Role of Blimp1 (Prdm1) in lung immune responses and tolerance

Blimp1 (Prdm1) 在肺免疫反应和耐受中的作用

• 批准号: 10180878
• 负责人: Gislaine A Martins
• 金额: $ 50.54万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-29 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10180878
• 关键词: ATAC-seq; Achievement; Acute; Adoptive Cell Transfers; Alveolar Macrophages; Asthma; Award; B lymphocyte-induced maturation protein 1; Bacteria; Bacterial Infections; Bacterial Model; Binding; CD4 Positive T Lymphocytes; Cells; Chronic; Complex; Development; Ensure; Environment; Equilibrium; Experimental Models; Exposure to; FOXP3 gene; Female; Flow Cytometry; Funding; Gene Expression; Gene Expression Regulation; Genetic; Genetic Transcription; Goals; Hematopoietic; Homeostasis; Human; IL17 gene; IL9 gene; Immune; Immune Tolerance; Immune response; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Interleukin-10; Intestinal Mucosa; Intestines; Invaded; Knock-in; Location; Lung; Lung Inflammation; Lymphocyte; Lymphoid Cell; MHC Class II Genes; Maintenance; Mediating; Messenger RNA; Modeling; Molecular; Mucous Membrane; Mus; Myelogenous; Myeloid Cells; Ovalbumin; PRDM1 gene; Pathogenesis; Pathway interactions; Play; Pneumonia; Production; Property; Pyroglyphidae; Regulation; Regulator Genes; Regulatory T-Lymphocyte; Reporter; Role; Severity of illness; Stimulus; Streptococcus pneumoniae; Structure of parenchyma of lung; Surface; T-Lymphocyte; Testing; Tissues; Transgenic Mice; Viral; Visualization; airway inflammation; allergic airway inflammation; chromatin immunoprecipitation; comparative; cytokine; histone modification; influenza infection; macrophage; novel; novel therapeutic intervention; novel therapeutics; particle; pathogen; prevent; pulmonary function; reproductive tract; response; sialic acid binding Ig-like lectin; single-cell RNA sequencing; tissue repair; transcription factor; transcriptome; transcriptome sequencing; two photon microscopy; ATAC-seq; Achievement; Acute; Adoptive Cell Transfers; Alveolar Macrophages; Asthma; Award; B lymphocyte-induced maturation protein 1; Bacteria; Bacterial Infections; Bacterial Model; Binding; CD4 Positive T Lymphocytes; Cells; Chronic; Complex; Development; Ensure; Environment; Equilibrium; Experimental Models; Exposure to; FOXP3 gene; Female; Flow Cytometry; Funding; Gene Expression; Gene Expression Regulation; Genetic; Genetic Transcription; Goals; Hematopoietic; Homeostasis; Human; IL17 gene; IL9 gene; Immune; Immune Tolerance; Immune response; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Interleukin-10; Intestinal Mucosa; Intestines; Invaded; Knock-in; Location; Lung; Lung Inflammation; Lymphocyte; Lymphoid Cell; MHC Class II Genes; Maintenance; Mediating; Messenger RNA; Modeling; Molecular; Mucous Membrane; Mus; Myelogenous; Myeloid Cells; Ovalbumin; PRDM1 gene; Pathogenesis; Pathway interactions; Play; Pneumonia; Production; Property; Pyroglyphidae; Regulation; Regulator Genes; Regulatory T-Lymphocyte; Reporter; Role; Severity of illness; Stimulus; Streptococcus pneumoniae; Structure of parenchyma of lung; Surface; T-Lymphocyte; Testing; Tissues; Transgenic Mice; Viral; Visualization; airway inflammation; allergic airway inflammation; chromatin immunoprecipitation; comparative; cytokine; histone modification; influenza infection; macrophage; novel; novel therapeutic intervention; novel therapeutics; particle; pathogen; prevent; pulmonary function; reproductive tract; response; sialic acid binding Ig-like lectin; single-cell RNA sequencing; tissue repair; transcription factor; transcriptome; transcriptome sequencing; two photon microscopy

PROJECT SUMMARY The lungs and upper airways are mucosal surfaces that are regularly exposed to the external environment. Like other mucosal surfaces in the body (e.g. intestines, and female reproductive tract) proper functioning of the lungs and airways requires avoidance of chronic inflammation. The pathways underlying immune homeostasis and tolerance to exogenous stimuli at mucosal surfaces are complex, diverse and poorly understood. During the last funding period, our studies have identified different molecular pathways regulated by the transcription factor Blimp1 (encoded by the Prdm1 gene) that promote immune homeostasis in the intestinal mucosa and potentially other mucosal surfaces such as the lungs. We have discovered that Blimp1 is specifically expressed in a subset of regulatory T lymphocytes in the intestines and that expression of Blimp1 in these cells is required to maintain their regulatory properties and prevent acquisition of inflammatory properties. In addition, our studies revealed that lack of Blimp1 in T cells is associated with increased expression of the inflammatory cytokine IL9 and worsened airway inflammation. During the funding period of the award we generated a new knock-in Blimp1 reporter mouse that allowed visualization of Blimp1 expression in hematopoietic cells at the steady state in different tissues, including environmental surfaces. The new finding that led us to form the basis for this renewal application was the observation that Blimp1 is constitutively expressed in lung resident alveolar macrophages at higher levels than the observed in other myeloid cells in the lung and in other tissues. More importantly, we found that deletion of Blimp1 in macrophages in mice compromised the response against the pneumoniae-causing bacteria Streptococcus pneumoniae, leading to exacerbated inflammatory responses, worsened lung tissue damage and increased bacterial burden. Moreover, we identified MHC class II and the regulatory molecules CD200R1 and IL10 as putative targets of Blimp1 in lung macrophages. Together, these observations led to our hypothesis that Blimp1 functions as critical regulator to maintain immune homeostasis in the lungs by restraining inflammatory activity of both lymphoid and myeloid cells. In this proposal we will define the cellular and molecular mechanisms by which Blimp1 promote immune homeostasis in the lung. We anticipate that achievement of the goals of this application will uncover novel mechanisms underlying control of immune response and tolerance in the lungs and will inform the development of new therapeutic approaches to treat chronic lung inflammatory conditions.

项目摘要 肺部和上呼吸道是粘膜表面，经常暴露于外部 环境。像体内的其他粘膜表面（例如肠和女性生殖 肺和气道的正确功能需要避免慢性炎症。这 免疫稳态的基础途径和对粘膜外源刺激的耐受性 表面很复杂，多样化且知名度不佳。在最后的资金期间，我们的学习 已经确定了由转录因子Blimp1调节的不同分子途径（编码 由PRDM1基因）促进肠粘膜中的免疫稳态和可能 其他粘膜表面，例如肺部。我们发现Blimp1是专门的 在肠道中的调节性T淋巴细胞子集中表达，而Blimp1的表达 在这些细胞中，需要维持其调节性能并防止获取 炎症特性。此外，我们的研究表明，T细胞中缺乏Blimp1是 与炎性细胞因子IL9的表达增加并导致气道恶化有关 炎。在奖励的资金期间，我们产生了一个新的敲门blimp1 记者小鼠允许在造血细胞中可视化Blimp1表达的小鼠 不同组织中的稳态，包括环境表面。新发现导致我们 构成这种更新应用的基础是观察到Blimp1是组成性的 在肺常驻肺泡巨噬细胞中表达的水平高于其他观察到的 肺和其他组织中的髓样细胞。更重要的是，我们发现Blimp1的删除 在小鼠的巨噬细胞中，损害了肺炎引起的细菌的反应 肺炎链球菌，导致加剧的炎症反应，肺部恶化 组织损伤并增加细菌负担。此外，我们确定了MHC II类和 调节分子CD200R1和IL10作为肺巨噬细胞中Blimp1的推定靶标。 总之，这些观察结果导致了我们的假设，即Blimp1是关键的调节剂 通过限制两种淋巴样的炎症活性来维持肺部免疫稳态 和髓样细胞。在此提案中，我们将定义细胞和分子机制 Blimp1在肺部促进免疫稳态。我们预计实现目标 该应用将发现免疫反应控制和 肺部的耐受性，并将告知开发新的治疗方法 慢性肺炎症条件。