Abstract
Aryl hydrocarbon receptor (AhR) and autophagy reportedly regulate immune responses in the skin. This study explored the effects of AhR activation on autophagy in human keratinocytes, and the relevance of AhR and autophagy in psoriasis pathogenesis. AhR activation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) repressed autophagy, while autophagy inhibition induced AhR activation in HaCaT cells and normal human epidermal keratinocytes (NHEKs). A particularly strong interaction between AhR and autophagy was observed in proinflammatory cytokines-stimulated keratinocytes, an in vitro model of psoriasis. In skin biopsies from psoriasis patients, a similar impact of AhR on autophagy and inflammation was observed. AhR inhibition blocked TCDD- and chloroquine-induced p65NF-κB and p38MAPK phosphorylation in proinflammatory cytokines-stimulated HaCaT cells. Moreover, higher expression of AhR and CYP1A1, and lower expression of LC3, were detected in psoriatic skin tissues, compared to the controls. These data demonstrated that AhR modulated autophagy leads to skin inflammation in human keratinocytes via the p65NF-κB/p38MAPK signaling pathways, suggesting that AhR signaling and autophagy might be involved in the pathogenesis of chronic inflammatory disorders such as psoriasis.
Highlights
Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that binds to exogenous and endogenous chemicals and modulates the expression of several genes, with positive or negative effects in various organs, including the skin [1]
We evaluated whether AhR activation regulated autophagy, or vice versa, in human keratinocytes under inflammatory conditions, as well as in skin biopsies from psoriasis patients, and explored the influence of AhR and autophagy on inflammation in skin biopsies from psoriasis patients
HaCaT cells and normal human epidermal keratinocytes (NHEKs) were treated with different concentrations of TCDD (0, 0.1, 1, 10, and 100 nM), rapamycin (0, 50, 100, 150, and 200 nM) or chloroquine (0, 10, 20, 30, 40, and 50 μg/mL)
Summary
Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that binds to exogenous and endogenous chemicals and modulates the expression of several genes, with positive or negative effects in various organs, including the skin [1]. Many ligands, such as vitamin D3 hydroxyderivatives can act on AhR [2]. To verify the impact of environmental factors on psoriasis, we focused on AhR effects on autophagy To this end, we evaluated whether AhR activation regulated autophagy, or vice versa, in human keratinocytes under inflammatory conditions, as well as in skin biopsies from psoriasis patients, and explored the influence of AhR and autophagy on inflammation in skin biopsies from psoriasis patients. We further analyzed the expression levels of AhR, CYP1A1, and LC3 in psoriatic skin tissue
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