β2-adrenergic signals downregulate the innate immune response and reduce host resistance to viral infection

Abstract

In humans, psychological stress has been associated with a higher risk of infectious illness. However, the mechanisms by which the stress pathway interferes with host response to pathogens remain unclear. We demonstrate here a role for the β2-adrenergic receptor (β2-AR), which binds the stress mediators adrenaline and noradrenaline, in modulating host response to mouse cytomegalovirus (MCMV) infection. Mice treated with a β2-AR agonist were more susceptible to MCMV infection. By contrast, β2-AR deficiency resulted in a better clearance of the virus, less tissue damage, and greater resistance to MCMV. Mechanistically, we found a correlation between higher levels of IFN-γ production by liver natural killer (NK) cells and stronger resistance to MCMV. However, the control of NK cell IFN-γ production was not cell intrinsic, revealing a cell-extrinsic downregulation of the antiviral NK cell response by adrenergic neuroendocrine signals. This pathway reduces host immune defense, suggesting that the blockade of the β2-AR signaling could be used to increase resistance to infectious diseases.

Cell-intrinsic adrenergic signaling controls the adaptive NK cell response to viral infection

“…NK-Adrb2 −/− and littermate NK cells degranulated similarly during ex vivo stimulation with pro-inflammatory cytokines, or PMA and ionomycin (Fig. S1, H and I), consistent with findings from Wieduwild et al (2020). In the mBMC infected with MCMV, NK-Adrb2 −/− NK cells exhibited a modest albeit reproducible defect in IFN-γ production, which was independent of their maturation stage (Fig.…”

“…However, whether NK cells can directly sense adrenergic signals had not been previously determined. Consistent with findings from Wieduwild et al (2020), cell-intrinsic adrenergic signaling was largely dispensable for NK cell development, homeostasis, and early effector function against MCMV infection. In contrast to the early innate responses, in the present study we show that cell-intrinsic adrenergic signaling was necessary to elicit robust adaptive NK cell responses, revealed in adoptive transfer experiments where NK cells could undergo large proliferative bursts.…”

“…Interestingly, Wieduwild et al (2020) show that indirect, cell-extrinsic adrenergic signaling acting through a nonneuronal, nonhematopoietic compartment negatively regulates IFN-γ production by liver NK cells, reducing host immune defense against viral challenge. In this case, the improved survival of Adrb2 −/− mice was attributed to increased IFN-γ production, a hallmark of the early NK cell effector function.…”

Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

“…Higher levels of IFN-γ produced by liver NK cells generate stronger resistance to MCMV. 92 During MCMV infection, the conversion of cNK cells into CD49a + CD49b + NK cells was observed in the liver, representing a transiently activated state of cNK cells with enhanced IFN-γ production and stronger cytotoxicity. 93 Additionally, NK cells produced IL-10 during the early stage of MCMV infection, which regulated T cell activation and prevented liver damage for a better disease outcome.…”

Adrenergic regulation of immune cell function and inflammation

“…This may be due, in part, to the effects of NE on driving alternative M2 macrophage development, which is characterized by an anti-inflammatory phenotype dominated by IL-10 rather than TNF-α and other inflammatory cytokines [21]. Indeed, these suppressive effects are seen in the innate response of NK cells to virus infection, as loss of ADRB2 enhances IFN-γ and lytic activity of NK cells in response to MCMV [33].…”