GPR35 function in the immune system

项目摘要/摘要 精确控制粒细胞迁移对于抵御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趋化受体的证据， 代谢物反应受体GPR35，在两种类型的药物转运中起重要作用 粒细胞转移到炎症部位。 中性粒细胞是先天免疫系统的主要早期反应者。中性粒细胞的招募 腹膜炎症已成为研究中性粒细胞转运的重要模型。中性粒细胞移动 从血液通过大网膜中的特殊血管进入腹膜。我们发现GPR35- 缺乏中性粒细胞被招募到炎症腹膜的效率较低，这反映了进入腹膜的效率较低。 进入这个腹部组织部位。我们认为中性粒细胞在连接GPR35配体后不久就会产生反应 GPR35信号通路有助于跨膜的转运。 内皮细胞。我们将通过对大网膜的整体和实时成像研究来验证这一假设。我们的 初步数据表明，GPR35在硫代乙酸酯引起的腹膜炎症中的作用依赖于类型 我是干扰素。我们将使用IFNAR FLOXED确定哪些细胞类型必须对GPR35功能的I型干扰素做出反应 小鼠和各种CRE驱动小鼠品系。这项工作将有助于确定哪些细胞类型是GPR35的来源 配体(S)。我们的初步数据显示，中性粒细胞募集对炎症淋巴的依赖程度与GPR35相似 节点(LN)。类似的方法将被用于研究GPR35如何促进中性粒细胞LN归巢。 第二种高表达GPR35的粒细胞类型是嗜酸性粒细胞。嗜酸性粒细胞被招募来 II型炎症部位是否会对组织内稳态产生深远影响。隐球菌 新生杆菌是一种机会性真菌病原体，在免疫功能严重受损的人中可导致致命疾病。 个人。对隐球菌在肺部的生长的保护是由1型免疫介导的。相比之下，输入 2免疫反应和嗜酸性粒细胞募集与病情加重有关。我们有 研究发现，GPR35缺陷小鼠对隐球菌感染的保护力有所提高。在预赛中 我们的实验发现，GPR35缺乏与嗜酸性粒细胞向感染者募集的减少有关 阿龙。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缺陷小鼠的清除和GPR35在嗜酸性粒细胞中的内在作用的测试。 这项工作将定义GPR35在中性粒细胞招募过程中的作用步骤，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 他们将为GPR35拮抗剂的治疗开发奠定理论基础。

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.