A novel pathway of Th17/Th2 induction: The role of cAMP signaling in DC

Th17/Th2 诱导的新途径：cAMP 信号在 DC 中的作用

基本信息

批准号：
10331024
负责人：
Eyal Raz
金额：
$ 71.98万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10331024
关键词：
Acute Address Adjuvant Agonist Allergic Disease Asthma Binding Biological Products Bronchodilation Cell membrane Cells Chromatin Chronic Conjunctivitis Crohn&apos s disease Cyclic AMP Dendritic Cells Dependence Dermatitis Development Disease Event Foundations G-Protein-Coupled Receptors GKLF protein GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Gene Expression Profile Genetic Genetic Transcription Genomics Human IRF4 gene ITGAX gene Immune Immunization Immunologics Immunotherapeutic agent Individual Knockout Mice Lung Mediating Mediator of activation protein Modification Mucous Membrane Multiple Sclerosis Mus Pathologic Pathology Pathway interactions Pharmacology Phenotype Property Proteome Psoriasis Pyroglyphidae RUNX3 gene Regulation Research Rhinitis Role Signal Transduction T cell differentiation T-Lymphocyte Testing adaptive immunity age related arm base chromatin modification cost cytokine eosinophilic asthma epigenomics immunopathology innovation insight knock-down metabolome monocyte mouse model neutrophil novel novel therapeutics overexpression receptor respiratory smooth muscle response single-cell RNA sequencing transcription factor

项目摘要

Abstract Th2 and Th17 are two major arms of adaptive immunity involved in protective and pathological responses. The range of their immune-mediated pathologies includes allergic diseases (Th2), Crohn’s disease (Th17), multiple sclerosis (Th17) and psoriasis (Th17). Despite the introduction of biologics such as anti-cytokines Abs, more effective and low-cost therapies are not yet available. We have identified a new pathway that regulates both Th2 and Th17 differentiation by cAMP levels in dendritic cells (DC). In this MPI RO1 application entitled: “A novel pathway of Th17/Th2 induction - the role of cAMP signaling in DC” we propose that exploring the underlying mechanisms and signaling events mediated through the G proteins; Gαs (Gnas) and Gαi (Gnai2), which stimulate and inhibit cAMP synthesis, respectively, can provide the foundation for such new therapies. The inhibition of this pathway (low cAMP) provokes Th2-inducing DC (pro-Th2 DC), and its activation (high cAMP) induces Th17-inducing DC (pro-Th17 DC). We generated two genetic mouse models; GnasΔCD11c that develop spontaneous Th2 bias and Gnai2ΔCD11c that develop a Th17 bias responses. We recently identified that different cAMP inducers regulate the expression levels of transcription factors in cDC2 cells that provoke Th17/Th2 differentiation such as interferon regulatory factor 4 (IRF4), IRF5, Kruppel-like factor 4 (KLF4) and Notch2. Here we shown that different cAMP inducers regulate the expression levels of these factors and switch the subsequent Th bias, which has led us to propose that the cDC2 cells represent a plastic DC subpopulation and that the cAMP levels dictate whether the cDC2 have a pro-Th17 and pro-Th2 bias. Hence, in this application we will explore and dissect the following topics: In SA1 - we will analyze whether increasing cAMP by genetic deletion of Gnai2 in DC causes a Th17-associated immunopathology overtime, in SA2 – we will determine and test the transcriptional network that defines the phenotypic pro-Th17 or pro-Th2 cDC2 subpopulations, in SA3 - we will test whether GPCR agonists (i.e., β2AR agonists) that increase cAMP levels, provoke Th17-driven neutrophilic asthma, and in SA4 - we will identify and functionally test novel pro-Th17 or pro-Th2 mediators produced by DC cells. In summary - our discovery that cAMP regulates the pro-Th2 and pro-Th17 inducing properties of cDCs has led to the identification of new pathway of Th2/Th17 regulation. The results will provide new insights into the plasticity of cDC2 and Th2- and Th17- biasing. It has the potential to advance basic immunological research and establish the basis for novel and innovative immunotherapeutic strategies.

抽象的 TH2和TH17是保护和病理涉及的自适应免疫学的两个主要臂回答。它们的免疫介导病理的范围包括过敏性疾病（TH2），克罗恩病（TH17），多发性硬化症（Th17）和牛皮癣（Th17）。尽管引入了在诸如抗循环动物ABS之类的生物学中，尚未进行更有效和低成本的疗法可用的。我们已经确定了一种新的途径，该途径通过树突状细胞（DC）中的营地水平。在此MPI RO1应用程序中的标题为“： TH17/TH2诱导 - CAMP信号在DC中的作用”，我们提出了探索基础的通过G蛋白介导的机制和信号事件； GαS（GNA）和GαI （GNAI2）分别刺激和抑制营地合成，可以提供基础用于这种新疗法。这种途径的抑制作用（低训练营）引起了Th2诱导DC （Pro-Th2 DC）及其激活（高cAMP）诱导Th17诱导的DC（Pro-Th17 DC）。我们产生了两个遗传小鼠模型； GNASΔCD11c发展出赞助的Th2偏置和 GNAI2ΔCD11C产生Th17偏置响应。我们最近确定了不同的营地诱导者调节引起CDC2细胞中转录因子的表达水平 Th17/Th2分化，例如干扰素调节因子4（IRF4），IRF5，类似Kruppel样因子4 （KLF4）和Notch2。在这里，我们表明不同的营地会影响调节表达水平在这些因素中，并切换了随后的第三个偏差，这使我们提出了CDC2 细胞代表塑料直流的亚群，并且营地水平决定了CDC2是否是否具有Pro-Th17和Pro-Th2偏见。因此，在此应用程序中，我们将探索和剖析以下主题：在SA1中 - 我们将分析是否通过GNAI2的遗传缺失增加营地在DC中，导致Th17相关的免疫病理学加班，在SA2中 - 我们将确定和测试定义表型Pro-Th17或Pro-Th2 CDC2的转录网络亚群，在SA3中 - 我们将测试增加的GPCR激动剂（即β2AR激动剂）是否会增加营地级别，引起17驱动的嗜中性粒细胞性哮喘，在SA4中 - 我们将确定和在功能上测试了由DC细胞产生的新型Pro-Th17或Pro-Th2介质。总而言之 - 我们的发现CAMP调节CDC的Pro-Th2和Pro-Th17诱导特性已导致 TH2/TH17调节的新途径的识别。结果将提供新的见解进入Cdc2和Th2-和Th17-偏置的可塑性。它有可能提高基本免疫学研究并建立新颖和创新的免疫治疗基础策略。