title: Aryl hydrocarbon receptor mediates both proinflammatory and anti-inflammatory effects in lipopolysaccharide-activated microglia.
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.
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan; Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Lee
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Lin
authors.forename: Pei-Chien
authors.initials: PC
authors.lastname: Hsu
authors.forename: Yu-Yo
authors.initials: YY
authors.lastname: Sun
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Huang
authors.forename: Jiun-Horng
authors.initials: JH
authors.lastname: Zhuo
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Wang
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Gan
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Hung
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Kuan
authors.forename: Feng-Shiun
authors.initials: FS
authors.lastname: Shie
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000276:immunology; D002843:Chromatin / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008070:Lipopolysaccharides; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D019363:Cytochrome P-450 CYP1A1; D008070:Lipopolysaccharides; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D052247:Nitric Oxide Synthase Type II; D018336:Receptors, Aryl Hydrocarbon; D014409:Tumor Necrosis Factor-alpha; C484722:Ahr protein, mouse; C496317:Nos2 protein, mouse; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse
keywords: MEK1/2; NF kappaB; TNFalpha; cytochrome P450 1A1; inflammatory neurotoxicity