Regulation of Adipose Tissue Inflammation By Antigen Presenting Cells

抗原呈递细胞对脂肪组织炎症的调节

• 批准号: 10229169
• 负责人: Carey N Lumeng
• 金额: $ 49.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-11 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10229169
• 关键词: Address; Adipose tissue; Adopted; Antibodies; Antigen-Presenting Cells; CTLA4 gene; Cell Communication; Cell Ontogeny; Cell Shape; Cell physiology; Cells; Chronic; Communication; Data; Dendritic Cells; Diabetes Mellitus; Disease; Ensure; Environment; Funding; Genes; Genetic; Genetic Models; Glucocorticoids; Goals; Grant; Health; Human; Hyperactivity; IL2RA gene; Immune; Immune response; Immune system; Immunosuppression; Impairment; Inflammation; Inflammatory; Insulin Resistance; Interferon Type II; Interleukin-2; Intervention; Lead; Leukocytes; Link; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathway interactions; Pharmacology; Predisposition; Production; Proteins; Publishing; Regulation; Research; Resolution; Role; Sampling; Sepsis; Severity of illness; Signal Induction; Signal Pathway; Signal Transduction; Stimulus; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; T-cell diversity; Testing; Thinness; Time; Virus Diseases; Work; adaptive immunity; base; cytokine; diabetic; dietary; effector T cell; exhaust; exhaustion; herpesvirus entry mediator; immunoregulation; improved; in vivo; inflammatory milieu; macrophage; novel; preservation; programmed cell death protein 1; receptor; respiratory; respiratory virus; single-cell RNA sequencing; vaccine response

Adipose tissue contains a network of leukocytes that respond to obesity by generating proinflammatory signals that contribute to metabolic disease. At the same time, there is strong evidence that many healthy immune responses are impaired in obesity and contribute to an increased severity of illness to many diseases that include respiratory viruses. We currently do not have a clear understanding of the mechanisms behind this dichotomy. Addressing this gap can reveal mechanisms by which a hyperactive immune system can be restrained to improve insulin resistance and can also identify mechanisms by which normal immune responses can be preserved to improve health in people with obesity. This proposal seeks to understand immune responses in adipose tissue by focusing on the mechanisms by which the innate and adaptive components of the adipose tissue immune system interact in mice and humans. Our central hypothesis is that the chronic pro-inflammatory environment generated by obesity triggers T cell and myeloid exhaustion. We further posit that the diversity of adipose tissue macrophages (ATM) and dendritic cells (ATDC) shape adipose tissue T cell responses that impair healthy resolution of adipose tissue inflammation. The premise for this hypothesis is based on the published work generated in the last grant cycle, as well as preliminary data demonstrating a impaired T cell activation capacity in obese adipose tissue from mice and humans associated with decrease diversity of T cells in obese humans and enrichment for novel subtypes of ATDC. Our approach will identify the mechanisms by which adipose tissue T cells become exhausted with dietary obesity by testing the hypothesis that the induction of T cell exhaustion profiles requires differential APC signals and the induction of BTLA receptors in T cells. We will also evaluate the hypothesis that endogenous glucocorticoids alter the ability of ATMs and ATDC to activate T cells in a way that promotes exhaustion. Completing these aims further advance the understanding of the cell-cell communication networks that are generated in adipose tissue and how they contribute to metabolic disease.

脂肪组织含有白细胞网络，通过产生导致代谢疾病的促炎信号来对肥胖做出反应。与此同时，有强有力的证据表明，许多健康的免疫反应因肥胖而受损，并导致包括呼吸道病毒在内的许多疾病的病情加重。我们目前对这种二分法背后的机制还没有清楚的了解。解决这一差距可以揭示抑制过度活跃的免疫系统以改善胰岛素抵抗的机制，还可以确定保留正常免疫反应以改善肥胖人群健康的机制。该提案旨在通过关注小鼠和人类脂肪组织免疫系统的先天性和适应性成分相互作用的机制来了解脂肪组织中的免疫反应。我们的中心假设是，肥胖产生的慢性促炎环境会引发 T 细胞和骨髓衰竭。我们进一步假设，脂肪组织巨噬细胞 (ATM) 和树突状细胞 (ATDC) 的多样性塑造了脂肪组织 T 细胞反应，从而损害了脂肪组织炎症的健康消退。这一假设的前提是基于上一个资助周期中发表的工作，以及初步数据，证明小鼠和人类肥胖脂肪组织中 T 细胞活化能力受损，与肥胖人类 T 细胞多样性降低和 ATDC 新型亚型富集相关。我们的方法将通过测试 T 细胞耗竭曲线的诱导需要差异 APC 信号和 T 细胞中 BTLA 受体的诱导这一假设，来确定脂肪组织 T 细胞因饮食肥胖而耗竭的机制。我们还将评估以下假设：内源性糖皮质激素会改变 ATM 和 ATDC 以促进衰竭的方式激活 T 细胞的能力。完成这些目标进一步加深了对脂肪组织中产生的细胞间通讯网络及其如何导致代谢疾病的理解。