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.

抽象的 过敏性哮喘是全世界最常见的慢性肺部疾病之一，尽管在这方面取得了进展 全球哮喘患病率持续上升。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 滤泡辅助细胞 13 (Tfh13) 必须首先被树突状细胞 (DC) 极化。然而，一个 关键的知识差距仍然存在：树突状细胞如何获得诱导 Tfh13 的能力？通过研究DC 对过敏刺激的反应，我们已经确定过敏原会诱导一种独特的代谢程序 DCs，其特征是谷氨酰胺代谢增加。我们发现过敏原刺激 DC 表现出异常的 TCA 循环代谢，导致 α-酮戊二酸和琥珀酸的积累 并降低富马酸盐和苹果酸盐的含量。我们假设 DC 谷氨酰胺代谢后 过敏原暴露对于 Tfh13 的极化至关重要。该提案的目标是 (1) 确定诱导 Tfh13 极化的谷氨酰胺代谢下游效应机制，(2) 阐明由异常 TCA 循环代谢物诱导的 DC 的关键机制变化，以及 (3) 确定该途径向人类 DC 的可翻译性。这项工作有望带来令人兴奋的新成果 开发新的治疗靶点和预防策略的途径 过敏性哮喘。