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

• 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
• 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

 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（由申请方提供）：pDC是系统性红斑狼疮（SLE）发病机制和病因学的重要介质，因为它们在活化后能够产生大量IFNα。这一点通过使用具有减少的pDC数目的小鼠模型将pDC与SLE疾病的进展直接联系起来的最近研究而突出。TLR诱导的pDC中IFNα的产生分别发生在TLR 7或TLR 9识别DNA或RNA时。我的初步数据表明，B细胞衔接蛋白（BCAP）促进TLR 9诱导的IFNα诱导。我们发现BCAP是最佳IFNα诱导所必需的，而炎症细胞因子水平在TLR 9刺激后受影响较小。BCAP是在许多造血细胞中表达的信号传导衔接蛋白分子，并且能够通过其四个YxxM基序募集PI 3 K。我们的实验室已经在巨噬细胞中表明，BCAP与已知调节pDC IFNα产生的两种信号蛋白磷脂酰肌醇-3激酶（PI 3 K）和DOCK 2相互作用。最近的数据显示TLR诱导的IRF 7易位至细胞核和随后由pDC产生的IFNα依赖于PI 3 K和DOCK 2依赖性IKKα磷酸化。在TLR刺激后，BCAP-/- pDC具有与PI 3 K抑制和DOCK 2缺陷的pDC相似的表型，表明BCAP可能通过这些信号通路中的一个或两个来调节TLR诱导的IFNα。DOCK 2是一种重要的Rac鸟嘌呤核苷酸交换因子（GEF），已知其控制pDC中的迁移和IFNα产生。PI 3 K通路对于许多细胞过程是重要的，例如增殖、吞噬作用和囊泡运输。目前尚不清楚pDC中TLR信号传导如何诱导PI 3 K活化，尽管我们的实验室已经在巨噬细胞中显示PI 3 K的B细胞适配器（BCAP）将TLR与PI 3 K活化联系起来。因此，在本提案中，我们试图检验BCAP通过pDC中的PI 3 K和/或DOCK 2活化调节TLR 9诱导的IFNα产生的假设，以确定其发生的机制，并检验pDC中的BCAP在体内小鼠模型中促进狼疮样疾病的假设。