Macrophage Immunometabolism alteration by intense beta agonist therapy.

强β激动剂治疗改变巨噬细胞免疫代谢。

基本信息

批准号：
10002645
负责人：
NATHANIEL M WEATHINGTON
金额：
$ 48.48万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10002645
关键词：
Acute Adenylate Cyclase Adrenergic Receptor Agonist Alveolar Macrophages Anabolism Area Asthma Bacteria Bronchoalveolar Lavage Bronchoconstriction Bronchodilator Agents CREB1 gene Cell Line Cells Cellular Metabolic Process Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Containment Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Disease Dose Drug Prescriptions Dyspnea E protein Endotoxins Enzymes Event Exhibits Exposure to FRAP1 gene Failure Gene Expression Gene Expression Profile Genes Glucose Glycolysis Glycolysis Induction Health Host Defense Human Hypoxia Inducible Factor Immune Immune response Impairment Infection Inflammation Isoproterenol Lead Leukocytes Ligands Link Lung Lung diseases Macrophage Activation Metabolic Metabolism Microbe Modeling Molecular Molecular Target Mus Nature Oxidative Phosphorylation Participant Pathway interactions Patients Pattern Performance Persons Phagocytosis Pharmaceutical Preparations Pharmacology Phenotype Production Proteins RNA Research Respiratory Burst Respiratory physiology Salmeterol Signal Transduction Signaling Molecule Smooth Muscle Myocytes Tissues asthmatic asthmatic patient cell type cohort cytokine defense response desensitization fighting genetic signature lipid metabolism lung injury macrophage monocyte mouse model novel overexpression particle pathogen prevent programs respiratory colonization respiratory smooth muscle response side effect single cell analysis transcription factor transcriptomics

项目摘要

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.

抽象的使用β激动剂作为支气管扩张剂治疗哮喘有效地针对气道平滑肌细胞以逆转支气管收缩并缓解呼吸困难，但是使用这些药物的慢性高剂量治疗的意外且无法识别的副作用可能肺泡巨噬细胞代谢的危险会对宿主防御产生不利影响或组织健康。我们确定肺泡巨噬细胞中独特的基因表达特征指示抑制通用细胞激活剂环状AMP（CAMP）用高剂量和长作用β激动剂治疗的严重哮喘。细胞机理研究表明，用β对人巨噬细胞或单核细胞的急性治疗激动剂异丙肾上腺素诱导腺苷环酶（AC）诱导快速cAMP合成。然而，一夜之间暴露后，这些细胞会脱敏对异丙肾上腺素。脱敏这些单核细胞中的中断导致它们无法产生营地激活其分子靶蛋白激酶A。长时间的β激动剂暴露会导致A 巨噬细胞的精神转录组表型，并在PKA-中抑制基因激活的CREB/CREM网络并模仿哮喘中发现的基因特征患者队列。在单细胞分析中，单核细胞比肺泡更大巨噬细胞。其他基因表达变化包括涉及细胞的途径糖酵解和脂质代谢等新陈代谢。 Beta激动剂抑制营地PKA 信号传导导致这些巨噬细胞随着新陈代谢而静止糖酵解和氧化磷酸化。 MTOR蛋白的激活被抑制长时间的β激动剂暴露，限制了对LP的糖酵解反应，这很重要用于病原体反应。同样，β激动剂诱导代谢静止巨噬细胞会损害其有效吞噬细菌颗粒或清除活细菌的能力来自共培养模型。用β激动剂salmeterol治疗的小鼠表现迟钝巨噬细胞对细菌或LPS诱导糖酵解的反应。这些观察表明肺泡巨噬细胞性能和宿主防御反应可能受到限制在使用慢性高剂量β激动剂的患者中，这是最常见的规定肺部疾病的药物。本应用程序旨在探索机制和强烈的β激动剂暴露对巨噬细胞性能的后果，这可能告知处方实践或导致最终开发新的替代疗法。