Abstract
The skin is our primary defense against noxious environmental agents. Upon injury, keratinocytes migrate directionally into the wound bed to initiate re-epithelialization, essential for wound repair and restoration of barrier integrity. Keratinocytes express a high level of beta2-adrenergic receptors (beta2-ARs) that appear to play a role in cutaneous homeostasis as aberrations in either keratinocyte beta2-AR function or density are associated with various skin diseases. Here we report the novel finding that beta-AR antagonists promote wound re-epithelialization in a "chronic" human skin wound-healing model. beta-AR antagonists increase ERK phosphorylation, the rate of keratinocyte migration, electric field-directed migration, and ultimately accelerate human skin wound re-epithelialization. We demonstrate that keratinocytes express two key enzymes required for catecholamine (beta-AR agonist) synthesis, tyrosine hydroxylase and phenylethanolamine-N-methyl transferase, both localized within keratinocyte cytoplasmic vesicles. Finally, we confirm the synthesis of epinephrine by measuring the endogenously synthesized catecholamine in keratinocyte extracts. Previously, we have demonstrated that beta-AR agonists delay wound re-epithelialization. Here we report that the mechanism for the beta-AR antagonist-mediated augmentation of wound repair is due to beta2-AR blockade, preventing the binding of endogenously synthesized epinephrine. Our work describes an endogenous beta-AR mediator network in the skin that can temporally regulate skin wound repair. Further investigation of this network will improve our understanding of both the skin repair process and the multiple modes of action of one of the most frequently prescribed class of drugs, hopefully resulting in a new treatment for chronic wounds.
Highlights
The skin is our primary defense against noxious environmental agents
We demonstrate that keratinocytes express two key enzymes required for catecholamine (-AR agonist) synthesis, tyrosine hydroxylase and phenylethanolamine-N-methyl transferase, both localized within keratinocyte cytoplasmic vesicles
We report the novel finding that -AR antagonists promote wound re-epithelialization by blocking an autocrine 2-AR network within the epidermis. -AR antagonists enhance the ability of keratinocytes to heal a scratch wound, increase the rate of single cell migration, increase ERK phosphorylation, enhance electric fields (EFs)-mediated directional migration, preserve a pro-migratory cyto-architecture, maintain normal proliferation rates, and accelerate skin wound re-epithelialization
Summary
We report the novel finding that -AR antagonists promote wound re-epithelialization in a “chronic” human skin wound-healing model. -AR antagonists increase ERK phosphorylation, the rate of keratinocyte migration, electric field-directed migration, and accelerate human skin wound re-epithelialization. Keratinocytes within the psoriatic lesions demonstrate a low cAMP response to 2-AR activation [8] These findings point to a role for the 2-AR in maintaining epidermal function and integrity. The first clues to a biological function for 2-AR in wound repair came from an early study demonstrating that -AR agonists delay skin wound healing in newt limbs [20]. We explore the mechanism for the -AR antagonist-mediated acceleration of wound repair, reporting the expression of protein for two key catecholamine (-AR agonist) synthesis enzymes that are localized within keratinocyte cytoplasmic granules/vesicles. Further investigation of this network will improve our understanding of the skin wound repair process and hopefully lead to the development of new therapies to enhance wound healing
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