786 IL-4 stimulates IL-1R2 upregulation in atopic dermatitis keratinocytes

Immune dysregulation and a defective epidermal barrier drives the pathogenesis of atopic dermatitis (AD). The IL-1 signaling network plays a critical role in innate immunity, affecting skin barrier function and impacting on the pathogenesis of AD. We identified the upregulation of IL-1R2, an understudied IL-1 signaling pathway decoy receptor, in basal and differentiating keratinocytes with in vitro 3D skin models mimicking AD. IL-1R2 has previously been show to be upregulated in immune cells in AD patients however the relevance and function in the epidermis has not been reported before. To further investigate IL-1R2 in epidermal cells we stimulated skin explants with AD related cytokines (IL-4, IL-13, IL17A, IL-22 and TNF). qPCR and RNAScope indicated that gene expression of IL-1R2 increased when stimulated with IL-4. RNAScope of IL-4 stimulated explants also showed that IL-1R2 expression was specifically increased in the basal and differentiating keratinocytes within the stratum granulosum compared to control explants. Combined RNAScope-Immuno Histochemistry also showed an upregulation of IL-1R2 in epidermal Langerhans cells, indicating additional cellular contribution to IL-1R2 decoy activity within the epidermis. Additionally, we identified that IL-1R2 expression was increased in AD patients’ lesional epidermis compared to non-lesional epidermis and also observed increased expression in keratinocytes from publicly available scRNAseq AD datasets . These findings in patient samples corroborated our results from the IL-4 treated 3D keratinocyte and explant skin models. These results show that IL-4 stimulates IL-1R2 expression in epidermal keratinocytes that could account for the upregulation observed in patient lesional skin. The upregulation of IL-1R2 in AD would reduce IL-1 family signaling as a pathomechanism to control inflammation in lesional AD skin.