Role of TNF receptor 2 on Pulmonary Group 2 Innate Lymphoid Cells

TNF 受体 2 对肺 2 组先天淋巴细胞的作用

• 批准号: 10378913
• 负责人: OMID AKBARI
• 金额: $ 78.42万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378913
• 关键词: ATAC-seq; Affect; Airway Disease; Allergic Disease; Anti-Inflammatory Agents; Anti-Tumor Necrosis Factor Therapy; Asthma; Automobile Driving; Biology; Blood; Bronchodilator Agents; Cell Survival; Cells; Clinical; Complement; Data; Development; Disease; Effector Cell; Epithelial Cells; Extrinsic asthma; Flow Cytometry; Generations; Genomics; Glycolysis; Goals; Health Care Costs; Homeostasis; Human; Hypersensitivity; Immune; Immunosuppressive Agents; Interleukin-10; Interleukin-13; Interleukin-5; Knowledge; Laboratories; Lead; Lung; Lymphoid Cell; Metabolic; Metabolic Pathway; Metabolism; Monitor; Morbidity - disease rate; Mus; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Phenotype; Population; Pre-Clinical Model; Prevalence; Production; Pulmonary Inflammation; Pulmonology; Reporting; Research; Respiratory Therapy; Role; Signal Transduction; Source; Stimulus; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Therapeutic; Translating; Tumor Necrosis Factor Receptor; Widespread Disease; Work; adaptive immunity; airway hyperresponsiveness; airway inflammation; asthmatic; asthmatic patient; base; cohort; cytokine; design; experience; fatty acid oxidation; immunoregulation; lipidomics; mouse model; novel therapeutics; response; side effect; standard of care; systemic toxicity; transcription factor; transcriptome; transcriptomics

Abstract The long-term goal of this project is to develop better therapies for respiratory inflammation and allergic asthma. Group 2 innate lymphoid cells (ILC2) are a recently identified cell population producing type 2 cytokines in response to a growing number of environmental signals and epithelial cell-derived cytokines. Studies show increased ILC2 activity in asthma and many widespread diseases, as ILC2s are sufficient to induce airway inflammation independent of adaptive immunity in mice. The proposed research plan is motivated by recent new observations from our laboratory and others that the TNF/TNFR2 axis controls ILC2- dependent airway inflammation (Cell Report 2019, J Allergy Clin Immunol. 2020). High levels of TNF are found in the lungs of asthmatic patients, however anti-TNF therapy is generally associated with systemic toxicity due to the existence of two distinct functionally different receptors for TNF: TNFR1 and TNFR2. Our results suggest that TNF enhanced the secretion of ILC2 effector cytokines IL-5 and IL-13 and increased survival via TNFR2 signaling, leading to airway inflammation. However, how the TNF/TNFR2 axis mechanistically affects ILC2s and subsequent development of airway inflammation remains to be explored. Based on our data, we hypothesize that blocking TNFR2 on ILC2s induces an immunoregulatory phenotype fueling on a distinct metabolic source, together favoring the reduction of AHR. In Specific Aim 1 (SA1), we have designed several approaches to characterize the effects of TNF on ILC2 effector functions and lung inflammation. Our preliminary data suggest that TNFR2 is heterogeneously expressed on activated ILC2s. We will therefore characterize the transcription factors driving the effects of TNF in ILC2s using a combination of single cell genomic and transcriptomic analysis. Furthermore, data from our laboratory and others suggest that metabolic processes in ILC2s are dependent on the generation of energy from fatty acid oxidation (FAO) and oxidative phosphorylation. Interestingly our results clearly show a metabolic shift towards glycolysis in TNFR2-/- ILC2s. Based on these results we intend to assess glycolysis and FAO mechanisms in WT and TNFR2-/- ILC2s in SA2. Finally, we previously showed that human ILC2s express TNFR2 and humanized ILC2 mice developed TNFR2-dependent AHR in response to TNF. Therefore, we intend to assess in the SA3 the relevance of our findings in asthmatic patients. We will collect lung and blood ILC2s from carefully selected cohorts of mild/moderate, severe asthmatics and healthy donors and correlate the levels of TNF in the BAL to the numbers of ILC2s/expression of TNFR2, as well as monitor other cells that express TNFR2. These studies, based on strong preliminary data, will focus on developing novel therapy for allergic asthma. In order to achieve these results we have assembled a team including leading experts in lung biology and the chief of clinical pulmonology to complement our extensive experience in pre-clinical models.

抽象的 该项目的长期目标是为呼吸道炎症和过敏性开发更好的疗法 哮喘。第2组先天淋巴样细胞（ILC2）是最近鉴定出的细胞种群，产生2型 细胞因子响应越来越多的环境信号和上皮细胞衍生的细胞因子。 研究表明，哮喘和许多广泛疾病的ILC2活性增加，因为ILC2足以使 诱导无关小鼠自适应免疫的气道炎症。拟议的研究计划是 由我们的实验室和其他人最近的新观察结果激励，因为TNF/TNFR2轴控制ILC2- 依赖气道炎症（2019细胞报告，J Allergy ClinImmunol。2020）。高水平的TNF是 在哮喘患者的肺中发现，但是抗TNF治疗通常与全身有关 由于存在两个不同功能不同的受体TNF：TNFR1和TNFR2引起的毒性。我们的 结果表明，TNF增强了ILC2效应细胞因子IL-5和IL-13的分泌，并增加了 通过TNFR2信号传导生存，导致气道炎症。但是，TNF/TNFR2轴如何 机械上会影响ILC2和随后的气道炎症发展尚待探讨。 根据我们的数据，我们假设阻止TNFR2在ILC2上诱导免疫调节表型 在独特的代谢来源上加油，共同利于减少AHR。在特定的目标1（SA1）中，我们 已经设计了几种方法来表征TNF对ILC2效应器功能和肺的影响 炎。我们的初步数据表明，TNFR2在活化的ILC2上表达异质。我们 因此，将表征通过使用的结合 单细胞基因组和转录组分析。此外，我们实验室和其他的数据表明 ILC2S中的代谢过程取决于脂肪酸氧化（FAO）的能量产生和 氧化磷酸化。有趣的是，我们的结果清楚地表明，在TNFR2 - / - 中向糖酵解的代谢转变 ILC2S。基于这些结果，我们打算评估WT和TNFR2 - / - ILC2S中的糖酵解和FAO机制 在SA2中。最后，我们先前表明人ILC2S表达TNFR2和人源化ILC2小鼠 TNFR2依赖性AHR响应TNF。因此，我们打算在SA3中评估我们的相关性 哮喘患者的发现。我们将从精心挑选的人群中收集肺和血液ILC2 轻度/中度，严重的哮喘患者和健康的供体，并将BAL中的TNF水平与 TNFR2的ILC2S/表达的数量，并监测表达TNFR2的其他细胞。这些研究， 基于强大的初步数据，将专注于开发新的过敏性哮喘治疗疗法。为了 达到这些结果，我们组建了一个团队，包括肺部生物学领域的主要专家和 临床肺病学以补充我们在临床前模型中的丰富经验。