Adrenergic Signaling at the Interface of Allergic Asthma and Viral Infections

Abstract

Upper respiratory viral infections are a major etiologic instigator of allergic asthma, and they drive severe exacerbations of allergic inflammation in the lower airways of asthma sufferers. Rhinovirus (RV), in particular, is the main viral instigator of these pathologies. Asthma exacerbations due to RV infections are the most frequent reasons for hospitalization and account for the majority of morbidity and mortality in asthma patients. In both critical care and disease control, long- and short-acting β2-agonists are the first line of therapeutic intervention, which are used to restore airway function by promoting smooth muscle cell relaxation in bronchioles. While prophylactic use of β2-agonists reduces the frequency and pathology of exacerbations, their role in modulating the inflammatory response is only now being appreciated. Adrenergic signaling is a component of the sympathetic nervous system, and the natural ligands, epinephrine and norepinephrine (NE), regulate a multitude of autonomic functions including regulation of both the innate and adaptive immune response. NE is the primary neurotransmitter released by post-ganglionic sympathetic neurons that innervate most all peripheral tissues including lung and secondary lymphoid organs. Thus, the adrenergic signaling pathways are in direct contact with both the central and peripheral immune compartments. We present a perspective on how the adrenergic signaling pathway controls immune function and how β2-agonists may influence inflammation in the context of virus-induced asthma exacerbations.

Keywords: adrenergic receptor; asthma; cytokine; inflammation; rhinovirus.

Figure 1

ADRB2-mediated suppression of inflammatory processes. Adrenergic signaling through the ADRB2 inhibits various virus-induced immune mediators. [1] Rhinovirus (RV) infects the upper airways by binding to ICAM-1 on the surface of lung ECs. RV infection of ECs upregulates ICAM-1 as well as IL-8, IL-6, CCL5, CCL11, and CXCL10 to recruit inflammatory cells. [2] Activation of the ADRB2 by either the natural ligands epinephrine and norepinephrine or by β2-agonists downregulates ICAM-1 as well as IL-8, CCL5, and GM-CSF from ECs. [3] ADRB2 signaling additionally inhibits pro-inflammatory mediators in innate and adaptive immune cells. Abbreviations: EC, epithelial cell; MC, mast cell; Mɸ, macrophage.