UBE2N is essential for maintenance of skin homeostasis and suppression of inflammation

Abstract

ABSTRACTUBE2N, a Lys63-ubiquitin conjugating enzyme, plays critical roles in embryogenesis and immune system development and function. However, its roles in adult epithelial tissue homeostasis and pathogenesis are unclear. We generated conditional mouse models that deletedUbe2nin skin cells in a temporally and spatially controlled manner. We found thatUbe2n-knockout (KO) in the adult skin keratinocytes induced a range of inflammatory skin defects characteristic of psoriatic and actinic keratosis. These included eczematous inflammation, epidermal and dermal thickening, parakeratosis, and increased immune cell infiltration, as well as signs of edema and blistering. Single cell transcriptomic analyses and RT-qPCR showed thatUbe2nKO keratinocytes expressed elevated myeloid cell chemo-attractants such asCxcl1andCxcl2and decreased the homeostatic T lymphocyte chemo-attractant,Ccl27a. Consistently, the infiltrating immune cells ofUbe2n-KO skin were predominantly myeloid-derived cells including neutrophils and M1-like macrophages that were highly inflammatory, as indicated by expression ofIl1βandIl24.Pharmacological blockade of the IL-1 receptor associated kinases (IRAK1/4) alleviated eczema, epidermal and dermal thickening, and immune infiltration of theUbe2nmutant skin. Together, these findings highlight a key role of keratinocyte-UBE2N in maintenance of epidermal homeostasis and skin immunity and identify IRAK1/4 as potential therapeutic target for inflammatory skin disorders.