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Targeting T cell glutamine metabolism in severe asthma

针对严重哮喘患者的 T 细胞谷氨酰胺代谢

基本信息

批准号：
10429985
负责人：
Dawn C Newcomb
金额：
$ 60.31万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-06 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10429985
关键词：
Affect Airway Disease Allergens Amino Acids Animal Model Asthma Automobile Driving Bronchial Spasm CD4 Positive T Lymphocytes CRISPR screen Cell physiology Cells Cellular Metabolic Process Characteristics Chromatin Clinic Clinical Cytometry Data Dependence Development Disease Electron Transport Enzymes Epigenetic Process Equilibrium Estrogen Receptors Female Frequencies Gene Expression Gene Targeting Generations Genes Genetic Glucose Glutamates Glutaminase Glutamine Glycolysis Guanine Nucleotide Exchange Factors Hexosamines High Fat Diet IL17 gene IL4 gene Immune In Vitro Incidence Inflammation Inflammatory Interleukin-17 Liquid substance Lung Lung Lavage Fluid Mediating Metabolic Metabolic Diseases Metabolic Marker Metabolic Pathway Metabolic dysfunction Metabolism Mitochondria Modeling Mucous body substance Mus Obesity Oxidation-Reduction Pathway interactions Patients Play Population Process Production Pulmonary Inflammation Pyroglyphidae Regulatory T-Lymphocyte Resistance Respiration Risk Risk Factors Role Sampling Severities T cell differentiation T cell regulation T-Lymphocyte T-Lymphocyte Subsets Testing Th2 Cells Therapeutic Translating Weight Woman airway hyperresponsiveness airway inflammation airway remodeling allergic airway inflammation alpha ketoglutarate asthma exacerbation asthmatic patient chronic inflammatory disease cytokine diet-induced obesity effector T cell eosinophil glucose metabolism health disparity high dimensionality immune function in vivo inhibitor male men metabolomics mitochondrial metabolism mouse model neutrophil new therapeutic target novel therapeutics obesity risk obesity-associated asthma peripheral blood programs sex therapy resistant uptake

项目摘要

SUMMARY Asthma is a debilitating disease of airway inflammation with increasing worldwide occurrence. With higher incidence in females, asthma is exacerbated by obesity and metabolic disease. Underlying asthma is activation of innate immune and T cells that drive inflammation. Airway inflammation in severe asthma is caused in part by an imbalance between effector CD4 T cells (including Th2 and Th17) and suppressive regulatory (Treg) T cells. This imbalance is particularly heightened in obese females and leads to increased eosinophils and/or neutrophils in the airway, increased airway hyperresponsiveness, and increased mucus production. It is now clear that T cell metabolism plays a critical role to regulate immune function and the distinct metabolic programs of each T cell subset can influence inflammation and play roles in asthma. In addition to a requirement of T cells for glycolysis, our data show that glutamine metabolism plays a key role to support inflammatory T cells in asthma. Metabolomics data from bronchoalveolar fluid and mass cytometry of T cells from donors with severe asthma showed markers of elevated glutaminolysis. While IL17 producing cells both in vitro and from lungs had the highest expression of metabolic markers, both Th17 and Th2 cells relied on glutamine for differentiation and cytokine production. Glutamine metabolism is regulated through uptake by the transporter ASCT2 and Glutaminase (GLS)-dependent conversion to glutamate and α-ketoglutarate that supports mitochondrial electron transport and regulates epigenetic marks that control chromatin and gene expression. We have now shown through inhibition, gene targeting, and in vivo primary T cell CRISPR screening in lung inflammation that ASCT2 and GLS are essential for Th17 and Th2 cells. These genes are dispensable for Treg and blocking glutamine uptake can instead enhance Treg differentiation. Importantly, we also show in an animal model that high fat diet fed female mice have selectively increased frequencies of Th17 cells. This effect is sex-specific, as high fat diet fed female, but not male, mice developed increased IL17 production and we show that the Estrogen Receptor (ERα) plays a key role in females to elevate CD4 T cell glycolysis and mitochondrial metabolism. We hypothesize that airway allergen exposure and inflammatory cytokines induce T cell glutamine metabolism, driving Th2 and Th17 cells that contribute to asthma incidence and severity in obese females. To test this hypothesis, we will: (1) Determine the role and mechanism of GLS and ASCT2-dependent glutamine metabolism to regulate the balance of Th2, Th17 and Treg cells in a mixed model of allergic airway inflammation and (2) Test if obesity- induced exacerbation of asthma severity in females is dependent on enhanced T cell glutamine metabolism in animal models and from peripheral blood and excised lungs of healthy and severe asthma normal weight or obese donors. These studies will establish metabolic mechanisms and if inhibiting glutamine uptake or metabolism through ASCT2 or GLS can shift the balance of Th17 and Th2 cells to instead favor Treg and protect against asthma to help alleviate this health disparity observed in females with metabolic disease.

总结