A role for arginase in skin epithelial differentiation and antimicrobial peptide production

A role for arginase in skin epithelial differentiation and antimicrobial peptide production

British Journal of Dermatology

10.1093/bjd/ljaf057

https://doi.org/10.1093/bjd/ljaf057

Denis C Szondi, Rachel A Crompton, Linus Oon, Nagavidya Subramaniam, Khek-Chian Tham, Sze Han Lee, Helen Williams, Joanne Pennock, Thiam C Lim, Carine Bonnard, Jason Wong, Leah A Vardy, Sheena M Cruickshank

Arginase, skin barrier, Antimicrobial peptides, polyamines

14 February 2025

Szondi, D. C., Crompton, R. A., Oon, L., Subramaniam, N., Tham, K.-C., Lee, S. H., Williams, H., Pennock, J., Lim, T. C., Bonnard, C., Wong, J., Vardy, L. A., & Cruickshank, S. M. (2025). A role for arginase in skin epithelial differentiation and antimicrobial peptide production. British Journal of Dermatology, 193(1), 125–135. https://doi.org/10.1093/bjd/ljaf057

Abstract 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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the Ministry of Health, National Medical Research Council - Open Fund - Individual Research Grant
Grant Reference no. : MOH-001217

https://oar.a-star.edu.sg/communities-collections/articles/22724

0007-0963
1365-2133

A*STAR Skin Research Labs

https://doi.org/10.1093/bjd/ljaf057