In a recent Journal of Experimental Medicine publication, Wieduwild et al. demonstrate that β2-adrenoceptor activation reduces the host viral resistance to experimental mouse cytomegalovirus (MCMV) infection mostly through the inhibition of interferon (IFN)-γ production in liver natural killers (NK) cells.
Psychological stress exerts complex and pleiotropic effects on immunity via the activation of the sympathetic nervous system (SNS) and the hypothalamic pituitary adrenal (HPA) axis.
In the Journal of Experimental Medicine study, Elisabeth Wieduwild and colleagues from Immunology Centre of Marseille-Luminy, Aix Marseille University, France, used the animal model of MCMV infection to study the role of the β2-AR pathway in controlling early immune responses and resistance to infection. MCMV is commonly used as a model of human CMV infection.
The investigators found that mice treated with a β2-AR agonist were more susceptible to MCMV infection. By contrast, β2-AR–deficient mice (Adrb2−/− mice) produced higher levels of inflammatory cytokines and were more resistant to MCMV infection than their littermate controls.
Previous studies indicate that NK cells play a major role in the early innate immune response to MCMV. Moreover, it appears that IFN-ϒ is crucial for antiviral protection, whereas NK lymphocytes are major producers of this cytokine.
In accordance with that Wieduwild et al. revealed increased levels of IFN-ϒ+ NK lymphocytes in the liver, but not in the spleen. Moreover, the frequency of IFN-γ–producing NK cells in the liver was higher in Adrb2−/− mice than in their Adrb2+/+ littermates.
The authors provide further evidence that upon MCMV infection, β2-AR selectively downregulates IFN-γ production by liver NK cells but not by spleen NK cells. They concluded that this “organ specific regulation is NK cell extrinsic and results in a systemic decrease in IFN-γ levels in the serum, potentially affecting host resistance to infection”.
NK-cells requires a pro-inflammatory signal, such as TNF-α and IL-6, to become fully activated to fight viral infections. Transgenic strategies to deplete cells from myeloid origin, such as neutrophils, macrophages, and monocytes, or delete the β2 gene in NCR1 lymphocytes did not affect susceptibility to MCMV infection.
However, β2 gene deletion in bone-marrow-derived hematopoietic cells through crossbreeding LysMCre/+ and Adrb2flx/flx (Adrb2LysMCre) mice increased TNFα and IL6, but not IFNϒ, production after viral infection. These results indicate that production of these cytokines by β2-adrenocetor stimulation requires an additional cell type not intrinsic to LysMCre/+ gene. As these Adrb2LysMCre mice lack the β2 gene in macrophages and neutrophils, but not in dendritic cells, and dendritic cells are an early source of TNFα during CMVM, these cells may be the first source of pro-inflammatory signals for NK activation.
After conducting experiments with 6-hydroxydopamine (6-OHDA) sympathectomy and sympathetic denervation, the investigators concluded that in this model of infection, the catecholamines produced by the adrenal gland and released systemically in the bloodstream, are the major players and effectors that act on β2-ARs to modulate proinflammatory signals and MCMV resistance.
In conclusion, the study indicates that during MCMV viral infection, catecholamines mostly derived from the adrenal glands, via stimulation of β2-receptors on non-hematopoietic cells suppress the release of pro-inflammatory signals, such as TNFα, thus preventing IFN-γ production in liver NK cells, and downstream, reducing the host immune response and resistance to infection.
The study also provides further insights into the mechanisms exerted by catecholamines and stress hormones such as adrenaline (epinephrine) in downregulating the immune responses to viral infections such as MCMV or CMV.