The Notch Signaling Pathway Regulates Basophil Responses During Helminth Infection

Notch 信号通路调节蠕虫感染期间嗜碱性粒细胞的反应

基本信息

批准号：
9986356
负责人：
Elia D Tait Wojno
金额：
$ 36.93万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9986356
关键词：
Address Adoptive Transfer Affect Basophils CD4 Positive T Lymphocytes Cells Cleaved cell Complex Data Development Disease Epithelial Cells Fc Receptor GATA3 gene Gene Expression Regulation Genes Genetic Transcription Helminths Immune In Vitro Infection Inflammation Inflammatory Inflammatory Response Interleukin-13 Interleukin-4 Intestines Ligand Binding Ligands Ligation Lymphocyte Maintenance Mediating Morbidity - disease rate Mus Notch Signaling Pathway Nuclear Translocation Parasites Parasitic infection Pathway interactions Peptide Hydrolases Phenotype Play Population Population Sizes Process Production Role Shapes Signal Transduction Source Testing Th2 Cells Time Transcriptional Activation Trichuris base cytokine experimental study gastrointestinal granulocyte helminth infection in vitro Assay in vivo loss of function neutralizing antibody notch protein novel therapeutics progenitor receptor binding response targeted treatment

项目摘要

PROJECT SUMMARY Intestinal helminth parasites infect millions of people worldwide and cause significant morbidity. Host- protective type 2 inflammation is characterized by activation of innate immune cells, polarization of naïve CD4+ T cells to T helper type 2 cells, anti-helminth epithelial cell responses, and worm expulsion. Recent studies have revealed that basophils, rare innate granulocytes, promote type 2 inflammation and worm expulsion, but the pathways that control basophil effector function following helminth infection remain incompletely defined. However, the Notch signaling pathway stands out as a key candidate that could regulate basophil responses in this context. Ligand binding to a Notch receptor leads to nuclear translocation of the Notch intracellular domain, which can promote transcriptional activation of canonical type 2 inflammation-associated target genes and the development of type 2 inflammatory responses. However, how Notch shapes basophil responses that regulate intestinal type 2 inflammation and helminth expulsion in vivo is unknown. To address this, in preliminary studies, we show for the first time that murine basophils expressed Notch 2 following infection with the intestinal helminth parasite Trichuris muris. Using mice in which Notch signaling is genetically blocked solely in basophils, we demonstrate that while Notch signaling was not required to maintain the basophil population in the steady state, it does contribute to optimal basophil population expansion and helminth clearance following T. muris infection. Finally, we show that Notch signaling regulates cytokine-elicited basophil activation in vitro. Collectively, these data led us to hypothesize that during intestinal helminth parasite infection, basophils upregulate Notch and respond to Notch ligands, mediating optimal basophil population expansion and effector function and efficient helminth expulsion. To test this, we propose three specific aims. Studies in Aim 1 will test how the Notch signaling pathway regulates basophil population expansion and differentiation during type 2 inflammation, employing in vitro assays and in vivo approaches during T. muris infection. Studies in Aim 2 will test how Notch signaling promotes basophil effector function and contributions to type 2 inflammation in vivo using adoptive transfer studies and infection with T. muris, with some studies focusing on the role of Notch 2 in this process. Studies in Aim 3 will test how Notch ligands or helminth proteases could activate Notch signaling in basophils to promote effector function and type 2 inflammation, using in vivo experiments during T. muris infection and in vitro assays. These studies will dissect how Notch signaling regulates basophil responses that drive type 2 inflammation in the intestine following helminth parasite infection. Our results will expand our understanding of intestinal type 2 inflammation and inform the development and use of therapies that target Notch to treat type 2 inflammatory diseases.

项目摘要肠道蠕虫寄生虫感染了全世界数百万的人，并引起了明显的发病率。主持人- 保护性2型炎症的特征是先天免疫细胞激活，幼稚的CD4+极化 T细胞到T辅助2型细胞，抗螺旋上皮细胞反应和蠕虫驱动。最近的研究已经揭示了嗜碱性粒细胞，罕见的先天粒细胞，促进2型注射和蠕虫驱动，但蠕虫感染后控制嗜碱性效应子功能的途径仍未完全定义。但是，Notch信号通路是可以调节嗜碱性粒细胞反应的关键候选者这个上下文。配体与缺口受体的结合导致缺口的核易位域，可以促进典型2型炎症相关靶基因的转录激活以及2型炎症反应的发展。但是，缺口如何塑造嗜碱性粒细胞反应调节体内2型肠道2注射和蠕虫驱动是未知的。为了解决这个问题初步研究，我们首次表明，鼠嗜碱性嗜碱性粒细胞在感染后表达了Notch 2 肠道蠕虫寄生虫Trichuris Muris。使用notch信号传导遗传阻塞的小鼠仅在嗜碱性粒细胞中，我们证明了虽然不需要保持凹源寄生虫稳定状态的人口确实有助于最佳的嗜碱性嗜嗜碱性人口扩张和蠕虫 T. muris感染后的间隙。最后，我们表明Notch信号调节细胞因子引起的。嗜碱性粒细胞在体外激活。总的来说，这些数据导致我们假设在肠蠕虫期间在人口扩展和效应子功能以及有效的蠕虫驱逐。为了测试这一点，我们提出了三个具体目标。 AIM 1的研究将测试Notch信号通路如何调节嗜碱性粒细胞 2型炎症期间的扩展和分化，采用体外测定和体内方法在T. muris感染期间。 AIM 2中的研究将测试Notch信号如何促进粒细胞效应子功能使用自适应转移研究对体内2型炎症的贡献，并用T. muris感染，一些研究重点介绍了Notch 2在此过程中的作用。 AIM 3中的研究将测试Notch配体或蠕虫蛋白酶可以激活嗜碱性粒细胞中的Notch信号，以促进效应子功能和2型炎症，使用th。Muris感染和体外测定期间的体内实验。这些研究将剖析 Notch信号传导如何调节在肠中驱动2型注射2型的嗜碱性粒子反应蠕虫寄生虫感染。我们的结果将扩大我们对2型肠道注射和告知靶向Notch治疗2型炎症性疾病的疗法的开发和使用。