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. 2025 Jun 20;193(1):125-135.
doi: 10.1093/bjd/ljaf057.

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

Denis C Szondi  1   2 , Rachel A Crompton  1 , Linus Oon  2 , Nagavidya Subramaniam  2 , Khek-Chian Tham  2 , Sze Han Lee  2 , Helen Williams  1 , Joanne Pennock  1 , Thiam C Lim  3 , Carine Bonnard  2   3   4 , Jason Wong  5 , Leah A Vardy  2 , Sheena M Cruickshank  1
Affiliations

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

Denis C Szondi et al. Br J Dermatol. .

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.

Plain language summary

Atopic dermatitis (‘AD’ for short) is a common skin condition. AD causes problems with the skin barrier (known as the ‘epidermis’). These problems can lead to infections that worsen symptoms. A healthy skin barrier involves a balance between cells multiplying (‘proliferating’) and changing their function (‘differentiating’). A key feature of AD is a disruption of this balance. A protein called arginase (or ‘ARG’) could control this process, as it influences skin barrier regulation and damage repair. This study was done in the UK and the Singapore A*STAR Skin Research Labs. It aimed to investigate the role of ARG in the skin barrier. We examined the function of ARG using laboratory techniques and analysing human skin samples. The largest amount of ARG was found in the top layers of human skin. In culture, the amount of ARG increased as the skin cells changed function. A larger amount of ARG increased the amount of some other proteins that help protect the upper layers of the skin barrier. ARG also increased the amount of antimicrobial proteins in the skin. Together, this suggests that ARG is involved in how the skin barrier works and its defence against microbes. Importantly, cells without ARG activity worked normally. This study identifies a role for ARG in the antimicrobial function of skin and promoting the differentiation of skin barrier cells. As the amount of ARG produced in people with AD is less, controlling the activity of ARG might help in the treatment of AD.

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Conflict of interest statement

Conflicts of interest: The authors declare no conflicts of interest.

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