Ankush Gosain1, Richard L Gamelli, Luisa A DiPietro. 1. Burn and Shock Trauma Institute, Department of Cell Biology, Neurobiology and Anatomy, Loyola University Medical Center, Maywood, Illinois, USA.
Abstract
BACKGROUND: The systemic response to injury is characterized by massive release of norepinephrine (NE) into the circulation as a result of global sympathetic activation. Multiple authors have demonstrated NE-mediated alterations in migration of circulating neutrophils to wounds. We hypothesized that NE further alters wound neutrophil phagocytic function through adrenergic signaling pathways. METHODS: A standard subcutaneous sponge wound model was used. Murine wound neutrophils were harvested at 24 and 120 h after injury and treated with physiological (10(-9) M) and pharmacologic (10(-6) M) doses of NE. Phagocytosis of green fluorescent protein-labeled Escherichia coli was assayed by flow cytometry. The signaling pathways mediating NE modulation of phagocytosis by wound neutrophils were defined by pharmacologic manipulation of alpha- and beta-adrenoreceptors and protein kinase A. RESULTS: Pharmacologic-dose NE, but not-physiological-dose NE, suppressed the phagocytic efficiency of 120-h wound neutrophils. This alteration in phagocytic efficiency appears to be mediated through alpha- and beta- adrenoreceptors and downstream protein kinase A. Phagocytosis by 24-h wound neutrophils was not impacted by NE treatment. CONCLUSIONS: The present study is the first to demonstrate NE-mediated alterations in the process of phagocytosis by wound neutrophils. We conclude that NE plays a temporally and dose-defined immunomodulatory role in cutaneous wound healing through alterations in phagocytosis by wound neutrophils and may represent a target for therapeutic manipulation of the innate immune response.
BACKGROUND: The systemic response to injury is characterized by massive release of norepinephrine (NE) into the circulation as a result of global sympathetic activation. Multiple authors have demonstrated NE-mediated alterations in migration of circulating neutrophils to wounds. We hypothesized that NE further alters wound neutrophil phagocytic function through adrenergic signaling pathways. METHODS: A standard subcutaneous sponge wound model was used. Murine wound neutrophils were harvested at 24 and 120 h after injury and treated with physiological (10(-9) M) and pharmacologic (10(-6) M) doses of NE. Phagocytosis of green fluorescent protein-labeled Escherichia coli was assayed by flow cytometry. The signaling pathways mediating NE modulation of phagocytosis by wound neutrophils were defined by pharmacologic manipulation of alpha- and beta-adrenoreceptors and protein kinase A. RESULTS: Pharmacologic-dose NE, but not-physiological-dose NE, suppressed the phagocytic efficiency of 120-h wound neutrophils. This alteration in phagocytic efficiency appears to be mediated through alpha- and beta- adrenoreceptors and downstream protein kinase A. Phagocytosis by 24-h wound neutrophils was not impacted by NE treatment. CONCLUSIONS: The present study is the first to demonstrate NE-mediated alterations in the process of phagocytosis by wound neutrophils. We conclude that NE plays a temporally and dose-defined immunomodulatory role in cutaneous wound healing through alterations in phagocytosis by wound neutrophils and may represent a target for therapeutic manipulation of the innate immune response.
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