Differential Response of Dopamine Mediated by β-Adrenergic Receptors in Human Keratinocytes and Macrophages: Potential Implication in Wound Healing

Abstract

Objective: Dopamine is an immunomodulatory neurotransmitter. In the skin, keratinocytes and macrophages produce proinflammatory cytokines and metalloproteinases (MMPs) which participate in wound healing. These cells have a catecholaminergic system that modulates skin pathophysiologic processes. We have demonstrated that dopamine modulates cytokine production in keratinocytes via dopaminergic and adrenergic receptors (ARs). The aim of this study was to evaluate the effect of dopamine and its interaction with β-ARs in human HaCaT keratinocytes and THP-1 macrophages. We evaluated the production of inflammatory mediators implicated in wound healing. Methods: Cells were stimulated with dopamine in the absence or presence of the β-adrenergic antagonist propranolol. Wound closure, MMP activity, and the production of IL-8, IL-1β, and IκB/NFκB pathway activation were determined in stimulated cells. Results: Dopamine did not affect the wound closure in human keratinocytes, but diminished the propranolol stimulatory effect, thus delaying cell migration. Similarly, dopamine significantly decreased MMP-9 activity and the propranolol-induced MMP activity. Dopamine significantly increased the p65-NFκB subunit levels in the nuclear extracts, which were reduced in the presence of propranolol in keratinocytes. On the other hand, dopamine significantly increased MMP-9 activity in THP-1 macrophages, but did not modify the propranolol-increased enzymatic activity. Dopamine significantly increased IL-8 production in human macrophages, an effect that was partially reduced by propranolol. Dopamine did not modify the p65-NFκB levels in the nuclear extracts in THP-1 macrophages. Conclusion: We suggest that the effect of dopamine via β-ARs depends on the physiological condition and the cell type involved, thus contributing to either improve or interfere with the healing process.

Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors

“…Several lines of evidence support this conclusion: (1) In vitro studies demonstrated that DA both binds and signals via α 2 -adrenergic receptors, albeit at lower affinities than NE 46,[78][79][80] . (2) DA has been shown to signal via immune cell and cardiac β-adrenergic receptors 81,82 . 3Computational modeling studies demonstrate strong structural homologies between DA's interactions at binding sites of adrenergic receptors and D 2 -like receptors 46,83 .…”

Correlation Between the Warrior/Worrier Gene on Post Burn Pruritus and Scarring: A Prospective Cohort Study

“…Other studies have suggested that dopamine affects wound healing by delaying cell migration through its effect on propranolol, which is known to affect cell migration and angiogenesis. Furthermore, dopamine seems to decrease the MMP-9 activity systemically, but increases MMP-9 activity in macrophages 18 . One study has shown that GLC756, a dopamine D2 agonist and D1 antagonist, has an anti-inflammatory effect on dermal fibroblasts, further implicating dopa-mine as a key modulator of wound healing and scar formation 19 .…”

“…Furthermore, dopamine seems to decrease the MMP-9 activity systemically, but increases MMP-9 activity in macrophages. 18 One study has shown that GLC756, a dopamine D2 agonist and D1 antagonist, has an antiinflammatory effect on dermal fibroblasts, further implicating dopamine as a key modulator of wound healing and scar formation. 19 Collectively, these studies suggest that catecholamines have multiple potential complex effects on the responses to cutaneous injury.…”

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“…CBDV is a partial agonist of dopamine D2-like receptors [100]. It has been shown recently that D2-like receptor agonism in the skin, promotes the recovery of the skin barrier and wound healing [101][102][103].…”