated the LPS‐induced microglial immune responses and LPS‐activated microglia‐mediated neurotoxicity. Similarly, LPS‐induced expressions of tumor necrosis factor α (TNFα) and inducible nitric oxide synthase (iNOS) were reduced in the cerebral cortex of AhR‐deficient mice. Intriguingly, LPS upregulated and activated AhR in the absence of AhR ligands via the MEK1/2 signaling pathway, which effects were associated with a transient inhibition of cytochrome P450 1A1 (CYP1A1). Although AhR ligands synergistically enhance LPS‐induced AhR activation, leading to suppression of LPS‐induced microglial immune responses, they cannot do so on their own in microglia. Chromatin immunoprecipitation results further revealed that LPS‐FICZ co‐treatment, but not LPS alone, not only resulted in co‐recruitment of both AhR and NFκB onto the κB site of TNFα gene promoter but also reduced LPS‐induced AhR binding to the DRE site of iNOS gene promoter. Together, we provide evidence showing that microglial AhR, which can be activated by LPS, exerts bi‐directional effects on the regulation of LPS‐induced neuroinflammation, depending on the availability of external AhR ligands. These findings confer further insights into the potential link between environmental factors and the inflammatory brain disorders. GLIA 2015;63:1138–1154