title: Norepinephrine suppresses wound macrophage phagocytic efficiency through alpha- and beta-adrenoreceptor dependent pathways.
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. We have recently demonstrated that NE modulates the recruitment of macrophages to the cutaneous wound. We hypothesized that NE suppresses wound macrophage phagocytic function through canonical adrenergic signaling pathways.
  
  
  METHODS
  Murine wound macrophages were harvested at 5 days after injury and treated with physiologic and pharmacologic dose norepinephrine. Phagocytosis of green fluorescent protein-labeled Escherichia coli was assayed by flow cytometry. The signaling pathways mediating NE modulation of wound macrophage phagocytosis were interrogated by pharmacologic manipulation of alpha- and beta-adrenoreceptors (ARs), intracellular cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). Tissue specificity was determined by comparison of wound macrophages to splenic macrophages.
  
  
  RESULTS
  Both physiologic and pharmacologic dose NE suppressed wound macrophage phagocytic efficiency. This effect was mediated by alpha- and beta-ARs in a dose-dependent fashion. Direct stimulation of cAMP-suppressed phagocytic efficiency and blockade of PKA signaling prevented NE-mediated suppression of phagocytic efficiency. Splenic macrophage phagocytic efficiency was less than that of wound macrophages and was not altered by NE.
  
  
  CONCLUSIONS
  NE has a profound immunosuppressive effect on wound macrophage function that is tissue specific and appears to be mediated through adrenergic receptors and their canonical downstream signaling pathway. Attenuation of post-injury immunosuppression represents another potential mechanism by which beta-AR blockade may reduce morbidity and mortality after severe injury.
authors: Burn and Shock Trauma Institute, Loyola University Medical Center, Maywood, Ill, USA.
authors: Ankush
authors: A
authors: Gosain
authors: Kuzhali
authors: K
authors: Muthu
authors: Richard L
authors: RL
authors: Gamelli
authors: Luisa A
authors: LA
authors: DiPietro
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology; D007546:Isoquinolines / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D009638:Norepinephrine / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013449:Sulfonamides / Q000494:pharmacology; D014947:Wounds and Injuries / Q000276:immunology* / Q000378:metabolism
chemical_list: D000316:Adrenergic alpha-Agonists; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D013449:Sulfonamides; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D009638:Norepinephrine
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