OVOL1-mediated suppression of ID1 coordinately regulates skin barrier maintenance and neutrophil accumulation in atopic dermatitis-like skin inflammation

Summary: Abstract Body: Skin is our outer permeability and immune defense barrier against myriad external assaults. Dysregulation of skin barrier maintenance leads to various skin disorders, with atopic dermatitis (AD) being particularly prominent. Human OVOL1 encodes a zinc finger transcriptional repressor and has been identified by genome-wide association studies to be an AD risk locus. However, its role in AD pathology and the underlying mechanisms remain largely unexplored. Here, we identify Ovol1 as an evolutionarily conserved target of the barrier-protecting aryl hydrocarbon receptor pathway and show that its skin epithelia-specific knockout (SSKO) in mice impairs barrier maintenance during homeostasis. Additionally, this knockout exacerbates skin inflammation in an AD mouse model induced by exposure to house dust mites (HDM) and the Staphylococcus aureus-derived toxin, staphylococcal enterotoxin B (SEB), two environmental agents linked to human AD pathogenesis. Mechanistically, Ovol1 binds directly to the promoter region of the inhibitor of DNA binding 1 (Id1) gene, suppressing its expression in keratinocytes. Inhibition of Id1 by the small molecule AGX51 restores skin barrier function and reduces neutrophil accumulation in SSKO mice exposed to HDM and SEB. Notably, AGX51 administration decreases the expression of neutrophil chemoattractants, such as CXCL1 and CXCL2, in ex vivo human skin explants from healthy individuals treated with an inflammatory cytokine cocktail. Finally, we observe a reduction in OVOL1 expression and an increase in ID1 expression in the epidermis of human AD skin lesions. Taken together, our study highlights a keratinocyte-intrinsic OVOL1-ID1 regulatory axis that promotes both epidermal and immune homeostasis against skin inflammation, implicating new therapeutic targets. Zeyu Chen¹, Yuling Shi¹, Xing Dai² 1. Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China. 2. University of California Irvine, Irvine, CA, United States. Epidermal Structure and Barrier Function