Epigenetic changes to the IL-17 promoter landscape in neutrophils

中性粒细胞中 IL-17 启动子景观的表观遗传变化

基本信息

批准号：
10058179
负责人：
Eric Pearlman
金额：
$ 23.54万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058179
关键词：
ATAC-seq Aerosols Agreement Applications Grants Aspergillus Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Bacterial Infections Binding Biological Assay CXC Chemokines California Cell Line Cells China Chromatin Chronic Cities Collaborations DNA Methylation Endothelial Cells England Epigenetic Process Epithelial Cells Event Exposure to Fungal Spores Fusarium Gene Expression Genes Genetic Transcription Goals High-Throughput Nucleotide Sequencing Human Human Pathology IL17 gene IL8 gene Immunization Immunize India Individual Infection Inflammation Inflammatory Inhalation Interleukin-17 Irrigation Italy Keratitis Lung Lymphoid Cell Malignant Neoplasms Mediator of activation protein Mexico Modeling Modification Molds Molecular Mus Mycoses Oral candidiasis Pathogenicity Patients Peritoneal Population Production Proteins RNA Regulatory Pathway Reporting Research Personnel Rheumatoid Arthritis Role Saudi Arabia Source Synovial Fluid T-Lymphocyte Transposase XCL1 gene chromatin immunoprecipitation cystic fibrosis patients cytokine epigenetic regulation experimental study genetic regulatory protein genomic locus healthy volunteer histone modification human disease insight mouse model neutrophil peripheral blood promoter receptor single-cell RNA sequencing subcutaneous transcription factor transcriptome γδ T cells

项目摘要

Abstract IL-17A (IL-17) is a pro-inflammatory cytokine that is secreted primarily by lymphoid cells, including CD4+ Th17 cells, γδ T cells, natural T cells and innate lymphoid cells (ILC17), and is induced following fungal and bacterial infections, and in autoimmune disease. IL-17 activates receptors on endothelial and epithelial cells to produce CXC chemokines such as IL-8, which is chemotactic for neutrophils. There are also multiple reports that neutrophils produce IL-17 in infected and autoimmune individuals, and in murine models of infection and autoimmunity. However, a recent study showed that the IL-17 locus is not in an active status in human neutrophils (Cassatella 2018). We reported Il17a gene expression in neutrophils during Aspergillus infections, and in neutrophils from fungal infected patients and healthy individuals in India, but not in healthy individuals in the USA. We therefore suggest that long-term exposure to fungal spores is a potential mediator of epigenetic modifications in neutrophils that results in accessibility of the IL-17 gene locus. We therefore propose to examine IL-17 promoter accessibility and histone modifications in this region using ATAC sequencing and ChIP-PCR in neutrophils from fungal infected patients in India compared with healthy individuals in the USA. Rheumatoid arthritis patients also produce IL-17 (Ortiz-Navarrete, 2019), indicating that chronic inflammation also leads to epigenetic modifications in the Il17a locus. Under conditions where the IL-17 locus is accessible, we will identify which transcription factors bind to this region. Epigenetic studies will also be conducted in Aspergillus infected and immunized mice that produce IL-17+ neutrophils, and we will use single cell RNA sequencing to characterize sub populations of IL-17+ neutrophils. Together, results of the proposed studies will identify the molecular events that underlie epigenetic regulation of IL-17 in neutrophils.

抽象的 IL-17A (IL-17) 是一种促炎细胞因子，主要由淋巴细胞分泌，包括 CD4+ Th17 细胞、γδ T 细胞、天然 T 细胞和先天淋巴细胞 (ILC17)，并在以下条件下诱导 IL-17 可激活内皮细胞和细菌感染以及自身免疫性疾病。上皮细胞产生 CXC 趋化因子，例如 IL-8，对中性粒细胞有趋化作用。还有多个报告表明，中性粒细胞在感染者和自身免疫个体以及小鼠体内产生 IL-17 然而，最近的一项研究表明，IL-17 基因座并不存在于感染和自身免疫模型中。人类中性粒细胞的活跃状态（Cassatella 2018）我们报告了中性粒细胞中的 Il17a 基因表达。在曲霉菌感染期间，以及来自印度真菌感染患者和健康个体的中性粒细胞中，但在美国的健康个体中则不然，因此我们建议长期接触真菌孢子。中性粒细胞表观遗传修饰的潜在介质，可导致 IL-17 基因的可及性因此，我们建议检查该区域的 IL-17 启动子可及性和组蛋白修饰。使用 ATAC 测序和 ChIP-PCR 对印度真菌感染患者的中性粒细胞进行比较美国的健康个体也产生 IL-17（Ortiz-Navarrete，2019），表明慢性炎症也会导致 Il17a 基因座的表观遗传修饰。在 IL-17 位点可接近的条件下，我们将确定哪些转录因子与该区域结合。还将在产生 IL-17+ 的曲霉菌感染和免疫小鼠中进行表观遗传学研究中性粒细胞，我们将使用单细胞 RNA 测序来表征 IL-17+ 亚群拟议研究的结果将共同确定潜在的分子事件。中性粒细胞中 IL-17 的表观遗传调控。