Role of monocyte/macrophage lectin receptors in obesity-induced inflammation

单核细胞/巨噬细胞凝集素受体在肥胖引起的炎症中的作用

• 批准号: 7871856
• 负责人: Carey N Lumeng
• 金额: $ 7.54万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-05 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871856
• 关键词: Address; Adhesions; Adipocytes; Adipose tissue; Adoptive Transfer; Affinity; Affinity Chromatography; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Applications Grants; Award; Binding; Binding Proteins; Biological Assay; Biology; Blood; Blood Circulation; Bone Marrow; C-Type Lectins; CX3CL1 gene; Cell Adhesion; Cell Communication; Cells; Chimeric Proteins; Data; Dendritic Cells; Dental crowns; Development; Diabetes Mellitus; Diet; Endothelial Cells; Equilibrium; FUS-1 Protein; Failure; Fatty acid glycerol esters; Fc Receptor; Funding; Galactose; Gene Expression; Generations; Glucose Intolerance; Goals; Homeostasis; Human; Immune response; Immunofluorescence Microscopy; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Interleukin-10; Kinetics; Knockout Mice; Lead; Lectin; Lectin Receptors; Ligands; Longevity; Macrophage Activation; Maintenance; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Metabolism; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathway interactions; Population; Property; Proteins; Regulation; Research; Role; Site; Spleen; Staging; Stromal Cells; Structure; T-Lymphocyte; Techniques; Testing; Tissues; Visceral; Work; cell motility; cytokine; in vitro Model; in vivo; macrophage; migration; monocyte; novel; programs; protective effect; public health relevance; receptor; research study; trafficking

DESCRIPTION (provided by applicant): Adipose tissue macrophages (ATMs) are a key component of the adipose tissue stromal cell population. With obesity, ATMs increase in number in visceral fat and also undergo qualitative changes in their inflammatory activity. ATMs in lean mice are comprised of Type 2 ATMs with low inflammatory capacity that express IL-10, an anti-inflammatory cytokine. With diet-induced obesity, the populations shifts to one where Type 1 ATMs predominates, a distinct ATM type with high inflammatory gene expression. The balance between these ATM subtypes is important since macrophage-mediated inflammation has been shown to be required for the develop insulin resistance in obesity. The goal of the PI's K08 award is to examine how the balance between Type 1 and Type 2 ATMs influences adipose tissue and metabolism via IL-10. During these studies, we developed novel techniques that allowed us to distinguish and study the two ATM types. Work during the award showed that Type 1 and Type 2 ATMs are generated by distinct recruitment pathways from circulating monocytes. In our studies, we discovered that Type 2 resident ATMs express both IL-10 and MGL1 (macrophage galactose-type c-type lectin 1) and Type 1 ATMs do not. In preliminary experiments, we examined MGL1 deficient mice and made the surprising finding that they are protected from glucose intolerance and insulin resistance with diet induced obesity. This protection is related to the fact that MGL1 is expressed on inflammatory 7/4hi monocytes in the blood and that these monocytes are decreased in obese Mgl1-/- mice compared to controls. These observations identify MGL1 as a novel receptor that regulates the levels of inflammatory monocytes similar to CCR2 and CX3CR1. The goal of this proposal is to delineate how MGL1 regulates monocyte function in obesity and how this influences the balance between Type 1 and Type 2 ATMs. We will elucidate how MGL1 functions in monocytes by addressing two primary aims: (1) To assess how MGL1 regulates monocyte stability and retention in the circulation. We will utilize adoptive transfer of monocytes from wild type and Mgl1-/- mice into lean and obese recipients to address the hypothesis that MGL1 is required for the maintenance of inflammatory monocytes in the blood. In vitro models of monocyte-endothelial cells adhesion will evaluate MGL1 mediated cell-cell interactions. (2) To identify MGL1 ligands in visceral adipose tissue in obesity. We will use affinity purification approaches to identify MGL1 ligands in adipose tissue using MGL1 fusion proteins. Overall, this proposal will expand upon a new research direction that has extended from the PI's K08 award. Funds from the R03 will support the independence of the PI as he builds his research program. Data generated from these studies will set the stage for a more expansive grant application. PUBLIC HEALTH RELEVANCE: Inflammatory changes in obesity have important consequences on the development of insulin resistance and diabetes. Many of these inflammatory changes relate to the activation of macrophages and monocytes, inflammatory cells that help direct immune responses. This proposal seeks to expand our understanding of a novel molecule that directs the activation of these monocytes with obesity. Results of this study could potentially lead to novel therapies for type 2 diabetes that are directed towards blocking obesity-induced inflammation.

描述（由申请方提供）：脂肪组织巨噬细胞（ATM）是脂肪组织基质细胞群的关键组分。随着肥胖，ATM在内脏脂肪中的数量增加，并且在其炎症活动中也发生了质的变化。瘦小鼠中的ATM由炎症能力较低的2型ATM组成，表达IL-10（一种抗炎细胞因子）。随着饮食诱导的肥胖，人群转变为1型ATM占主导地位，这是一种具有高炎症基因表达的独特ATM类型。这些ATM亚型之间的平衡是重要的，因为巨噬细胞介导的炎症已被证明是肥胖症中胰岛素抵抗发展所必需的。PI的K 08奖项的目标是研究1型和2型ATM之间的平衡如何通过IL-10影响脂肪组织和代谢。在这些研究中，我们开发了新的技术，使我们能够区分和研究这两种ATM类型。在获奖期间的工作表明，1型和2型ATM是由循环单核细胞的不同招募途径产生的。在我们的研究中，我们发现2型常驻ATM表达IL-10和MGL 1（巨噬细胞半乳糖型c型凝集素1），而1型ATM不表达。在初步的实验中，我们检查了MGL 1缺陷小鼠，并取得了令人惊讶的发现，它们受到保护，免受葡萄糖耐受不良和胰岛素抵抗与饮食诱导的肥胖。这种保护作用与MGL 1在血液中的炎性7/4 hi单核细胞上表达以及与对照组相比，这些单核细胞在肥胖的MGL 1-/-小鼠中减少的事实有关。这些观察结果确定MGL 1是一种新型受体，可调节炎症单核细胞的水平，类似于CCR 2和CX 3CR 1。该提案的目标是描述MGL 1如何调节肥胖症中的单核细胞功能，以及这如何影响1型和2型ATM之间的平衡。我们将通过解决两个主要目标来阐明MGL 1如何在单核细胞中发挥作用：（1）评估MGL 1如何调节单核细胞在循环中的稳定性和保留。我们将利用过继转移的单核细胞从野生型和MGL 1-/-小鼠到瘦和肥胖的受体，以解决的假设，MGL 1是需要维持血液中的炎性单核细胞。单核细胞-内皮细胞粘附的体外模型将评价MGL 1介导的细胞-细胞相互作用。(2)目的：鉴定肥胖症内脏脂肪组织中MGL 1配体。我们将使用亲和纯化方法，以确定MGL 1融合蛋白在脂肪组织中的MGL 1配体。总的来说，这项建议将扩大一个新的研究方向，已从PI的K 08奖延伸。来自R 03的资金将支持PI的独立性，因为他建立了他的研究计划。这些研究产生的数据将为更广泛的赠款申请奠定基础。 公共卫生相关性：肥胖的炎症变化对胰岛素抵抗和糖尿病的发展有重要影响。这些炎症变化中的许多与巨噬细胞和单核细胞的激活有关，这些炎症细胞有助于直接免疫反应。这项提议旨在扩大我们对一种新分子的理解，这种分子指导肥胖症患者单核细胞的激活。这项研究的结果可能会导致2型糖尿病的新疗法，这些疗法旨在阻断肥胖引起的炎症。