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.

摘要 该项目的长期目标是开发更好的治疗呼吸道炎症和过敏性疾病的方法。 哮喘组2先天淋巴样细胞（ILC 2）是最近鉴定的产生2型的细胞群体 细胞因子响应于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中ILC 2活性增加，因为ILC 2足以 不依赖于小鼠获得性免疫诱导气道炎症。拟议的研究计划是 受我们实验室和其他实验室最近的新观察结果的启发，TNF/TNFR 2轴控制ILC 2- 依赖性气道炎症（Cell Report 2019，J Allergy Clin Immunol. 2020）。高水平的TNF 在哮喘患者的肺中发现，然而抗TNF治疗通常与全身性 由于存在两种功能不同的TNF受体：TNFR 1和TNFR 2而导致的毒性。我们 结果表明TNF增强ILC 2效应细胞因子IL-5和IL-13的分泌， 通过TNFR 2信号传导存活，导致气道炎症。然而，TNF/TNFR 2轴 机制上影响ILC 2，并且随后气道炎症的发展仍有待探索。 基于我们的数据，我们假设阻断ILC 2上的TNFR 2诱导免疫调节表型， 在不同的代谢源上加燃料，共同有利于AHR的降低。在具体目标1（SA 1）中，我们 已经设计了几种方法来表征TNF对ILC 2效应器功能和肺功能的影响， 炎症我们的初步数据表明，TNFR 2是异质性表达的活化ILC 2。我们 因此，将使用以下组合来表征驱动ILC 2中TNF作用的转录因子： 单细胞基因组和转录组分析。此外，我们实验室和其他机构的数据表明， ILC 2的代谢过程依赖于脂肪酸氧化产生的能量（FAO）， 氧化磷酸化有趣的是，我们的结果清楚地表明，TNFR 2-/- ILC2。基于这些结果，我们打算评估WT和TNFR 2-/-ILC 2中的糖酵解和FAO机制。 在SA 2中。最后，我们先前表明人ILC 2表达TNFR 2，并且人源化ILC 2小鼠发育为 TNFR 2依赖性AHR对TNF的应答。因此，我们打算在《战略分析3》中评估我们的 哮喘患者的发现。我们将从仔细选择的队列中收集肺和血液ILC 2， 轻度/中度，重度哮喘患者和健康供体，并将BAL中TNF水平与 ILC 2的数量/TNFR 2的表达，以及监测表达TNFR 2的其他细胞。这些研究， 基于强有力的初步数据，将致力于开发过敏性哮喘的新疗法。为了 为了取得这些成果，我们组建了一个团队，包括肺生物学领域的顶尖专家和 临床肺病学，以补充我们在临床前模型方面的丰富经验。