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Crosstalk between FceRI and MAVS signaling pathways in mast cells

肥大细胞中 FceRI 和 MAVS 信号通路之间的串扰

基本信息

批准号：
10040848
负责人：
TOSHIAKI KAWAKAMI
金额：
$ 27.45万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-22 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10040848
关键词：
Acute Adaptor Signaling Protein Affinity Allergens Allergic Disease Allergic Reaction Antigens Antiviral Agents Asthma Basophils Binding Cell Density Cells Cytokine Gene Cytoplasm Data Disulfides Double-Stranded RNA Eicosanoids Enzymes Event Family Genes Genetic Transcription Genetically Engineered Mouse Health Care Costs Histamine Production Histamine Release IRF3 gene ITAM IgE IgE Receptors In Vitro Infection Inflammatory Influenza A virus Interferon Type I Interleukin-13 Interleukin-4 LCP2 gene Ligands Link Lung Inflammation MAP Kinase Gene Mast Cell Stabilizer Mediating Mediator of activation protein Mitochondria Molecular Morbidity - disease rate Mus NF-kappa B Outer Mitochondrial Membrane PTPN6 gene Passive Cutaneous Anaphylaxis Pathogenesis Pathway interactions Patients Pattern recognition receptor Peptide Hydrolases Pharmacology Phase Phosphoric Monoester Hydrolases Phosphorylation Play Prevalence Prevention strategy Preventive Preventive Intervention Production Prostaglandins Protein Family Protein Tyrosine Kinase Protein Tyrosine Phosphatase Pulmonary Pathology RNA RNA Helicase RNA Viruses Receptor Signaling Regulation Respiratory System Role Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Structure T-Lymphocyte TBK1 gene TLR3 gene TLR7 gene TNF gene Therapeutic Toll-like receptors Transcriptional Activation Tretinoin Tyrosine Tyrosine Phosphorylation Ubiquitin Virus Diseases activating transcription factor asthma exacerbation base chemokine crosslink cysteinyl-leukotriene cytokine experimental study i(19)in vivo influenzavirus innovation insight mast cell melanoma mortality novel novel therapeutics pathogen phospholipase C gamma prevent prion-like receptor recruit respiratory infection virus respiratory virus response src Homology Region 2 Domain src-Family Kinases transcription factor

项目摘要

Project Summary The prevalence of asthma and allergic diseases has been increasing for the last several decades. IgE plays a central role for the pathogenesis of asthma and allergic diseases. IL-4 and IL-13 stimulate the production of IgE. Multivalent allergen induces the cross-linking of IgE-bound high-affinity IgE receptors (FceRI) on mast cells and basophils. Cross-linking of FceRI initiates activation of several protein-tyrosine kinases (PTKs) including receptor-associated Lyn and other Src PTKs, which phosphorylate tyrosine residues of the immunoreceptor tyrosine-based activation motifs (ITAMs) in signaling subunits of the receptor." Tyrosine- phosphorylated g subunits recruit Syk, the PTK essential for triggering downstream activation events (i.e., degranulation of preformed allergenic mediators and de novo synthesis and secretion of eicosanoids and various cytokines and chemokines), eventually leading to the initiation of allergic reactions. Respiratory virus infection-induced acute exacerbations of asthma represent severe morbidity, mortality, and burdensome healthcare costs. Host cells infected with influenza A virus (IAV) sense the infection by pattern recognition receptors such as RIG-I. Signaling by RIG-I-like receptors (RLRs) occurs through the adaptor mitochondrial antiviral-signaling protein (MAVS) at the outer membrane of the mitochondria. Once activated, MAVS in turn activates TBK1 and IKKe, leading to phosphorylation and activation of the transcription factors IRF3/IRF7 and NF-kB. IRF3 and IRF7 activate the transcription of type I interferon (IFN) genes while NF-kB activates that of inflammatory cytokine genes. Mast cells are also implicated in virus infections. Mast cell production of cytokines and chemokines during IAV infection occurs in a RIG-I/MAVS-dependent mechanism, whereas histamine production occurs through a RIG-I/MAVS-independent mechanism. Mast cell- deficient mice and ketotifen (mast cell stabilizer)-treated mice showed reduced IAV-induced lung pathology compared to mast cell-sufficient mice and untreated mice, respectively. Therefore, it is likely that mast cells contribute to asthma exacerbations via the crosstalk between FceRI and antiviral signaling pathways. Our preliminary data demonstrates that MAVS, among the signaling molecules of RLR antiviral pathways, uniquely and strongly inhibits Syk activity in antigen/IgE-induced mast cell activation. Thus, Syk may be negatively regulated by a Syk- and/or MAVS-associated tyrosine phosphatase(s). In Aim 1, we will investigate whether Syk is regulated by TULA-2 or SHP-1/2 in a MAVS-dependent manner. These candidate phosphatases will be intensively analyzed for this possibility. In Aim 2, we will investigate the in vivo and in vitro roles of mast cell-expressed MAVS and Syk in IAV infection. Therefore, through this project, we will gain mechanistic insights into how Syk is regulated by MAVS in mast cells and how the crosstalk between FceRI and antiviral RLR signaling pathways impacts IAV infection. Such information will be basis for novel therapeutic/preventive interventions of IAV-induced asthma exacerbations.

项目摘要哮喘和过敏性疾病的患病率在过去几十年中一直在增加。IgE发挥着在哮喘和过敏性疾病的发病机制中起中心作用。IL-4和IL-13刺激产生 IgE。多价变应原诱导肥大细胞表面IgE结合的高亲和力IgE受体（FceRI）交联细胞和嗜碱性粒细胞。FceRI的交联引发几种蛋白酪氨酸激酶（PTK）的活化包括受体相关的林恩和其它Src PTK，其磷酸化酪氨酸残基，免疫受体酪氨酸激活基序（ITAM）在受体的信号转导亚基。“酪氨酸- 磷酸化的g亚基募集Syk，触发下游激活事件所必需的PTK（即，预先形成的变应原介质的脱粒和类花生酸的从头合成和分泌，各种细胞因子和趋化因子），最终导致过敏反应的开始。呼吸道病毒感染引起的哮喘急性加重代表严重的发病率、死亡率，和沉重的医疗费用。感染甲型流感病毒（IAV）的宿主细胞通过以下方式感知感染：模式识别受体如RIG-I。RIG-I样受体（RLR）的信号传导通过在线粒体的外膜处的衔接线粒体抗病毒信号蛋白（MAVS）。一旦激活后，MAVS依次激活TBK 1和IKKe，导致磷酸化和转录激活因子IRF 3/IRF 7和NF-κ B。IRF 3和IRF 7激活I型干扰素（IFN）基因的转录， NF-kB激活炎性细胞因子基因。肥大细胞也与病毒感染有关。桅杆在IAV感染期间细胞产生细胞因子和趋化因子发生在RIG-I/MAVS依赖的细胞内。机制，而组胺的产生通过RIG-I/MAVS独立的机制发生。肥大细胞- 缺陷型小鼠和酮替芬（肥大细胞稳定剂）治疗的小鼠表现出降低的IAV诱导的肺病理学分别与肥大细胞充足的小鼠和未处理的小鼠相比。因此，肥大细胞很可能通过FceRI和抗病毒信号通路之间的串扰导致哮喘恶化。我们的初步数据表明，MAVS，在RLR抗病毒途径的信号分子，在抗原/IgE诱导的肥大细胞活化中独特且强烈地抑制Syk活性。因此，Syk可以是受Syk和/或MAVS相关酪氨酸磷酸酶负调控。在目标1中，我们将研究 Syk是否以MAVS依赖性方式受THP-2或SHP-1/2调节。这些候选磷酸酶将被深入分析这种可能性。在目标2中，我们将研究体内和体内肥大细胞表达的MAVS和Syk在IAV感染中的体外作用因此，通过这个项目，我们将获得关于Syk如何在肥大细胞中被MAVS调节以及FceRI之间的串扰如何的机制见解，抗病毒RLR信号通路影响IAV感染。这些信息将成为小说的基础。 IAV诱导的哮喘急性发作的治疗/预防干预。