The skin is our outer permeability and immune defense barrier against myriad external assaults.Aryl hydrocarbon receptor(AhR)senses environmental factors and regulates barrier robustness and immune homeostasis.AhR ago...The skin is our outer permeability and immune defense barrier against myriad external assaults.Aryl hydrocarbon receptor(AhR)senses environmental factors and regulates barrier robustness and immune homeostasis.AhR agonists have been approved by the FDA for psoriasis treatment and are in clinical trials for the treatment of atopic dermatitis(AD),but the underlying mechanism of action remains poorly defined.Here,we report that OVOL1/Ovol1 is a conserved and direct transcriptional target of AhR in epidermal keratinocytes.We show that OVOL1/Ovol1 influences AhR-mediated regulation of keratinocyte gene expression and that OVOL1/Ovol1 ablation in keratinocytes impairs the barrier-promoting function of AhR,exacerbating AD-like inflammation.Mechanistically,we have identified Ovol1’s direct downstream targets genome-wide and provided in vivo evidence supporting the role of Id1 as a functional target in barrier maintenance,disease suppression,and neutrophil accumulation.Furthermore,our findings reveal that an IL-1/dermalγδT cell axis exacerbates type 2 and 3 immune responses downstream of barrier perturbation in Ovol1-deficient AD skin.Finally,we present data suggesting the clinical relevance of OVOL1 and ID1 functions in human AD skin.Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis in the context of skin inflammation,identifying new therapeutic targets.展开更多
基金support from the China Scholarship Council(Grant No.201906260233)support from the National Science Foundation(NSF)-Simons Predoctoral Fellowship(NSF grant DMS1763272 and Simons Foundation grant 594598)+7 种基金supported by the NIH T32 Immunology Research Training Grant(Al 060573)supported by NSF predoctoral fellowship DGE-1839285supported by grants from the National Natural Science Foundation of China(No.81872522,82073429,and 82430101)the Innovation Program of the Shanghai Municipal Education Commission(No.2019-01-07-00-07-E00046)supported by National Institutes of Health Grants R01-AR068074,R35-GM145307,U01-AR073159,P30-AR075047NSF grant DMS1763272Simons Foundation grant 594598UC Irvine Office of Research.
文摘The skin is our outer permeability and immune defense barrier against myriad external assaults.Aryl hydrocarbon receptor(AhR)senses environmental factors and regulates barrier robustness and immune homeostasis.AhR agonists have been approved by the FDA for psoriasis treatment and are in clinical trials for the treatment of atopic dermatitis(AD),but the underlying mechanism of action remains poorly defined.Here,we report that OVOL1/Ovol1 is a conserved and direct transcriptional target of AhR in epidermal keratinocytes.We show that OVOL1/Ovol1 influences AhR-mediated regulation of keratinocyte gene expression and that OVOL1/Ovol1 ablation in keratinocytes impairs the barrier-promoting function of AhR,exacerbating AD-like inflammation.Mechanistically,we have identified Ovol1’s direct downstream targets genome-wide and provided in vivo evidence supporting the role of Id1 as a functional target in barrier maintenance,disease suppression,and neutrophil accumulation.Furthermore,our findings reveal that an IL-1/dermalγδT cell axis exacerbates type 2 and 3 immune responses downstream of barrier perturbation in Ovol1-deficient AD skin.Finally,we present data suggesting the clinical relevance of OVOL1 and ID1 functions in human AD skin.Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis in the context of skin inflammation,identifying new therapeutic targets.
