GPR35 function in the immune system

GPR35 在免疫系统中的功能

• 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
• 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

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.

项目总结/摘要 精确控制粒细胞迁移对于抵抗感染和避免感染至关重要。 过度的组织损伤在初步工作中，我们已经获得了一种新的化学引诱物受体的证据， 代谢物反应性受体GPR 35，在两种类型的代谢物的运输中具有重要作用。 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应答者。中性粒细胞的募集 发炎的腹膜已作为研究嗜中性粒细胞运输的重要模型。中性粒细胞移动 通过网膜中的特殊血管从血液进入腹膜。我们发现GPR 35- 缺乏的中性粒细胞较少有效地募集到发炎的腹膜，这反映了较少有效的进入 注射到这个腹部组织部位我们认为中性粒细胞在附着GPR 35配体后不久就对GPR 35配体产生反应 炎症的网膜内皮细胞，并且GPR 35信号传导有助于穿过 内皮细胞我们将使用网膜的整体安装和真实的时间成像研究来检验这一假设。我们 初步数据表明，在巯基乙酸盐引起的腹膜炎症中，GPR 35的功能取决于类型 I IFN.我们将使用IFNAR floxed确定哪些细胞类型必须响应I型IFN以实现GPR 35功能。 小鼠和各种Cre-driver小鼠品系。这项工作将有助于确定哪些细胞类型是GPR 35的来源 配体。我们的初步数据显示，中性粒细胞募集到炎症淋巴结的相似GPR 35依赖性 节点（LN）。类似的方法将用于研究GPR 35如何促进中性粒细胞LN归巢。 高度表达GPR 35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型炎症的部位是否可以对组织稳态产生深远的影响。隐球菌 新生菌是一种机会性真菌病原体，可在严重免疫功能低下的患者中引起致命疾病。 个体肺中隐球菌生长的保护作用是由1型免疫介导的。相比之下， 2免疫应答和嗜酸性粒细胞的募集与疾病的恶化有关。我们有 发现GPR 35缺陷小鼠对隐球菌感染的保护作用增强。初步 我们的实验发现，GPR 35缺乏与嗜酸性粒细胞对感染者的招募减少有关。 肺。在这项探索性研究的目标2中，我们将开始定义改进隐球菌免疫的基础。 在GPR 35缺陷小鼠中的清除和测试GPR 35在嗜酸性粒细胞中的内在作用。 这项工作将确定GPR 35在中性粒细胞募集过程中发挥作用的步骤，它将开始， 明确GPR 35配体的来源，阐明GPR 35对隐球菌感染的负面影响， 从肺部清除。这些发现将为更广泛地理解GPR 35提供框架 在体内发挥作用，并且它们将为GPR 35拮抗剂的治疗开发建立基本原理。