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

• 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
• 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

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.

项目概要 过去几十年来，哮喘和过敏性疾病的患病率一直在增加。 IgE 起着 在哮喘和过敏性疾病的发病机制中发挥核心作用。 IL-4 和 IL-13 刺激产生 免疫球蛋白E。多价过敏原诱导肥大上 IgE 结合的高亲和力 IgE 受体 (FceRI) 交联 细胞和嗜碱性粒细胞。 FceRI 的交联启动多种蛋白酪氨酸激酶 (PTK) 的激活 包括受体相关的 Lyn 和其他 Src PTK，它们磷酸化 受体信号亚基中基于免疫受体酪氨酸的激活基序 (ITAM)。” 磷酸化的 g 亚基招募 Syk，这是触发下游激活事件所必需的 PTK（即 预先形成的过敏介质的脱颗粒以及类二十烷酸和类二十烷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发生。 呼吸道病毒感染引起的哮喘急性发作代表着严重的发病率、死亡率、 以及繁重的医疗费用。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，例如 RIG-I。 RIG-I 样受体 (RLR) 的信号传导通过 线粒体外膜上的接头线粒体抗病毒信号蛋白（MAVS）。一次 激活后，MAVS 反过来激活 TBK1 和 IKKe，导致转录的磷酸化和激活 因子 IRF3/IRF7 和 NF-kB。 IRF3 和 IRF7 激活 I 型干扰素 (IFN) 基因的转录，同时 NF-kB 激活炎症细胞因子基因。肥大细胞也与病毒感染有关。桅杆 IAV 感染期间细胞产生的细胞因子和趋化因子依赖于 RIG-I/MAVS 机制，而组胺的产生是通过 RIG-I/MAVS 独立机制发生的。肥大细胞- 缺陷小鼠和酮替芬（肥大细胞稳定剂）治疗的小鼠表现出 IAV 诱导的肺部病理减轻 分别与肥大细胞充足的小鼠和未治疗的小鼠进行比较。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 作为 RLR 抗病毒途径的信号分子， 独特且强烈地抑制抗原/IgE 诱导的肥大细胞活化中的 Syk 活性。因此，Syk 可能是 受 Syk 和/或 MAVS 相关酪氨酸磷酸酶负调节。在目标 1 中，我们将调查 Syk 是否以 MAVS 依赖性方式受 TULA-2 或 SHP-1/2 调节。这些候选人 将针对这种可能性对磷酸酶进行深入分析。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 关于肥大细胞中 Syk 如何受 MAVS 调节以及 FceRI 之间如何串扰的机制见解 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 引起的哮喘加重的治疗/预防干预措施。