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.

项目摘要/摘要粒细胞迁移的精确控制对于抗击感染和避免组织过多的损害。在初步工作中，我们获得了新的趋化受体的证据，代谢产物反应性受体GPR35，在贩运两种类型的贩运中起重要作用粒细胞到炎症部位。中性粒细胞是先天免疫系统的主要早期反应者。招募中性粒细胞发炎的腹膜已成为研究中性粒细胞运输的重要模型。中性粒细胞移动通过大脑中的专门血管从血液进入腹膜。我们发现GPR35- 缺乏中性粒细胞不太有效地招募到发炎的腹膜，这反映了效率较低的进入进入这个腹部组织部位。我们提出，固定后不久，中性粒细胞对GPR35配体有反应对于发炎的胶质内皮和GPR35信号传导有助于跨越内皮。我们将使用Omentum的整个MONT和实时成像研究检验这一假设。我们的初步数据表明，硫甘氨酸中的GPR35功能引起的腹膜炎症取决于类型我ifn。我们将确定哪种单元类型必须使用IFNAR FLOXED响应GPR35函数I型IFN 小鼠和各种Cre-Driver小鼠线。这项工作将有助于确定哪些细胞类型是GPR35的来源配体（S）。我们的初步数据表明，中性粒细胞募集的GPR35依赖性相似节点（LNS）。类似的方法将用于研究GPR35如何促进中性粒细胞LN归巢。高度表达GPR35的第二种粒细胞类型是嗜酸性粒细胞。嗜酸性粒细胞被招募到 2型炎症部位是否可以对组织稳态产生深远的影响。隐球菌 Neoformans是一种机会性真菌病原体，可能导致严重免疫损害的致命疾病个人。防止肺中隐球菌生长的保护是通过1型免疫介导的。相比之下，类型 2免疫反应和嗜酸性粒细胞的募集与疾病的加剧有关。我们有发现缺乏GPR35的小鼠可以改善免受隐孢菌感染的保护。在初步实验我们发现GPR35缺乏症与嗜酸性粒细胞的募集较低有关肺。在这项探索性研究的AIM 2中，我们将开始定义改进的加密秒的基础 GPR35缺乏小鼠的清除，并测试GPR35在嗜酸性粒细胞中的内在作用。这项工作将定义GPR35在中性粒细胞招募期间起作用的步骤，它将开始定义GPR35配体的来源，它将阐明GPR35如何对隐球菌产生负面影响肺部清除。这些发现将为更广泛地理解GPR35提供一个框架在体内功能，它们将建立一个基本原理，用于GPR35拮抗剂的治疗发展。