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

使用β受体激动剂作为支气管扩张剂治疗哮喘可有效靶向气道 平滑肌细胞逆转支气管收缩和缓解呼吸困难，然而， 慢性高剂量治疗的非预期和未被认识的副作用， 药物可能是肺泡巨噬细胞代谢紊乱对 宿主防御或组织健康。我们发现了一个独特的基因表达签名， 巨噬细胞，表明抑制通用细胞激活剂环磷酸腺苷（cAMP）， 使用高剂量长效β受体激动剂治疗的重度哮喘患者。 细胞机制研究表明，急性治疗人巨噬细胞或 单核细胞与β激动剂异丙肾上腺素诱导快速cAMP合成， 腺苷酸环化酶（AC）。然而，这些细胞变得脱敏异丙肾上腺素后， 过夜暴露。脱敏是由于AC酶丰度下调 和AC负调节因子β-抑制蛋白的诱导，这些单核细胞不能 对常规刺激产生cAMP，相应地不能激活蛋白质 激酶A长时间的β激动剂暴露会导致一种紊乱的转录组学 巨噬细胞的表型与PKA激活的基因抑制 CREB/CREM网络，包括几种有益的上皮生长因子和模拟物 在哮喘患者队列中发现的基因特征。如果没有有效的cAMP- PKA信号，这些巨噬细胞变得代谢紊乱， 基础糖酵解和氧化磷酸化。此外，经典的巨噬细胞 通过TLR与LPS连接的激活快速诱导糖酵解并增加细胞游离 葡萄糖发挥宿主防御反应。细胞长期暴露于β激动剂 消除了对LPS的糖酵解反应，降低了细胞对病原体的能力， 应答这些观察结果表明，肺泡巨噬细胞的性能和宿主 使用慢性高剂量β激动剂的患者的防御反应可能有限， 它们是肺部疾病最常用的处方药。这 应用程序旨在探索密集测试的机制和后果 对巨噬细胞性能的激动作用，这可能会告知处方实践或导致 新的替代疗法的最终发展。

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.