Metabolic perturbations in conventional dendritic cells modulate Tfh13 induction in asthmatic sensitization

传统树突状细胞的代谢扰动调节哮喘致敏中的 Tfh13 诱导

• 批准号: 10587341
• 负责人: Rebecca Kelley Martin
• 金额: $ 55.37万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-25 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587341
• 关键词: Affinity; Allergens; Allergic; Antibodies; Antigen Presentation Pathway; Antigens; Asthma; B-Lymphocytes; Biological Assay; Blood; Bronchoconstriction; Carbon; Cell Nucleus; Cells; Chronic; Chronic lung disease; Citric Acid Cycle; Data; Dendritic Cells; Development; Disease; Effector Cell; Energy Metabolism; Enzymes; Exhibits; Extrinsic asthma; Flow Cytometry; Fumarates; Gene Expression; Genetic Transcription; Glucose; Glutaminase; Glutamine; Goals; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; IgE; In Vitro; Inflammation; Knowledge; Label; Lung; Malates; Mediastinal lymph node group; Metabolic; Metabolism; Mus; O Antigens; Pathway interactions; Prevalence; Prevention strategy; Production; Pulmonary Inflammation; Regulation; Signal Transduction; Stimulus; Succinates; T-Lymphocyte; Testing; Tonsil; Work; airborne allergen; airway hyperresponsiveness; alpha ketoglutarate; asthma model; asthmatic; chronic respiratory disease; clinical translation; cytokine; demethylation; environmental allergen; extracellular; fatty acid oxidation; high dimensionality; in vivo; inhibitor; mast cell; metabolomics; migration; new therapeutic target; polarized cell; programs; response; transcriptome sequencing

Abstract Allergic asthma is among the most common chronic lung diseases worldwide, and despite advances in treatment asthma prevalence continues to rise globally. Allergic asthma is largely driven by IgE antibodies that target environmental allergens. The production of allergen-specific IgE requires T follicular helper 13 cells (Tfh13) which must first be polarized by dendritic cells (DCs). However, a critical knowledge gap remains: how do DCs gain the ability to induce Tfh13s? By studying DC responses to allergic stimuli, we have determined that allergens induce a unique metabolic program in DCs, characterized by increased glutamine metabolism. We identified that allergen stimulated DCs exhibit aberrant TCA cycle metabolism, which leads to accumulation of α-ketoglutarate and succinate and reduced levels of fumarate and malate. We hypothesize that DC glutamine metabolism after allergen exposure is critical for polarization of Tfh13s. The goals of this proposal are (1) to ascertain effector mechanisms downstream of glutamine metabolism that induce Tfh13 polarization, (2) to elucidate key mechanistic changes in DCs induced by aberrant TCA cycle metabolites, and (3) to determine the translatability of this pathway into human DCs. This work promises an exciting new avenue for development of novel therapeutic targets and preventive strategies for the management of allergic asthma.

摘要 过敏性哮喘是世界范围内最常见的慢性肺部疾病之一，尽管在治疗方面取得了进展， 治疗哮喘患病率在全球范围内持续上升。过敏性哮喘主要由IgE驱动 针对环境过敏原的抗体。过敏原特异性IgE的产生需要T 滤泡辅助13细胞（Tfh 13），其必须首先被树突状细胞（DC）极化。但 关键的知识差距仍然存在：DC如何获得诱导Tfh 13的能力？通过学习DC 对过敏刺激的反应，我们已经确定，过敏原诱导一个独特的代谢程序， DC，其特征在于谷氨酰胺代谢增加。我们发现过敏原刺激的DC TCA循环代谢异常，导致α-酮戊二酸和琥珀酸蓄积 并降低富马酸盐和苹果酸盐的水平。我们假设，DC谷氨酰胺代谢后， 过敏原暴露对于Tfh 13 s的极化是关键的。本提案的目标是（1） 确定谷氨酰胺代谢下游诱导Tfh 13极化的效应机制，（2） 阐明由异常TCA循环代谢物诱导的DC中的关键机制变化，以及（3） 确定该途径向人DC中的可翻译性。这项工作预示着一个令人兴奋的新的 开发新的治疗靶点和预防策略的途径， 过敏性哮喘