Adipocyte-derived exosomes in macrophage regulation

脂肪细胞来源的外泌体在巨噬细胞调节中的作用

• 批准号: 10388517
• 负责人: Joshua Harrison Goodman
• 金额: $ 4.61万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-09-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388517
• 关键词: Acute; Adipocytes; Adipose tissue; Adult; Affect; Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Automobile Driving; Biology; Bone Marrow; Cardiovascular Diseases; Cells; Chemotactic Factors; Chemotaxis; Dementia; Deposition; Development; Diabetes Mellitus; Embryo; Endosomes; Endothelial Cells; Etiology; Fasting; Fatty acid glycerol esters; Fetal Liver; Functional disorder; Genetic Transcription; Health; Hematopoiesis; Hematopoietic stem cells; Human; Hypertrophy; Immune; In Vitro; Inflammation; Inflammatory; Infusion procedures; Injections; Insulin Resistance; Laboratories; Lipids; Lipolysis; Lung diseases; Malignant Neoplasms; Mediating; Membrane; Metabolic; Metabolic stress; Molecular; Monitor; Mus; Obesity; Organ; Outcome; PPARG gene; Pathology; Pathway interactions; Peripheral; Phenotype; Play; Population; Process; Production; Refuse Disposal; Regulation; Role; Signal Transduction; Source; Stimulus; Testing; Time; Tissues; Work; Yolk Sac; burden of illness; exosome; extracellular vesicles; graduate student; in vivo; insight; lipid metabolism; macrophage; mature animal; monocyte; novel therapeutic intervention; obesity development; precursor cell; progenitor; programs; recruit; response; stem cells

Project Summary Obesity is a common condition that is associated with poor health outcomes, and a significant portion of these pathologies are mediated by dysfunction and dysregulation of adipose tissue at a cellular and molecular level. Adipose tissue contains a unique population of macrophages (adipose tissue macrophages, or ATMs). These ATMs accumulate in obesity and mediate a number of key processes and pathologies in adipose tissue, including lipid handling, inflammation, and insulin resistance. Multiple populations of ATMs exist: a tissue- resident, anti-inflammatory population is descended from yolk sac embryonic hematopoietic progenitors and is present at all times; a pro-inflammatory population is derived from circulating monocyte precursors in adults and is recruited under conditions of metabolic stress such as obesity. Exosomes are small, secreted, endosome-derived, membrane-bound extracellular vesicles. Adipocytes constitutively release lipid-containing exosomes (adipocyte-derived exosomes, or AdExos), and the rate of their secretion is increased during states of increased ATM accumulation, including obesity and acute fasting. AdExos can also act as macrophage chemoattractants and drive reprogramming of bone marrow-derived macrophages toward an ATM-like transcriptional and phenotypic identity. However, many questions regarding the full scope and effects of AdExos remain unaddressed. We hypothesize that AdExos regulate the accumulation and differentiation of macrophages in adipose tissue via pathways canonically known to regulate ATMs. Given that AdExo production is increased in conditions during which monocyte recruitment and ATM recruitment occurs, and that AdExos both act directly as macrophage chemoattractants and drive production of monocyte chemoattractant factors in adipose tissue, we believe that AdExos regulate monocyte recruitment to adipose tissue. Aim 1 seeks to establish this role in an in vivo setting by monitoring the effect of direct AdExo injection on chemoattraction and accumulation of monocytes. Previous work has examined the effect of AdExos on the identity of bone marrow-derived macrophages, but not more relevant precursors such as yolk sac hematopoietic progenitors and peripheral monocytes. Aim 2 seeks to test the relationship between progenitor cell identity and the effect of AdExo exposure on cell fate. While we have established that AdExos may play a role in both ATM recruitment and ATM identity, we do not know the mechanisms that govern these actions. Aim 3 seeks to test whether pathways known to canonically regulate ATM differentiation and identity, like the CCR2 axis and PPARG, respectively, are also responsible for the AdExo-mediated regulation of these processes in ATMs.

项目概要 肥胖是一种与不良健康结果相关的常见病症，并且很大一部分 这些病理是由脂肪组织在细胞和分子方面的功能障碍和失调介导的 等级。脂肪组织含有独特的巨噬细胞群（脂肪组织巨噬细胞，或 ATM）。 这些 ATM 在肥胖症中积累并介导脂肪组织中的许多关键过程和病理学， 包括脂质处理、炎症和胰岛素抵抗。存在多个 ATM 群体：组织- 常驻抗炎群体是卵黄囊胚胎造血祖细胞的后代， 始终在场；促炎细胞群源自成人循环单核细胞前体 并在肥胖等代谢应激条件下被招募。外泌体很小，可以分泌， 内体衍生的、膜结合的细胞外囊泡。脂肪细胞持续释放含脂质 外泌体（脂肪细胞衍生的外泌体，或 AdExos），并且其分泌率在状态期间增加 ATM 积累增加，包括肥胖和急性禁食。 AdExos 也可以充当巨噬细胞 化学引诱剂并驱动骨髓源性巨噬细胞重编程为 ATM 样细胞 转录和表型同一性。然而，关于其全部范围和影响的许多问题 AdExos 仍未得到解决。我们假设 AdExos 调节 脂肪组织中的巨噬细胞通过已知的典型途径调节 ATM。鉴于 AdExo 在单核细胞募集和 ATM 募集发生的条件下，产量会增加，并且 AdExos 既直接充当巨噬细胞趋化剂，又驱动单核细胞趋化剂的产生 脂肪组织中的因素，我们认为 AdExos 调节单核细胞向脂肪组织的募集。目标1 试图通过监测直接注射 AdExo 对体内的影响来确定这种作用。 单核细胞的化学吸引和积累。之前的工作已经检验了 AdExos 对 骨髓来源的巨噬细胞的身份，但不是更相关的前体细胞，例如卵黄囊 造血祖细胞和外周单核细胞。目标 2 旨在测试祖细胞之间的关系 细胞身份以及 AdExo 暴露对细胞命运的影响。虽然我们已经确定 AdExos 可能会发挥 尽管我们不知道控制这些行为的机制。 目标 3 旨在测试已知的途径是否能够规范地调节 ATM 分化和身份，例如 CCR2 轴和 PPARG 也分别负责 AdExo 介导的这些调节 ATM 中的流程。