Keratinocyte arginase 1 regulates proinflammatory responses and drives re-epithelialization via lipocalin 2

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BACKGROUND: Chronic skin wounds exhibit impaired re-epithelialization due to defective keratinocyte migration and excessive inflammatory signals. Arginase 1 (ARG1) is an enzyme expressed by keratinocytes that is important for skin wound healing. However, the mechanisms underpinning keratinocyte ARG1 function in wound closure are not fully understood. OBJECTIVES: To investigate the role of ARG1 in keratinocyte wound closure and inflammatory responses. METHODS: In vitro two-dimensional wounding assays using ARG1-inhibited keratinocytes were used to explore the function of ARG1 in keratinocyte scratch closure. ARG1 was also assessed in human skin wounds. RESULTS: ARG1 was strongly expressed in the perilesional regions of acute wounds, but its expression was dysregulated in chronic ulcers, with high expression in the upper layers of the hyperplastic epidermis. ARG1 inhibition in keratinocytes led to a significant decrease in two-dimensional scratch closure, augmented interleukin-1 family- and tumour necrosis factor-α-driven proinflammatory signalling, and significant downregulation of lipocalin 2 (LCN2). LCN2 expression was partially dependent on Janus kinase/signal transducer and activator of transcription signalling. Keratinocyte LCN2 neutralization led to delayed scratch wound closure, while LCN2 expression in response to bacterial challenge was impaired upon ARG1 inhibition. ARG1 metabolic products, putrescine and urea, could rescue keratinocyte migration and LCN2 expression in ARG1-inhibited cells. CONCLUSIONS: ARG1 plays a major role in keratinocyte re-epithelialization, regulating inflammation and LCN2 production in sterile and infected wound conditions. Dysregulated expression in chronic ulcers may reflect altered enzymatic capacity to drive re-epithelialization or attempts to reduce inflammation and promote antimicrobial function. In culture, impaired wound responses of ARG1 inhibited cells can be rescued by its downstream products putrescine and urea, highlighting the complexity of ARG1 control of wound healing. Manipulation of the ARG1 pathway may have the potential to be used for the management of skin conditions such as infected chronic lesions; however, further study of the pathway is needed to fully understand the role of ARG1 in chronic wounds.

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