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 language | English |
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Pages (from-to) | 1138-1154 |
Number of pages | 17 |
Journal | GLIA |
Volume | 63 |
Issue number | 7 |
DOIs | |
Publication status | Published - Jul 1 2015 |
Externally published | Yes |
Keywords
- Cytochrome P450 1A1
- Inflammatory neurotoxicity
- MEK1/2
- NF kappaB
- TNFalpha
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Neurology
- General Medicine