Alpha and beta adrenergic receptors modulate keratinocyte migration

Abstract

Keratinocyte migration into skin wounds is the step of the healing process that correlates with the wound closure rate. Keratinocyte migration, and wound epithelialization are decreased when beta 2-adrenergic receptors (B2AR) are activated by 1 μM epinephrine/adrenaline, resulting in delayed wound healing in human and mouse skin. In the present study, we found paradoxically, that in a subset of keratinocyte strains exposure to low concentrations of epinephrine (0.1 nM) increased, rather than decreased, their migratory rate. We find that both the alpha- and the beta-adrenergic receptors are expressed in human keratinocytes, and expression of alpha-2 AR subtypes demonstrated for the first time. Therefore, we tested if the alpha-AR could be modulating the increased migratory response observed in these cell strains. By using specific inhibitors to alpha-AR, we demonstrated that blocking A2B-AR could reverse the rapid cell migration induced by the 0.1 nM epinephrine. Phosphorylation of ERK was elevated after 1–10 minutes of the low epinephrine treatment and the A2B-AR inhibitor blocked the ERK phosphorylation. The results suggest that both the A2B-AR and B2AR mediate keratinocyte migration, in which with a low level of epinephrine treatment, A2B-AR could alter the B2AR signals and regulate the migration rate.

Treatment of Hydroxyurea-Induced Ulcers With Timolol

“…In the skin, β-2 adrenergic receptors (B2AR) are expressed on keratinocytes and fibroblasts. Receptor antagonism has been shown to promote keratinocyte migration and reepithelization . The B2AR antagonists also enhance angiogenesis, fibroblast function, and migratory speed .…”

Mechanism and application of β‐adrenoceptor blockers in soft tissue wound healing

“…Studies have indicated that β‐AR activation impedes the healing process by targeting repair cells that are closely associated with healing during all phases (Figure 3). Conversely, β‐blockers reverse these adverse effects and promotes wound healing 6 (Figure 4).…”

“…When the soft tissue is wounded, stressors stimulate the adrenal medulla and presynaptic neurons to release high amounts of the catecholamine hormones, epinephrine and norepinephrine (NE), which binds to β‐adrenergic receptors (β‐AR) distributed on cells membrane and delaying the soft tissue wound healing 4,5 . In addition, the mechanism research revealed that cells involved in wound repair, such as keratinocytes and inflammatory cells, expressed β‐AR, meanwhile, they synthesized and secreted catecholamine‐adrenergic hormones 6 . It is tempting to present that long‐term exposure to higher levels of catecholamines, whether in the blood circulation or locally derived by repair cells themselves, may probably be a fundamentally harmful factor in the soft tissue wound healing process.…”

“…Second, β‐AR activation inhibits extracellular regulated protein kinases (ERK) phosphorylation, preventing the migration of keratinocytes to the wound bed, and hence damaging wound reepithelialization 18 . In addition, β‐AR activation reduces angiogenesis and alters fibroblast function affecting wound contraction 6 . During the final tissue remodeling phase, β‐AR activation is associated with increased expression of matrix metalloproteinases (MMP) 19 .…”

“…4,5 In addition, the mechanism research revealed that cells involved in wound repair, such as keratinocytes and inflammatory cells, expressed β-AR, meanwhile, they synthesized and secreted catecholamine-adrenergic hormones. 6 It is tempting to present that long-term exposure to higher levels of catecholamines, whether in the blood circulation or locally derived by repair cells themselves, may probably be a fundamentally harmful factor in the soft tissue wound healing process.…”