Epigenetic changes to the IL-17 promoter landscape in neutrophils

摘要 IL-17A(IL-17)是一种促炎细胞因子，主要由淋巴样细胞分泌，包括 CD4+Th17细胞、γδT细胞、自然T细胞和先天淋巴样细胞(ILC17)，其诱导方式如下 真菌和细菌感染，以及自身免疫性疾病。IL-17激活内皮细胞和血管内皮细胞表面受体 上皮细胞产生CXC趋化因子，如IL-8，对中性粒细胞具有趋化作用。确实有 还有多份报告称，中性粒细胞在感染和自身免疫的个体以及小鼠体内产生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基因座不在 中性粒细胞的活跃状态(Cassatella，2018年)。我们报道了IL17A基因在中性粒细胞中的表达 在曲霉感染期间，以及在印度真菌感染患者和健康人的中性粒细胞中， 但在美国健康的人身上不是这样。因此，我们认为长期接触真菌孢子是一种 中性粒细胞表观遗传修饰导致IL-17基因可及性的潜在介体 轨迹。因此，我们建议研究IL-17启动子的可及性和该区域的组蛋白修饰 应用ATAC测序和芯片聚合酶链式反应对印度真菌感染患者的中性粒细胞进行比较 在美国健康的人。类风湿性关节炎患者也会产生IL-17(Ortiz-Navarrete，2019)， 这表明慢性炎症也会导致IL17A基因座的表观遗传修饰。在……下面 在IL-17基因座可达的条件下，我们将确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感染和免疫产生IL-17+的小鼠身上进行 中性粒细胞，我们将使用单细胞RNA测序来表征IL-17+的亚群 中性粒细胞。总而言之，拟议的研究结果将确定构成基础的分子事件 中性粒细胞IL-17的表观遗传调控。

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.