Catecholamine Stress Alters Neutrophil Trafficking and Impairs Wound Healing by β 2 -Adrenergic Receptor–Mediated Upregulation of IL-6

Kim, Min Ho; Gorouhi, Farzam; Ramírez, Sandra; Granick, Jennifer L.; Byrne, Barbara A.; Soulika, Athena M.; Simon, Scott I.; Isseroff, Roslyn Rivkah

doi:10.1038/jid.2013.415

Cited by 101 publications

(77 citation statements)

References 49 publications

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“…In line with these findings, sustained systemic administration of epinephrine in mice results in β 2 AR-mediated increases in the activation of macrophages and production of IL-6. 45,46 …”

Section: Discussionmentioning

confidence: 99%

“…β 2 ARs are located on peripheral terminals 33-37 and cell bodies 38-40 of primary afferent nociceptors; keratinocytes; 41-43 immune cells; 44-47 and adipocytes 48 in the periphery and neurons 49,50 and glial cells 51 in the central nervous system. β 3 ARs are located on primary afferent nociceptors, 52 adipocytes 48 and immune cells 45,46 in the periphery and noradrenergic neurons in brain. 53 Thus, we hypothesized that peripheral, spinal, and/or central β 2 - and β 3 ARs contribute to persistent COMT-dependent pain.…”

Section: Introductionmentioning

confidence: 99%

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Persistent Catechol-O-methyltransferase–dependent Pain Is Initiated by Peripheral β-Adrenergic Receptors

2016

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Background Patients with chronic pain disorders exhibit increased levels of catecholamines alongside diminished activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. The authors found that acute pharmacologic inhibition of COMT in rodents produces hypersensitivity to mechanical and thermal stimuli via β-adrenergic receptor (βAR) activation. The contribution of distinct βAR populations to the development of persistent pain linked to abnormalities in catecholamine signaling requires further investigation. Methods Here, the authors sought to determine the contribution of peripheral, spinal, and supraspinal βARs to persistent COMT-dependent pain. They implanted osmotic pumps to deliver the COMT inhibitor OR486 (Tocris, USA) for 2 weeks. Behavioral responses to mechanical and thermal stimuli were evaluated before and every other day after pump implantation. The site of action was evaluated in adrenalectomized rats receiving sustained OR486 or in intact rats receiving sustained βAR antagonists peripherally, spinally, or supraspinally alongside OR486. Results The authors found that male (N = 6) and female (N = 6) rats receiving sustained OR486 exhibited decreased paw withdrawal thresholds (control 5.74 ± 0.24 vs. OR486 1.54 ± 0.08, mean ± SEM) and increased paw withdrawal frequency to mechanical stimuli (control 4.80 ± 0.22 vs. OR486 8.10 ± 0.13) and decreased paw withdrawal latency to thermal heat (control 9.69 ± 0.23 vs. OR486 5.91 ± 0.11). In contrast, adrenalectomized rats (N = 12) failed to develop OR486-induced hypersensitivity. Furthermore, peripheral (N = 9), but not spinal (N = 4) or supraspinal (N = 4), administration of the nonselective βAR antagonist propranolol, the β2AR antagonist ICI-118,511, or the β3AR antagonist SR59230A blocked the development of OR486-induced hypersensitivity. Conclusions Peripheral adrenergic input is necessary for the development of persistent COMT-dependent pain, and peripherally-acting βAR antagonists may benefit chronic pain patients.

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“…In line with these findings, sustained systemic administration of epinephrine in mice results in β 2 AR-mediated increases in the activation of macrophages and production of IL-6. 45,46 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Persistent Catechol-O-methyltransferase–dependent Pain Is Initiated by Peripheral β-Adrenergic Receptors

2016

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“…Elevations in systemic epinephrine, relative to normal levels, have been found to impair wound healing in mice (Romana-Souza et al, 2010;Kim et al, 2014). However, the role of systemic elevation of norepinephrine is less clear.…”

Section: Discussionmentioning

confidence: 99%

Acute Wounding Alters the Beta2-Adrenergic Signaling and Catecholamine Synthetic Pathways in Keratinocytes

Sivamani

Shi

Griffiths

et al. 2014

Journal of Investigative Dermatology

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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.

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“…Interestingly, the chronic inflammation was mediated by β2-adrenergic receptor signaling in macrophages that promoted IL-6 production. Therefore, while β2-adrenergic receptor signaling is protective in downregulating excessive inflammation during endotoxemia, in response to persistent exposure to adrenaline, it can have detrimental effects by promoting inflammation and impairing keratinocyte responses that are necessary for wound healing [26]. …”

Section: Catecholaminesmentioning

confidence: 99%

Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system

2015

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Catecholamines and adipokines function as hormones; catecholamines as neurotransmitters in the sympathetic nervous system, and adipokines as mediators of metabolic processes. It has become increasingly clear, however, that both also function as immunomodulators of innate and adaptive immune cells, including macrophages. Macrophages can respond to, as well as produce their own catecholamines. Dopamine, noradrenaline, and adrenaline are the most abundant catecholamines in the body, and can induce both pro-inflammatory and anti-inflammatory immune responses in macrophages, as well as non-immune processes such as thermogenesis. Though they are responsive to adipokines, particularly lipoproteins, leptin, and adiponectin, macrophages generally do synthesize their own adipokines, with the exception being resistin-like molecules. Adipokines contribute to adverse metabolic and immune response by stimulating lipid accumulation, foam cell formation and pro-inflammatory cytokine production in macrophages. Adipokines can also promote balance or resolution during metabolic and immune processes by promoting reverse lipid transport and expression of Th2 cytokines. This review will explore the mechanisms by which catecholamines and adipokines influence macrophage function in neural pathways, immunity and metabolism.

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Catecholamine Stress Alters Neutrophil Trafficking and Impairs Wound Healing by β 2 -Adrenergic Receptor–Mediated Upregulation of IL-6

Cited by 101 publications

References 49 publications

Persistent Catechol-O-methyltransferase–dependent Pain Is Initiated by Peripheral β-Adrenergic Receptors

Persistent Catechol-O-methyltransferase–dependent Pain Is Initiated by Peripheral β-Adrenergic Receptors

Acute Wounding Alters the Beta2-Adrenergic Signaling and Catecholamine Synthetic Pathways in Keratinocytes

Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system

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