| Author |
Sivamani, Raja K. Shi, Biao Griffiths, Elizabeth Vu, Shirley M. Lev-Tov, Hadar A. Dahle, Sara Chigbrow, Marianne La, Thi Dinh Mashburn, Chelcy Peavy, Thomas R. Isseroff, R. Rivkah |
| Description |
Country affiliation: United States Author Affiliation: Sivamani RK ( Department of Dermatology, University of California, Davis, Davis, California, USA.); Shi B ( Department of Dermatology, University of California, Davis, Davis, California, USA.); Griffiths E ( Department of Dermatology, University of California, Davis, Davis, California, USA.); Vu SM ( Department of Dermatology, University of California, Davis, Davis, California, USA.); Lev-Tov HA ( 1] Department of Dermatology, University of California, Davis, Davis, California, USA [2] Department of Dermatology, Veterans Affairs Medical Center, Mather, California, USA.); Dahle S ( Department of Podiatry, Veterans Affairs Medical Center, Mather, California, USA.); Chigbrow M ( Department of Dermatology, University of California, Davis, Davis, California, USA.); La TD ( Department of Dermatology, University of California, Davis, Davis, California, USA.); Mashburn C ( Department of Biological Sciences, California State University, Sacramento, California, USA.); Peavy TR ( Department of Biological Sciences, California State University, Sacramento, California, USA.); Isseroff RR ( 1] Department of Dermatology, University of California, Davis, Davis, California, USA [2] Department of Dermatology, Veterans Affairs Medical Center, Mather, California, USA.) |
| Abstract |
Keratinocyte migration is critical for wound re-epithelialization. Previous studies showed that epinephrine activates the beta2-adrenergic receptor (B2AR), impairing keratinocyte migration. Here, we investigated the keratinocyte catecholamine synthetic pathway in response to acute trauma. Cultured keratinocytes were scratch wounded and expression levels of the B2AR and catecholamine synthetic enzymes tyrosine hydroxylase and phenylethanolamine-N-methyltransferase were assayed. The binding affinity of the B2AR was measured. Wounding downregulated B2AR, tyrosine hydroxylase, and phenylethanolamine-N-methyltransferase expression, but pre-exposure to timolol, a beta-adrenergic receptor antagonist, delayed this effect. In wounded keratinocytes, B2AR-binding affinity remained depressed even after its expression returned to prewounding levels. Keratinocyte-derived norepinephrine increased after wounding. Norepinephrine impaired keratinocyte migration; this effect was abrogated with B2AR-selective antagonist ICI-118,551 but not with B1AR-selective antagonist bisoprolol. Finally, for clinical relevance, we determined that norepinephrine was present in freshly wounded skin, thus providing a potential mechanism for impaired healing by local B2AR activation in wound-edge keratinocytes. Taken together, the data show that keratinocytes modulate catecholamine synthetic enzymes and release norepinephrine after scratch wounding. Norepinephrine appears to be a stress-related mediator that impairs keratinocyte migration through activation of the B2AR. Future therapeutic strategies evaluating modulation of norepinephrine-related effects in the wound are warranted. |
