Beta2-adrenergic receptor activation delays wound healing

Keratinocytes migrate directionally into the wound bed to initiate re-epithelialization, necessary for wound closure and restoration of barrier function. They solely express the beta2-adrenergic receptor (beta2-AR) subtype of beta-ARs and can also synthesize beta-AR agonists generating a hormonal me...

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Bibliographic Details
Published in:The FASEB journal 2006-01, Vol.20 (1), p.76
Main Authors: Pullar, Christine E, Grahn, Jennifer C, Liu, Wei, Isseroff, R Rivkah
Format: Article
Language:English
Subjects:
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-2 Receptor Antagonists
Animals
Cell Adhesion
Cell Proliferation
Cells, Cultured
Extracellular Signal-Regulated MAP Kinases - metabolism
Humans
Keratinocytes - drug effects
Keratinocytes - metabolism
Male
Mice
Mice, Inbred C57BL
Okadaic Acid - pharmacology
Phosphorylation
Protein Transport
Pseudopodia - metabolism
Receptors, Adrenergic, beta-2 - metabolism
Skin
Vinculin - metabolism
Wound Healing - drug effects
Wound Healing - physiology
Wounds and Injuries - metabolism
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Summary:Keratinocytes migrate directionally into the wound bed to initiate re-epithelialization, necessary for wound closure and restoration of barrier function. They solely express the beta2-adrenergic receptor (beta2-AR) subtype of beta-ARs and can also synthesize beta-AR agonists generating a hormonal mediator network in the skin. Emerging studies from our laboratory demonstrate that beta-AR agonists decrease keratinocyte migration via a protein phosphatase (PP) 2A-dependent mechanism. Here we have extended our investigations to observe the effects of beta2-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, beta2-AR activation is anti-motogenic and anti-mitogenic with both mechanisms being PP2A dependent. beta2-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 beta2-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.
ISSN:1530-6860