Macrophage Immunometabolism alteration by intense beta agonist therapy.

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ABSTRACT 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 of these monocytes causes them to fail to generate cAMP with corresponding failure to activate its molecular target 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 and mimics the gene signature discovered in the asthmatic patient cohort. In single cell analysis, monocytes are more impacted than alveolar macrophages. Other gene expression changes include pathways involved in cell metabolism like glycolysis and lipid metabolism. Beta agonist suppression of cAMP-PKA signaling causes these macrophages to become metabolically quiescent with decreased glycolysis and oxidative phosphorylation. Activation of the mTOR protein is suppressed by prolonged beta agonist exposure, limiting the glycolytic response to LPS, which is important for pathogen responses. Likewise, beta-agonist induced metabolic quiescence in macrophages impairs their ability to effectively engulf bacterial particles or clear live bacteria from a co-culture model. Mice treated with the beta agonist salmeterol show sluggish macrophage responses to bacteria or LPS induction of glycolysis. 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 intense beta agonist exposure on macrophage performance, which may inform prescribing practice or lead to the eventual development of new alternate therapies.