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

• 批准号: 10192651
• 负责人: Eric Pearlman
• 金额: $ 19.63万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192651
• 关键词: ATAC-seq; Aerosols; Agreement; Applications Grants; Aspergillus; Autoimmune; Autoimmune Diseases; 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

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.

摘要 IL-17 A（IL-17）是主要由淋巴细胞分泌的促炎细胞因子，包括 CD 4 + Th 17细胞、γδ T细胞、天然T细胞和先天性淋巴样细胞（ILC 17），并且在以下诱导 真菌和细菌感染以及自身免疫性疾病。IL-17激活内皮细胞上的受体， 上皮细胞产生CXC趋化因子，如IL-8，其对中性粒细胞具有趋化性。有 也有多个报道中性粒细胞在感染和自身免疫个体中产生IL-17， 感染和自身免疫的模型。然而，最近的一项研究表明，IL-17基因座并不位于 人中性粒细胞的活性状态（Cassatella 2018）。我们报道了IL 17 a基因在中性粒细胞中的表达， 在曲霉菌感染期间，以及在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没有。因此，我们认为，长期暴露于真菌孢子是一个 中性粒细胞表观遗传修饰的潜在介导物，导致IL-17基因的可及性 基因座因此，我们建议检查IL-17启动子可及性和组蛋白修饰在这一地区 使用ATAC测序和ChIP-PCR在印度真菌感染患者的中性粒细胞中进行比较， 在美国健康的人。风湿性关节炎患者也会产生IL-17（Ortiz-Navartite，2019）， 表明慢性炎症也导致Il 17 a基因座中的表观遗传修饰。下 在IL-17基因座可接近的条件下，我们将鉴定哪些转录因子与该区域结合。 表观遗传学研究也将在曲霉菌感染和免疫的产生IL-17+的小鼠中进行。 我们将使用单细胞RNA测序来表征IL-17+的亚群， 中性粒细胞总之，拟议研究的结果将确定导致癌症的分子事件。 中性粒细胞中IL-17的表观遗传调节。