Chronic stimulation desensitizes β2 adrenergic receptor responses in Natural Killer cells

Abstract

Psychosocial stress affects the function of the immune system via activation of the sympathetic nervous system and the release of the neurotransmitter epinephrine. Acute and chronic stress can have opposing effects on the immune system and chronic stress is correlated with higher incidences of infections and cancer. Here, we study the effect of epinephrine on the function of human Natural Killer (NK) cells as important innate lymphocytes for immune reactions against infections and cancer. Epinephrine-mediated stimulation of the β2 adrenergic receptor (β2AR) on NK cells inhibited early signaling events and blocked the function of the integrin LFA-1. This led to a reduced adhesion of NK cells to ICAM-1, explaining how NK cells are mobilized into the peripheral blood upon acute stress. Additionally, epinephrine stimulation transiently reduced NK cell degranulation, serial killing, cytokine production, and affected metabolic changes upon NK cell activation via the cAMP-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, recapitulating the opposing effects of acute versus chronic stress. 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.