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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.

项目总结