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The Impact of Tissue Sialylation on Macrophage Polarization and Function

组织唾液酸化对巨噬细胞极化和功能的影响

基本信息

批准号：
10188417
负责人：
Brian A Cobb
金额：
$ 63.8万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-10 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188417
关键词：
Anti-Inflammatory Agents Antigen Presentation B-Lymphocytes Binding Binding Proteins CD22 gene Categories Cell Differentiation process Cell physiology Cells Characteristics Coupled Cytoplasmic Tail Data Development Disease Disease susceptibility Drops Environment Exposure to Galactose Health Hepatocyte Homeostasis Human ITIM Immune Immune Evasion Immune response Immunoglobulin G Immunologics Inflammatory Knockout Mice Kupffer Cells Light Link Liver Liver neoplasms Lung Lung Neoplasms Maintenance Mediating Mus Outcome PTPN6 gene Pathology Phenotype Phosphoric Monoester Hydrolases Play Polysaccharides Protein Family Proteins Receptor Signaling Research Role Severities Sialic Acids Sialyltransferases Signal Transduction Site Solid Neoplasm Specificity Steatohepatitis Surface T-Cell Activation T-Lymphocyte Testing Therapeutic Tissues Tumor-associated macrophages Vertebrates Wild Type Mouse Work autoreactive B cell base checkpoint receptors conditional knockout effector T cell falls immune checkpoint immune health in vivo liver inflammation macrophage novel recruit sialic acid binding Ig-like lectin sialylation therapeutic target tissue repair tumor microenvironment

项目摘要

Summary Tissue-resident macrophages play important roles in maintain tissue homeostasis. They broadly fall into two categories: classically-activated and pro-inflammatory macrophages (M1) and alternatively-activated and anti- inflammatory macrophages (M2). Within immune privileged tissues, such as the lung and liver, macrophages, such as liver Kupffer cells, are typically described as M2. Our preliminary data suggests that the M2 phenotype in the liver depends at least in part upon the glycome of the surrounding parenchyma, particularly the hepatocytes. We have found that α2,6-linked sialic acids upon hepatocyte surface glycans promotes normal M2 polarization, but that loss of this sialylation drives M1 polarization and subsequent aberrant T cell activation which leads to increased inflammatory disease susceptibility. In this proposal, we seek to determine the mechanism by which α2,6-sialylated glycans in the liver drives changes in resident macrophage phenotype and T cell activation. The proposed studies are broken into three aims, with the first two focused upon the influence of α2,6-sialylated glycans on macrophage function and signaling, and the third focused upon the mechanism underlying increased T cell activation and disease in the absence of sialylation. We believe that these studies will introduce a novel immune checkpoint receptor which binds sialylated glycans, inhibits signal transduction, promotes M2 polarization, and leads to immune homeostasis.

摘要组织驻留巨噬细胞在维持组织动态平衡方面发挥着重要作用。它们大致分为两类分类：经典激活和促炎巨噬细胞(M1)和交替激活和抗炎巨噬细胞炎性巨噬细胞(M2)。在免疫特权组织内，如肺和肝脏，巨噬细胞，如肝脏枯否细胞，通常被描述为M2。我们的初步数据表明，M2表型在肝脏中，至少部分地取决于周围实质的糖类，特别是肝细胞。我们发现肝细胞表面糖链上的α-2，6-联结唾液酸促进正常M2 极化，但这种唾液酸化缺失会导致M1极化和随后的异常T细胞激活这会增加炎症性疾病的易感性。在这项建议中，我们寻求确定肝脏中α2，6-唾液酸化多聚糖驱动驻留巨噬细胞表型改变和 T细胞活化。拟议的研究分为三个目标，前两个重点是影响 α的2，6-唾液酸聚糖对巨噬细胞功能和信号转导的影响；第三种侧重于其机制在没有唾液酸化的情况下，潜在的T细胞活化和疾病。我们相信这些研究将引入一种新的免疫检查点受体，它结合唾液酸聚糖，抑制信号转导，促进M2分化，导致免疫动态平衡。