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.
Mammalian Eag1 (Kv10.1) potassium (K+) channels are widely expressed in the brain. Several mutations in the gene encoding human Eag1 K+ channel have been associated with congenital neurodevelopmental anomalies. Currently very little is known about the molecules mediating protein synthesis and degradation of Eag1 channels. Herein we aim to ascertain the protein degradation mechanism of rat Eag1 (rEag1). We identified cullin 7 (Cul7), a member of the cullin-based E3 ubiquitin ligase family, as a novel rEag1 binding partner. Immunoprecipitation analyses confirmed the interaction between Cul7 and rEag1 in heterologous cells and neuronal tissues. Cul7 and rEag1 also exhibited significant co-localization at synaptic regions in neurons. Over-expression of Cul7 led to reduced protein level, enhanced ubiquitination, accelerated protein turn-over, and decreased current density of rEag1 channels. We provided further biochemical and morphological evidence suggesting that Cul7 targeted endoplasmic reticulum (ER)- and plasma membrane-localized rEag1 to the proteasome and the lysosome, respectively, for protein degradation. Cul7 also contributed to protein degradation of a disease-associated rEag1 mutant. Together, these results indicate that Cul7 mediates both proteasomal and lysosomal degradations of rEag1. Our findings provide a novel insight to the mechanisms underlying ER and peripheral protein quality controls of Eag1 channels.
Problem: 11β-Hydroxysteroid dehydrogenase 2 (11β-HSD2) catalyzes active glucocorticoids into their inactive products, preventing the passage of glucocorticoids into the fetus from maternal circulation. Peroxisome proliferator-activated receptor (PPAR)γ is a member of the nuclear receptor superfamily that regulates the expression of placental 11β-HSD2. Nuclear factor-kappa B (NF-κB) is a transcription factor that regulates inflammatory signaling. This study aimed to investigate the association among 11β-HSD2, PPAR-γ, and NF-κB p65 in small-for-gestational-age (SGA) infants.
Method of study:Forty-six SGA and 46 appropriate-for-gestational-age (AGA) infants were enrolled in this study. Both newborns and placentas were weighed.Placental 11β-HSD2 levels were measured using Western blotting. Placental PPAR-γ and NF-κB p65 were detected by immunohistochemistry. Placental inflammatory cytokines were evaluated by real-time RT-PCR.Results: 11β-HSD2 levels were lower in SGA placentas than those in AGA placentas.Placental PPAR-γ-positive nuclei were less in SGA than those in AGA. By contrast, placental NF-κB p65-positive nuclei were more in SGA than those in AGA. The levels of CRP, , several inflammatory cytokines, were higher in SGA placentas. Correlation analysis showed that neonatal weight was positively associated with PPAR-γ and 11β-HSD2 in SGA placentas. By contrast, neonatal weight was inversely correlated with NF-κB p65 in SGA placentas. 11β-HSD2 was positively correlated with PPAR-γ in SGA placentas.
The original version of this article unfortunately contained a mistake in Fig. 7d. The authors observed that the image of the GFAP/DAPI in the saline-treated wild type mice (WT Saline) was inadvertently rotated left 90-degree by mistake. The corrected representative image is given below. This correction does not change the values of quantification and the text of the figure legend, results, discussion, and conclusion. We apologize for any confusion caused to the readers.
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