GPR35 function in the immune system

GPR35 在免疫系统中的功能

基本信息

批准号：
10415205
负责人：
Jason G Cyster
金额：
$ 24.23万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415205
关键词：
Abdomen Address Adhesions Agreement Blood Blood Vessels Case Study Cells Chemotactic Factors Complement Cre driver Cryptococcus Cryptococcus neoformans Cryptococcus neoformans infection Data Dependence Disease Endothelium Enzymes Foundations G-Protein-Coupled Receptors GPR35 gene Growth Homeostasis Homing IFNAR1 gene Image Immune Immune response Immune system Immunity Individual Infection Inflammation Inflammatory Injury Innate Immune System Integrins Interferons Irritants Kynurenic Acid Left Ligands Location LoxP-flanked allele Lung Measures Mediating Metabolic Mus Myeloid Cells Neutrophil Infiltration Omentum Pattern Peptides Peritoneal Peritoneum Physiological Play Positioning Attribute Process Production Research Role Selectins Signal Transduction Site Source Study models Testing Therapeutic Thioglycolates Time Tissues Tryptophan Work antagonist cell type chemokine cytokine eosinophil experimental study fMet-Leu-Phe receptor fighting gain of function mutation granulocyte imaging approach imaging study improved in vivo lipid mediator lymph nodes migration neutrophil pathogen pathogenic fungus real-time images receptor recruit therapeutic development tissue injury trafficking two photon microscopy

项目摘要

Project Summary/Abstract The precise control of granulocyte migration is critical for fighting off infection and for avoiding excessive tissue damage. In preliminary work we have obtained evidence for a new chemoattractant receptor, the metabolite-responsive receptor GPR35, having an important role in the trafficking of two types of granulocyte to sites of inflammation. Neutrophils are the major early responders of the innate immune system. Recruitment of neutrophils to the inflamed peritoneum has served as an important model for studying neutrophil trafficking. Neutrophils move from blood into the peritoneum via specialized blood vessels in the omentum. We have found that GPR35- deficient neutrophils are less efficiently recruited to the inflamed peritoneum and this reflects less efficient entry into this abdominal tissue site. We propose that neutrophils respond to GPR35 ligands soon after attachment to the inflamed omental endothelial and that GPR35 signaling contributes to transmigration across the endothelium. We will test this hypothesis using whole mount and real time imaging studies of omentum. Our preliminary data indicate that GPR35 function in thioglycolate elicited peritoneal inflammation depends on type I IFN. We will determine what cell types must respond to type I IFN for GPR35 function using IFNAR floxed mice and various Cre-driver mouse lines. This work will help determine which cell types are a source of GPR35 ligand(s). Our preliminary data show a similar GPR35-dependence of neutrophil recruitment to inflamed lymph nodes (LNs). Similar approaches will be used to study how GPR35 contributes to neutrophil LN homing. A second granulocyte type that highly expresses GPR35 is eosinophils. Eosinophils are recruited to sites of type 2 inflammation whether they can have profound influences on tissue homeostasis. Cryptococcal neoformans is an opportunistic fungal pathogen that can cause fatal disease in severely immune compromised individuals. Protection from Cryptococcal growth in the lungs is mediated by type 1 immunity. By contrast, type 2 immune responses and recruitment of eosinophils is associated with exacerbation of disease. We have found that GPR35-deficient mice have improved protection from Cryptococcal infection. In preliminary experiments we find that GPR35-deficiency is associated with lower recruitment of eosinophils to the infected lung. In Aim 2 of this exploratory study we will begin to define the basis for the improved Cryptococcal clearance in GPR35-deficient mice and test for intrinsic roles of GPR35 in eosinophils. The work will define the step that GPR35 functions at during neutrophil recruitment, it will begin to define the sources of GPR35 ligand, and it will elucidate how GPR35 negatively impacts on Cryptococcal clearance from the lung. These findings will provide a framework for more broadly understanding GPR35 function in vivo, and they will establish a rationale for the therapeutic development of GPR35 antagonists.

项目概要/摘要粒细胞迁移的精确控制对于抵抗感染和避免感染至关重要过度的组织损伤。在前期工作中，我们已经获得了新趋化受体的证据，代谢物响应受体 GPR35，在两种类型的转运中发挥重要作用粒细胞到达炎症部位。中性粒细胞是先天免疫系统的主要早期反应者。募集中性粒细胞发炎的腹膜已成为研究中性粒细胞贩运的重要模型。中性粒细胞移动通过大网膜中的专门血管从血液进入腹膜。我们发现GPR35- 缺乏的中性粒细胞被招募到发炎的腹膜的效率较低，这反映了进入效率较低进入这个腹部组织部位。我们认为中性粒细胞在附着后不久就会对 GPR35 配体做出反应 GPR35 信号传导有助于跨网膜内皮细胞的迁移内皮细胞。我们将使用大网膜的整体安装和实时成像研究来检验这一假设。我们的初步数据表明，GPR35 在巯基乙酸引发的腹膜炎症中的功能取决于类型我干扰素。我们将使用 IFNAR floxed 确定哪些细胞类型必须响应 I 型 IFN 才能发挥 GPR35 功能鼠标和各种 Cre-driver 鼠标系列。这项工作将有助于确定哪些细胞类型是 GPR35 的来源配体。我们的初步数据显示，中性粒细胞向发炎淋巴募集具有类似的 GPR35 依赖性节点 (LN)。类似的方法将用于研究 GPR35 如何促进中性粒细胞 LN 归巢。高表达 GPR35 的第二种粒细胞类型是嗜酸性粒细胞。嗜酸性粒细胞被募集到 2 型炎症部位是否会对组织稳态产生深远影响。隐球菌属新型隐球菌是一种机会性真菌病原体，可在严重免疫功能低下的人中引起致命疾病个人。 1 型免疫介导防止肺部隐球菌生长。相比之下，输入 2 免疫反应和嗜酸性粒细胞的募集与疾病的恶化有关。我们有发现 GPR35 缺陷小鼠对隐球菌感染的保护能力有所提高。在初步实验中我们发现 GPR35 缺陷与感染者的嗜酸性粒细胞募集减少有关肺。在这项探索性研究的目标 2 中，我们将开始定义改进的隐球菌的基础 GPR35 缺陷小鼠的清除并测试 GPR35 在嗜酸性粒细胞中的内在作用。这项工作将确定 GPR35 在中性粒细胞招募过程中发挥作用的步骤，它将开始定义 GPR35 配体的来源，并将阐明 GPR35 如何对隐球菌产生负面影响从肺部清除。这些发现将为更广泛地理解 GPR35 提供一个框架体内功能，他们将为 GPR35 拮抗剂的治疗开发奠定基础。