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

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.

项目概要 肺和上呼吸道是经常暴露于外界的粘膜表面 环境。与身体的其他粘膜表面（例如肠和女性生殖器）一样 肺部和气道的正常功能需要避免慢性炎症。这 粘膜免疫稳态和对外源刺激耐受的潜在途径 表面是复杂的、多样的并且人们知之甚少。在上一个资助期间，我们的研究 已经确定了由转录因子 Blimp1（编码 由 Prdm1 基因）促进肠粘膜的免疫稳态，并可能 其他粘膜表面，例如肺。我们发现Blimp1是专门 在肠道中的调节性 T 淋巴细胞亚群中表达，并且 Blimp1 的表达 这些细胞需要维持其调节特性并防止获得 炎症特性。此外，我们的研究表明，T 细胞中缺乏 Blimp1 与炎症细胞因子 IL9 表达增加和气道恶化有关 炎。在该奖项的资助期间，我们生成了一个新的敲入式飞艇1 报告小鼠可以在造血细胞中可视化 Blimp1 表达 不同组织（包括环境表面）中的稳态。新发现让我们 构成本次更新申请的基础是观察到 Blimp1 本质上是 在肺常驻肺泡巨噬细胞中的表达水平高于在其他细胞中观察到的水平 肺和其他组织中的骨髓细胞。更重要的是，我们发现Blimp1的删除 小鼠巨噬细胞对引起肺炎的细菌的反应受到影响 肺炎链球菌，导致炎症反应加剧，肺部恶化 组织损伤和细菌负担增加。此外，我们还确定了 MHC II 类和 调节分子 CD200R1 和 IL10 作为肺巨噬细胞中 Blimp1 的假定靶标。 总之，这些观察结果得出了我们的假设，即 Blimp1 充当关键调节因子 通过抑制两侧淋巴的炎症活动来维持肺部的免疫稳态 和骨髓细胞。在本提案中，我们将定义细胞和分子机制 Blimp1 促进肺部免疫稳态。我们预计目标的实现 该应用将揭示免疫反应控制的新机制 肺部耐受性并将为新治疗方法的开发提供信息 慢性肺部炎症。