Aryl hydrocarbon receptor mediates both proinflammatory and anti-inflammatory effects in lipopolysaccharide-activated microglia

Yi Hsuan Lee, Chun Hua Lin, Pei Chien Hsu, Yu Yo Sun, Yu Jie Huang, Jiun Horng Zhuo, Chen Yu Wang, Yu Ling Gan, Chia Chi Hung, Chia Yi Kuan, Feng Shiun Shie

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23 Citations (Scopus)

Abstract

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 Main Points: LPS upregulates and activates AhR in microglia. AhR mediates the LPS-induced pro-inflammatory responses in microglia and mouse brain. AhR ligand application shunts LPS-activated AhR to the anti-inflammatory mode involving AhR-NFκB crosstalk.

Original languageEnglish
Pages (from-to)1138-1154
Number of pages17
JournalGLIA
Volume63
Issue number7
DOIs
Publication statusPublished - Jul 1 2015
Externally publishedYes

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Keywords

  • Cytochrome P450 1A1
  • Inflammatory neurotoxicity
  • MEK1/2
  • NF kappaB
  • TNFalpha

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology
  • Medicine(all)

Cite this

Lee, Y. H., Lin, C. H., Hsu, P. C., Sun, Y. Y., Huang, Y. J., Zhuo, J. H., Wang, C. Y., Gan, Y. L., Hung, C. C., Kuan, C. Y., & Shie, F. S. (2015). Aryl hydrocarbon receptor mediates both proinflammatory and anti-inflammatory effects in lipopolysaccharide-activated microglia. GLIA, 63(7), 1138-1154. https://doi.org/10.1002/glia.22805