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.

项目总结