Rachel A. Crompton

Background: Arginase 1 (ARG1) is an enzyme expressed by keratinocytes that drives several functions linked to skin barrier function. However, the mechanisms underpinning keratinocyte ARG1 function in barrier homeostasis have not been fully elucidated. Atopic dermatitis (AD) is linked to impaired skin barrier via altered keratinocyte differentiation and susceptibility to infection. Objectives: To investigate the role of ARG1 in keratinocyte differentiation and antimicrobial responses. Methods: In vitro two-dimensional differentiation assays using ARG knockdown or ARG inhibited keratinocytes were used to explore the function of ARG1 in keratinocyte differentiation and barrier formation. ARG1 was also assessed in an ex vivo model of AD. Results: ARG1 was strongly expressed in the apical layers of human skin, corresponding to high ARG1 expression in late differentiated ­keratinocytes. ARG was downregulated in an ex vivo AD model relative to control, suggesting that altered ARG1 is clinically relevant. ARG1 ­inhibition in keratinocytes led to a significant decrease in the late differentiation markers filaggrin, involucrin and loricrin, and significant downregulation of antimicrobial peptides (AMPs), lipocalin 2, kallikreins and small proline-rich proteins. ARG forms part of the urea cycle and the action of ARG on L-arginine causes the production of L-ornithine and urea. In turn, L-ornithine is catabolized for putrescine production. Supplementation with ARG products, putrescine and urea could rescue late keratinocyte differentiation and AMP expression in ARG-deficient cells. Conclusions: ARG1 activity plays a major role in keratinocyte differentiation and AMP production. ARG1 is downregulated in an AD model, and in cell systems its function can be rescued by the ARG1 downstream products putrescine and urea. Manipulation of the ARG1 pathway may have the potential to be used for the management of skin conditions such as AD.