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

基本信息

批准号：
10540821
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
项目类别：
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/10540821
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 Separation 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 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 Receptors, Tumor Necrosis Factor, Type II 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 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

项目摘要

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开发更好的呼吸道炎症和过敏疗法哮喘。第 2 组先天淋巴细胞 (ILC2) 是最近鉴定的产生 2 型淋巴细胞的细胞群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，哮喘和许多常见疾病中 ILC2 活性增加，因为 ILC2 足以诱导小鼠气道炎症，与适应性免疫无关。拟议的研究计划是受到我们实验室和其他实验室最近的新观察的启发，即 TNF/TNFR2 轴控制 ILC2- 依赖性气道炎症（细胞报告 2019，J 过敏临床免疫学杂志 2020）。高水平的 TNF 是哮喘患者的肺部发现了 TNF，但抗 TNF 治疗通常与全身性疾病相关。由于存在两种功能不同的 TNF 受体：TNFR1 和 TNFR2，因此产生毒性。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 ILC2 效应细胞因子 IL-5 和 IL-13 的分泌。通过 TNFR2 信号传导生存，导致气道炎症。然而，TNF/TNFR2 轴如何其机制如何影响 ILC2 以及气道炎症的后续发展仍有待探索。根据我们的数据，我们假设阻断 ILC2 上的 TNFR2 会诱导免疫调节表型促进独特的代谢来源，共同有利于减少 AHR。在具体目标 1 (SA1) 中，我们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 在激活的 ILC2 上异质表达。我们因此，将使用以下组合来表征驱动 ILC2 中 TNF 作用的转录因子单细胞基因组和转录组分析。此外，我们实验室和其他实验室的数据表明 ILC2 中的代谢过程依赖于脂肪酸氧化 (FAO) 产生的能量氧化磷酸化。有趣的是，我们的结果清楚地表明 TNFR2-/- 中代谢转向糖酵解 ILC2。基于这些结果，我们打算评估 WT 和 TNFR2-/- ILC2 中的糖酵解和 FAO 机制在SA2中。最后，我们之前证明人类 ILC2 表达 TNFR2，并开发出人源化 ILC2 小鼠 TNFR2 依赖性 AHR 对 TNF 的反应。因此，我们打算在 SA3 中评估我们的相关性哮喘患者的研究结果。我们将从精心挑选的队列中收集肺和血液 ILC2 轻度/中度、重度哮喘患者和健康供体，并将 BAL 中的 TNF 水平与 ILC2 数量/TNFR2 表达，以及监测表达 TNFR2 的其他细胞。这些研究，基于强有力的初步数据，将专注于开发过敏性哮喘的新疗法。为了为了实现这些成果，我们组建了一个团队，其中包括肺生物学领域的顶尖专家和首席科学家临床肺病学，以补充我们在临床前模型方面的丰富经验。