PGI2 regulation of CD4+ Th2 metabolism in allergic airway inflammation

PGI2 对过敏性气道炎症中 CD4 Th2 代谢的调节

• 批准号: 10696335
• 负责人: Ray Stokes Peebles
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696335
• 关键词: Allergens; Allergic Disease; Allergic inflammation; Allergic rhinitis; Alternaria; Amino Acids; Animals; Antiinflammatory Effect; Arachidonic Acids; Asthma; Award; Basic Science; CD4 Positive T Lymphocytes; CRISPR screen; Cell Separation; Cells; Cellular Metabolic Process; Chronic Disease; Data; Development; Disease; Disease Pathway; Effector Cell; Energy-Generating Resources; Enzymes; Eosinophilia; Epoprostenol; Extrinsic asthma; Funding; Genetic; Glucose; Glucose Transporter; Glutamate Metabolism Pathway; Glutamates; Glutaminase; Glutamine; Glycolysis; Glycolysis Inhibition; Health; Human; Human Biology; Hypersensitivity; In Vitro; Inflammatory; Interleukin-13; Interleukin-5; Link; LoxP-flanked allele; Lung; Lymphocyte; Metabolic; Metabolic Pathway; Metabolism; Military Personnel; Morbidity - disease rate; Mucous body substance; Mus; Nutrient; Pathogenicity; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Positron-Emission Tomography; Prevalence; Principal Investigator; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Public Health; Publishing; Pulmonary Hypertension; Regulation; Reporter; Resources; Role; Signal Transduction; Testing; Therapeutic; United States; United States Food and Drug Administration; Veterans; airway inflammation; allergic airway disease; allergic airway inflammation; analog; clinically relevant; cytokine; experimental study; fluorodeoxyglucose positron emission tomography; glucose uptake; human disease; in vivo; in vivo Model; metabolomics; model organism; novel; novel therapeutics; pharmacologic; programs; receptor; restraint; translational study; uptake

Asthma is one of the most common chronic diseases in the United States. There is mounting evidence that medications that inhibit the cyclooxygenase (COX) pathway of arachidonic acid metabolism are linked to new onset asthma, strongly suggesting that COX metabolic products inhibit the development of asthma. These data are supported by numerous mechanistic animal studies published by the Principal Investigator (PI) which revealed that COX inhibition increased lung expression of the CD4 T helper 2 (Th2) cytokines IL-5 and IL-13 that are important in airway eosinophilia, mucus expression, and airway responsiveness (AR), all hallmarks of allergic asthma. Several studies by the PI and other groups revealed that the COX product prostaglandin (PG)I2 restrains the development of allergic inflammation by inhibiting proinflammatory cytokine secretion by CD4 Th2 cells; however, the mechanisms by which PGI2 exerts these anti-inflammatory effects are not completely defined. Our novel, unpublished preliminary data reveals that PGI2 signaling inhibited glycolysis, glycolytic capacity, and glycolytic reserve in CD4 Th2 cells, suggesting that PGI2 has a critical role in CD4 T cell immunometabolism. We provide evidence in our preliminary data that PGI2 decreases CD4 Th2 expression of Glut1, the glucose transporter that is essential for the uptake of glucose and amino acids into the cell and which is required for glycolysis. Additional preliminary data of targeted metabolomics identified the glutamine metabolism pathway as being substantially regulated when CD4 Th2 cells were polarized in the presence or absence of the PGI2 analog cicaprost. However, the mechanisms by which PGI2 signaling inhibits glycolysis and the glutamine metabolic pathway are not known. In this application, we will test the overall hypothesis that PGI2 restrains allergen-induced airway inflammation by inhibiting glucose and glutamine metabolism in Th2 effector cells, thus defining the immunometabolic mechanisms by which PGI2 restrains allergic inflammation in the lung. In this application, we will use complementary genetic and pharmacologic approaches, both in vivo and in in vitro experiments using primary CD4 T lymphocytes. We will create novel model organisms to definitively determine how regulates glycolysis and glutamine metabolism using conditional mice floxed for the PGI2 receptor IP, that were specifically created through funding of the last cycle of this Merit Award. This current Merit proposal is clinically relevant in defining the immunometabolic mechanisms by which PGI2 inhibits CD4 differentiation and function in allergic airway inflammation, thus providing support for the use of PGI2 in the treatment of allergic diseases such as asthma. The proposed experiments will be paradigm shifting by being the first to define how a prostaglandin regulates immunometabolism and will advance the field and the health of our nation's Veterans by discovering new therapeutic pathways for diseases that are exacerbated by increases in the glycolytic and glutaminolysis pathways. Further, these studies may define new mechanisms by which PGI2 is beneficial in other diseases states, such as pulmonary hypertension, for which CD4 T lymphocytes are becoming increasingly recognized as having a pathogenic role. Thus, this application provides an opportunity for basic science discovery, as well as having important treatment implications for hypersensitivity diseases, including asthma. PGI2

哮喘是美国最常见的慢性疾病之一。越来越多的证据 抑制花生四烯酸代谢的环氧合酶（考克斯）途径的药物与 新发哮喘，强烈提示考克斯代谢产物抑制哮喘的发展。 这些数据得到了主要研究者（PI）发表的大量机制动物研究的支持 其揭示了考克斯抑制增加了CD 4辅助性T细胞2（Th 2）细胞因子IL-5和IL-10的肺表达。 IL-13在气道嗜酸性粒细胞增多、粘液表达和气道反应性（AR）中起重要作用， 过敏性哮喘的症状PI和其他小组的几项研究表明，考克斯产品 前列腺素（PG）I2通过抑制促炎细胞因子抑制过敏性炎症的发展 然而，PGI 2发挥这些抗炎作用的机制 并没有完全定义。我们新的、未发表的初步数据显示， PGI2 信号传导抑制 糖酵解、糖酵解能力和糖酵解储备在CD 4 Th 2细胞中，表明PGI 2具有 在CD 4 T细胞免疫代谢中的关键作用。我们在初步数据中提供的证据表明，PGI 2 降低Glut 1的CD 4 Th 2表达，Glut 1是葡萄糖摄取所必需的葡萄糖转运蛋白， 糖酵解所需的氨基酸。其他目标的初步数据 代谢组学鉴定了谷氨酰胺代谢途径，当CD 4 Th 2细胞在PGI 2类似物cicaprost存在或不存在下极化。但 的机制 PGI2 信号传导抑制糖酵解和谷氨酰胺代谢途径是未知的。 在本申请中，我们将检验PGI 2抑制过敏原诱导的气道炎症的总体假设。 通过抑制Th 2效应细胞中的葡萄糖和谷氨酰胺代谢来抑制炎症，从而定义了 PGI 2抑制肺部变应性炎症的免疫代谢机制。 在本申请中，我们将使用互补的遗传和药理学方法，无论是在体内， 在使用原代CD 4 T淋巴细胞的体外实验中。我们将创造新的模式生物， 确定如何调节糖酵解和谷氨酰胺代谢使用条件小鼠floxed为PGI 2 接受者知识产权，是通过该优异奖的最后一个周期的资金专门创建的。该电流 Merit提案在定义PGI 2抑制CD 4的免疫代谢机制方面具有临床相关性 在过敏性气道炎症中的分化和功能，从而为PGI 2在过敏性气道炎症中的应用提供支持。 治疗过敏性疾病，如哮喘。拟议的实验将是范式转移， 第一个定义前列腺素如何调节免疫代谢，并将推动该领域和健康 我们国家的退伍军人通过发现新的治疗途径的疾病，加剧了 糖酵解和β-氨基糖苷分解途径增加。此外，这些研究可能会定义新的机制， PGI 2在其他疾病状态中是有益的，例如肺动脉高压，对于这些疾病，CD 4 T 淋巴细胞越来越被认为具有致病作用。因此，本申请 为基础科学发现提供了机会，并对治疗具有重要意义。 过敏性疾病，包括哮喘。 PGI2

项目成果

Prostaglandin I2 and T Regulatory Cell Function: Broader Impacts.

前列腺素 I2 和 T 调节细胞功能：更广泛的影响。

• DOI: 10.1089/dna.2021.0515
• 发表时间: 2021
• 期刊: DNA and cell biology
• 影响因子: 3.1
• 作者: Norlander,AllisonE;Peebles,RStokes
• 通讯作者: Peebles,RStokes

The emerging role of IL-23 in asthma and its clinical implications.

IL-23 在哮喘中的新作用及其临床意义。

• DOI: 10.1080/1744666x.2023.2125380
• 发表时间: 2023
• 期刊: Expert review of clinical immunology
• 影响因子: 4.4
• 作者: Wu,AshleyY;Peebles,RStokes
• 通讯作者: Peebles,RStokes

MUCing up the airway in asthma.

哮喘患者气道中的MUC。

• DOI: 10.1016/j.jaci.2021.09.032
• 发表时间: 2021
• 期刊: The Journal of allergy and clinical immunology
• 作者: PeeblesJr,RStokes

Mouse Models of Respiratory Syncytial Virus Infection.

• DOI: 10.1007/978-1-0716-2364-0_2
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)

Reply to Yasuma et al.

回复 Yasuma 等人。

• DOI: 10.1164/rccm.202309-1622le
• 发表时间: 2023
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Norlander,AllisonE;Abney,Masako;Cephus,Jacqueline-Yvonne;Roe,CarolineE;Irish,JonathanM;Shelburne,NicholasJ;Newcomb,DawnC;Hemnes,AnnaR;PeeblesJr,RStokes
• 通讯作者: PeeblesJr,RStokes