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

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 beta 2-adrenergic receptor (beta 2AR) 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 beta 2AR agonists resulted in the desensitization of the beta 2AR via a PKA feedback loop-initiated G-protein switch. Therefore, acute epinephrine stimulation of chronically beta 2AR stimulated NK cells no longer resulted in inhibited signaling and reduced LFA-1 activity. Sustained stimulation by long-acting beta 2-agonists (LABA) not only inhibited NK cell functions but also resulted in desensitization of the beta 2AR. 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. beta 2-adrenergic receptor (beta 2AR) stimulation of NK cells inhibits inside-out signaling and LFA-1 activation, explaining the mobilization of NK cells upon acute stress. Repeated or sustained beta 2AR stimulation desensitizes beta 2AR via G-protein switch. Local administration of long-acting beta 2-agonists does not interfere with systemic NK cell functions in asthma patients. image