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 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.
Pullar
Christine E
CE
Department of Dermatology, University of California Davis, Davis, CA 95616, USA. cepullar@ucdavis.edu
Grahn
Jennifer C
JC
Liu
Wei
W
Isseroff
R Rivkah
RR
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D012867:Skin; D016596:Vinculin / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*; D014947:Wounds and Injuries / Q000378:metabolism
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D018343:Receptors, Adrenergic, beta-2; D016596:Vinculin; D019319:Okadaic Acid; D048049:Extracellular Signal-Regulated MAP Kinases