Oxidative burst and Dectin-1-triggered phagocytosis affected by norepinephrine and endocannabinoids: implications for fungal clearance under stress. (10th January 2018)

• Record Type: Journal Article
• Authors: Buchheim, Judith-Irina; Hoskyns, Spencer; Moser, Dominique; Han, Bing; Deindl, Elisabeth; Hörl, Marion; Biere, Katharina; Feuerecker, Matthias; Schelling, Gustav; Choukèr, Alexander
• Is Part Of: International immunology. Volume 30:Number 2(2018)
• Page Start: 79
• Page End: 89
• Publication Date: 2018-01-10
• Subjects: endocannabinoid system -- fungal infections -- mTOR -- reactive oxygen species -- WNK1; Immunology -- Periodicals; 616.079
• DOI: 10.1093/intimm/dxy001
• Languages: English
• ISSNs: 0953-8178

Abstract

Abstract : Norepinephrine and a cannabinoid can modify leukocyte responses to fungi Abstract: A prolonged stress burden is known to hamper the efficiency of both the innate and the adaptive immune systems and to attenuate the stress responses by the catecholaminergic and endocannabinoid (EC) systems. Key mechanisms of innate immunity are the eradication of pathogens through phagocytosis and the respiratory burst. We tested the concentration-dependent, spontaneous and stimulated ( via TNFα and N-formylmethionine-leucyl-phenylalanine) release of reactive oxygen species (ROS) by human polymorphonuclear leukocytes (PMNs) in vitro in response to norepinephrine (NE) and AM1241, a pharmacological ligand for the EC receptor CB2 . We evaluated phagocytosis of Dectin-1 ligating zymosan particles and tested the cytokine response against Candida antigen in an in vitro cytokine release assay. Increasing concentrations of NE did not affect phagocytosis, yet stimulated ROS release was attenuated gradually reaching maximum suppression at 500 nM. Adrenergic receptor (AR) mechanisms using non-AR-selective (labetalol) as well as specific α-(prazosin) and β-(propranolol) receptor antagonists were tested. Results show that only labetalol and propranolol were able to recuperate cytotoxicity in the presence of NE, evidencing a β-receptor-mediated effect. The CB2 agonist, AM1241, inhibited phagocytosis at 10 µM and spontaneous peroxide release by PMNs. Use of the inverse CB2 receptor agonist SR144528 led to partial recuperation of ROS production, confirming the functional role of CB2 . Additionally, AM1241 delayed early activation of monocytes and induced suppression of IL-2 and IL-6 levels in response to Candida via lower activity of mammalian target of rapamycin (mTOR). These findings provide new insights into key mechanisms of innate immunity under stressful conditions where ligands to the sympatho-adrenergic and EC system are released.