Chronic stimulation desensitizes β2‐adrenergic receptor responses in natural killer cells

• Published in: European journal of immunology 2024-12, Vol.54 (12), p.e2451299-n/a
• Main Authors: Jürgens, Martin, Claus, Maren, Wingert, Sabine, Niemann, Jens Alexander, Picard, Lea Katharina, Hennes, Elisabeth, Haasler, Ina, Hellwig, Birte, Overbeck, Nina, Reinders, Jörg, Rahnenführer, Jörg, Schedel, Michaela, Capellino, Silvia, Watzl, Carsten
• Format: Article
• Language: English
• Subjects: acute stress; adhesion; Adrenergic beta-2 Receptor Agonists - pharmacology; Adrenergic receptors; Agonists; Basic; cAMP; Cell activation; Cell Adhesion - drug effects; Cell Degranulation - drug effects; Cell signaling; Cells, Cultured; chronic stress; Cyclic AMP-Dependent Protein Kinases - metabolism; cytotoxicity; Degranulation; Epinephrine; Epinephrine - pharmacology; Humans; Innate immunity; Intercellular Adhesion Molecule-1 - metabolism; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Kinases; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocyte Function-Associated Antigen-1 - immunology; Lymphocyte Function-Associated Antigen-1 - metabolism; Lymphocytes; Metabolic rate; Natural killer cells; Peripheral blood; Protein kinase A; Receptors, Adrenergic, beta-2 - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.202451299

Adrenergic receptors (ARs) are preferentially expressed by innate lymphocytes such as natural killer (NK) cells. Here, we study the effect of epinephrine‐mediated stimulation of the β2‐adrenergic receptor (β2AR) on the function of human NK cells. Epinephrine stimulation inhibited early NK cell signaling events and blocked the function of the integrin LFA‐1. This reduced the adhesion of NK cells to ICAM‐1, explaining how NK cells are mobilized into the peripheral blood upon epinephrine release during acute stress or exercise. Additionally, epinephrine stimulation transiently reduced NK cell degranulation, serial killing, and cytokine production and affected metabolic changes upon NK cell activation via the cAMP‐protein kinase A (PKA) pathway. Repeated exposure to β2AR agonists resulted in the desensitization of the β2AR via a PKA feedback loop‐initiated G‐protein switch. Therefore, acute epinephrine stimulation of chronically β2AR stimulated NK cells no longer resulted in inhibited signaling and reduced LFA‐1 activity. Sustained stimulation by long‐acting β2‐agonists (LABA) not only inhibited NK cell functions but also resulted in desensitization of the β2AR. However, peripheral NK cells from LABA‐treated asthma patients still reacted unchanged to epinephrine stimulation, demonstrating that local LABA administration does not result in detectable systemic effects on NK cells. β2‐adrenergic receptor (β2AR) stimulation of NK cells inhibits inside‐out signaling and LFA‐1 activation, explaining the mobilization of NK cells upon acute stress. Repeated or sustained β2AR stimulation desensitizes β2AR via G‐protein switch. Local administration of long‐acting β2‐agonists does not interfere with systemic NK cell functions in asthma patients.