Role of CD40 in Obesity-Induced Adipose Tissue Inflammation & Insulin Resistance

CD40 在肥胖引起的脂肪组织炎症中的作用

• 批准号: 8265988
• 负责人: David L Morris
• 金额: $ 5.22万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-18 至 2014-02-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265988
• 关键词: Adipocytes; Adipose tissue; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Biological Assay; Biology; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD40 Ligand; Cell Communication; Cell Maturation; Cells; Cellular Immunity; Cessation of life; Chimera organism; Coculture Techniques; Communication; Complement; Cultured Cells; Data; Development; Diabetes Mellitus; Diet; Environment; Fatty acid glycerol esters; Functional disorder; Generations; Glycoproteins; Goals; Hematopoietic; Hypertrophy; ITGAX gene; Immune; Immunologist; Immunology; In Vitro; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interferons; Interleukin-12; Interleukin-6; Lead; Learning; Leukocytes; Macrophage Activation; Measures; Mediating; Metabolic Diseases; Metabolism; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathogenesis; Pathway interactions; Positioning Attribute; Production; Regulation; Research; Research Personnel; Research Training; Role; Shapes; Signal Pathway; Signal Transduction; Source; System; T cell response; T-Cell Activation; T-Lymphocyte; TLR4 gene; TNF gene; TNFRSF5 gene; TNFSF5 gene; Techniques; Testing; Tissues; Training; Tumor Necrosis Factor Receptor; Visceral; Work; base; cytokine; design; in vivo; macrophage; meetings; novel; research study; response; skills

DESCRIPTION (provided by applicant): Obesity-induced inflammation is a contributing factor in the pathogenesis of insulin resistance and Type 2 diabetes. Both adipose tissue macrophages (ATMs) and adipose tissue T cells (ATTs) accumulate during obesity. ATMs and ATTs produce pro-inflammatory signals that impair insulin action in adipose tissue. However, a clear understanding of how ATTs and ATMs communicate to initiate and sustain adipose tissue inflammation and generate insulin resistance during obesity is lacking. Our group is exploring the hypothesis that communication between ATMs and ATTs in adipose tissue is central to shaping the inflammatory environment in fat. We have found that CD40 expression is increased in visceral fat during diet-induced obesity and that ATMs express CD40. CD40 is a transmembrane glycoprotein belonging to the TNF receptor superfamily. The ligand for CD40, CD40L (or CD154), is highly expressed on activated T lymphocytes. CD40- CD40L signaling has been shown to be critical for T cell priming, effector function, and initiation of T cell- mediated immunity. Our preliminary data support a model in which signals derived from high fat diet exposure induce CD40 on ATMs to promote activation and expansion of CD4+ ATTs. The central hypothesis of this application is that the CD40-CD40L pathway mediates communication between ATMs and ATTs to promote ATM activation to drive expansion of antigen-specific CD4+ ATTs and induce inflammation and insulin resistance during obesity. The goal of this training proposal is for the trainee to rigorously test this model while learning and applying immunology techniques to measure ATM function and ATT responses in cultured cells and in fat. In Aim 1, we will determine how CD40 expression in ATMs is regulated by adipocytes. Specifically, we will test the working hypothesis that adipocyte hypertrophy and death activates TLR4 and NF-:B signaling pathways in ATMs to induce CD40 expression. In Aim 2, we will examine the effects of CD40 activation on the biology of M1 and M2 ATMs. The proposed experiments will test whether CD40 activation induced maturation and cytokine production by ATMs, and whether CD40 activation participates in the regulation of ATTs by ATMs. In Aim 3, we will test the working hypothesis that CD40 activation in leukocytes is principally responsible for the generation of inflammatory signals in visceral fat during obesity. The proposed experiments will provide a clear understanding as to whether and how CD40-CD40L signaling contributes to obesity- induced inflammation. The training proposal is specifically designed to promote cross training in the fields of immunology and metabolism. The trainee will develop expertise in ATM biology and regulation of obesity- induced inflammation, learn key immunological concepts relevant to the regulation of ATMs and ATTs, and receive training in state of the art techniques used by immunologists and obesity researchers.

描述（由申请人提供）：肥胖引起的炎症是胰岛素抵抗和 2 型糖尿病发病机制中的一个促成因素。肥胖期间脂肪组织巨噬细胞 (ATM) 和脂肪组织 T 细胞 (ATT) 都会积累。 ATM 和 ATT 产生促炎信号，损害脂肪组织中的胰岛素作用。然而，对于 ATT 和 ATM 如何进行通信以引发和维持脂肪组织炎症并在肥胖期间产生胰岛素抵抗尚缺乏清晰的了解。我们的小组正在探索这样一种假设：脂肪组织中的 ATM 和 ATT 之间的通讯对于塑造脂肪中的炎症环境至关重要。我们发现饮食诱导的肥胖期间内脏脂肪中 CD40 表达增加，并且 ATM 表达 CD40。 CD40是属于TNF受体超家族的跨膜糖蛋白。 CD40 的配体 CD40L（或 CD154）在活化的 T 淋巴细胞上高度表达。 CD40-CD40L 信号转导已被证明对于 T 细胞启动、效应器功能和 T 细胞介导的免疫启动至关重要。我们的初步数据支持一个模型，其中来自高脂肪饮食暴露的信号诱导 ATM 上的 CD40，以促进 CD4+ ATT 的激活和扩展。本申请的中心假设是，CD40-CD40L 通路介导 ATM 和 ATT 之间的通讯，从而促进 ATM 激活，从而驱动抗原特异性 CD4+ ATT 的扩张，并在肥胖期间诱导炎症和胰岛素抵抗。本培训计划的目标是让学员严格测试该模型，同时学习和应用免疫学技术来测量培养细胞和脂肪中的 ATM 功能和 ATT 反应。在目标 1 中，我们将确定脂肪细胞如何调节 ATM 中的 CD40 表达。具体来说，我们将测试脂肪细胞肥大和死亡激活 ATM 中的 TLR4 和 NF-:B 信号通路以诱导 CD40 表达的工作假设。在目标 2 中，我们将研究 CD40 激活对 M1 和 M2 ATM 生物学的影响。拟议的实验将测试 CD40 激活是否诱导 ATM 成熟和细胞因子产生，以及 CD40 激活是否参与 ATM 对 ATT 的调节。在目标 3 中，我们将检验以下假设：白细胞中 CD40 的激活主要负责肥胖期间内脏脂肪中炎症信号的产生。拟议的实验将清楚地了解 CD40-CD40L 信号传导是否以及如何促进肥胖引起的炎症。该培训计划专门旨在促进免疫学和代谢领域的交叉培训。学员将发展 ATM 生物学和肥胖引起的炎症调节方面的专业知识，学习与 ATM 和 ATT 调节相关的关键免疫学概念，并接受免疫学家和肥胖研究人员使用的最先进技术的培训。