Derangement of alveolar macrophage immunuometabolism by prolonged beta agonist therapy: Implications for host defense and tissue health

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The use of beta agonists as bronchodilator therapy for asthma effectively targets airway smooth muscle cells to reverse bronchoconstriction and relieve breathlessness, however an unintended and unrecognized side effect of chronic high dose therapy with these drugs may be that derangement of alveolar macrophage metabolism adversely impacts host defense or tissue health. We identify a unique gene expression signature in alveolar macrophages indicating suppression of the universal cell activator cyclic AMP (cAMP) in persons with severe asthma treated with high dose and long acting beta agonists. Cellular mechanistic studies reveal that acute treatment of human macrophages or monocytic cells with the beta agonist Isoproterenol induces rapid cAMP synthesis by adenylyl cyclase (AC). However, these cells become desensitized to isoproterenol after overnight exposure. Desensitization is due to downregulation of AC enzyme abundance and induction of the AC negative regulator β-arrestin, and these monocytes fail to generate cAMP to conventional stimuli with corresponding failure to activate Protein Kinase A. Prolonged beta agonist exposure causes a deranged transcriptomic phenotype of macrophages with suppression of genes in the PKA-activated CREB/CREM network that includes several salutary epithelial growth factors and mimics the gene signature discovered in the asthmatic patient cohort. Without effective cAMP- PKA signaling, these macrophages become metabolically deranged with decreases in basal glycolysis and oxidative phosphorylation. Furthermore, classical macrophage activation by TLR ligation with LPS rapidly induces glycolysis and increases cellular free glucose to exert host defensive responses. Prolonged cellular exposure to beta agonist eliminates the glycolytic response to LPS, reducing cellular capacity for pathogen responses. These observations suggest that alveolar macrophage performance and host defense responses may be limited in patients using chronic high dose beta agonists, which are among the most commonly prescribed agents for lung disease. This application seeks to explore the mechanism and consequences of intensive beta agonism on macrophage performance, which may inform prescribing practice or lead to the eventual development of new alternate therapies.