BCAP regulation of TLR-induced IFNa in plasmacytoid DC

BCAP 对浆细胞样 DC 中 TLR 诱导的 IFNa 的调节

基本信息

批准号：
9125462
负责人：
Talyn Chu
金额：
$ 4.36万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9125462
关键词：
1-Phosphatidylinositol 3-Kinase Adaptor Signaling Protein Affect Antibodies Antigen-Antibody Complex Antigens Apoptosis Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity Autologous B-Lymphocytes Binding Cell Count Cell Maturation Cell Nucleus Cell physiology Cells Chimera organism Chronic Clinical Complex Cytotoxic T-Lymphocytes DNA Data Dendritic Cells Deposition Disease Etiology Family Fluorescence Microscopy GTP Binding Guanine Nucleotide Exchange Factors Hematopoietic Immune Immune system Infection Inflammatory Interferon Type I Interferon-alpha Interferons Knock-out Lead Link Lupus Malignant Neoplasms Measures Mediator of activation protein Memory Mutate Natural Killer Cells Nuclear Translocation Nucleic Acids Organ Pathogenesis Pathway interactions Patients Phagocytosis Phenotype Phenylalanine Phosphorylation Production Property Proteins Proto-Oncogene Proteins c-akt RNA Recruitment Activity Regulation Role Severities Severity of illness Signal Pathway Signal Transduction Signaling Protein Source Systemic Lupus Erythematosus TLR7 gene Testing Therapeutic Tissues Toxic effect Tyrosine Viral Western Blotting adaptive immunity cytokine cytotoxicity in vivo lupus-like macrophage migration mouse model mutant novel overexpression pleiotropism prevent protein expression public health relevance research study response retroviral transduction sensor trafficking viral detection

项目摘要

DESCRIPTION (provided by applicant): pDC are important mediators for the pathogenesis and etiology of systemic lupus erythematosus (SLE) due to their ability to produce large amounts of IFNα upon activation. This is highlighted by recent studies directly linking pDC to progression of SLE disease using mouse models with reduced pDC numbers. TLR-induced IFNα production in pDC occurs upon DNA or RNA recognition by TLR7 or TLR9 respectively. My preliminary data suggest that B cell adaptor protein (BCAP) promotes TLR9-induced IFNα induction. We found that BCAP is required for optimal IFNα induction while inflammatory cytokine levels are less affected upon TLR9 stimulation. BCAP is a signaling adaptor protein molecule expressed in many hematopoietic cells and is capable of recruiting PI3K through its four YxxM motifs. Our lab has shown in macrophages that BCAP interacts with two signaling proteins known to regulate pDC IFNα production, phosphatidylinositol-3 kinase (PI3K) and DOCK2. Recent data has shown that TLR-induced IRF7 translocation to the nucleus and subsequent IFNα production by pDC is dependent on PI3K and on DOCK2 dependent IKKα phosphorylation. Upon TLR stimulation, BCAP-/- pDC have a similar phenotype to PI3K inhibited and DOCK2-deficient pDC, suggesting that BCAP may regulate TLR-induced IFNα through one or both of these signaling pathways. DOCK2 is an important Rac guanine nucleotide exchange factor (GEF), which is known to control migration and IFNα production in pDC. The PI3K pathway is important for many cellular processes, such as proliferation, phagocytosis and vesicular trafficking. It is not known how PI3K activation is induced by TLR signaling in pDCs, although our lab has shown in macrophages that B cell adaptor for PI3K (BCAP) links TLRs to PI3K activation. Therefore, in this proposal, we seek to test the hypothesis that BCAP regulates TLR9- induced IFNα production via PI3K and/or DOCK2 activation in pDC, to determine the mechanism by which this occurs, and to test the hypothesis that BCAP in pDC promotes lupus-like disease in an in vivo mouse model.

描述（由申请人提供）：pDC 是系统性红斑狼疮 (SLE) 发病机制和病因学的重要介质，因为它们在激活后能够产生大量 IFNα，最近将 pDC 与 SLE 疾病进展直接联系起来的研究强调了这一点。使用 pDC 数量减少的小鼠模型，pDC 中的 DNA 或 RNA 分别被 TLR7 或 TLR9 识别，产生 IFNα。蛋白 (BCAP) 促进 TLR9 诱导的 IFNα 诱导，我们发现 BCAP 是最佳 IFNα 诱导所必需的，而 BCAP 是在许多造血细胞中表达的信号转导蛋白分子，并且能够募集 PI3K。我们的实验室通过其四个 YxxM 基序在巨噬细胞中证明了 BCAP 与已知调节 pDC IFNα 产生的两种信号蛋白相互作用。最近的数据表明，TLR 诱导的 IRF7 易位到细胞核以及随后 pDC 产生的 IFNα 依赖于 PI3K 和 DOCK2 依赖性 IKKα 磷酸化。与 PI3K 抑制和 DOCK2 缺陷的 pDC 具有相似的表型，表明 BCAP 可能通过一种方式调节 TLR 诱导的 IFNα DOCK2 是一种重要的 Rac 鸟嘌呤核苷酸交换因子 (GEF)，已知它可以控制 pDC 中的迁移和 IFNα 产生。 PI3K 途径对于许多细胞过程（例如增殖、吞噬作用和囊泡运输）非常重要。目前尚不清楚 pDC 中 TLR 信号传导如何诱导 PI3K 激活，尽管我们的实验室已在巨噬细胞中证明 PI3K 的 B 细胞适配器 (BCAP) 连接因此，在本提案中，我们试图检验 BCAP 通过 pDC 中 PI3K 和/或 DOCK2 激活调节 TLR9 诱导的 IFNα 产生的假设，以确定发生这种情况的机制，并检验以下假设： pDC 中的 BCAP 在体内小鼠模型中促进狼疮样疾病。