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Department of Dermatology, University of California, Davis, California, USA
1Correspondence: Department of Dermatology, University of California Davis, TB 192, One Shields Ave, Davis, CA 95616, USA. E-mail: cepullar{at}ucdavis.edu
Keratinocytes migrate directionally into the wound bed to initiate re-epithelialization, necessary for wound closure and restoration of barrier function. They solely express the ß2-adrenergic receptor (ß2-AR) subtype of ß-ARs and can also synthesize ß-AR agonists generating a hormonal mediator network in the skin. Emerging studies from our laboratory demonstrate that ß-AR agonists decrease keratinocyte migration via a protein phosphatase (PP) 2A-dependent mechanism. Here we have extended our investigations to observe the effects of ß2-AR activation on keratinocyte polarization, migration, and ERK phosphorylation at the wound edge, cytoskeletal organization, phospho-ERK intracellular localization, proliferation, human skin wound re-epithelialization, wound-induced ERK phosphorylation, and murine skin wound healing. We demonstrate that in keratinocytes, ß2-AR activation is anti-motogenic and anti-mitogenic with both mechanisms being PP2A dependent. ß2-AR activation dramatically alters the organization of the actin cytoskeleton and prevents localization of phospho-ERK to the lamellipodial edge and its colocalization with vinculin. Finally, we demonstrate a ß2-AR-mediated delay in re-epithelialization and decrease in wound-induced epidermal ERK phosphorylation in human skin wounds and a delay in re-epithelialization in murine tail-clip wounds. Our work uncovers novel keratinocyte biology and a previously unrecognized role for the adrenergic hormonal mediator network in the wound repair process.— Pullar, C. E., Grahn, J. C., Liu, W., Isseroff, R. R. ß2-Adrenergic receptor activation delays wound healing.
Key Words: wound re-epithelialization • ERK activation • keratinocyte migration • focal adhesions
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