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: 9113707
• 负责人: Carey N Lumeng
• 金额: $ 38.75万
• 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 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113707
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Biological Assay; Biology; Birth; Body Weight decreased; CD4 Positive T Lymphocytes; Caloric Restriction; Cardiovascular Diseases; Cell Communication; Cell physiology; Cells; Child health care; Clinical; Clinical Research; Communication; Complex; Cross-Sectional Studies; Data; Dendritic Cells; Development; Diabetes Mellitus; Diet; Disease; Equilibrium; Fatty acid glycerol esters; Female; Fostering; Functional disorder; Funding; Goals; Grant; Homeostasis; Human; Human Biology; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunologics; In Vitro; Individual; Inflammation; Inflammatory; Insulin Resistance; Interleukin-6; Lead; Leukocytes; Link; Maintenance; Malignant Neoplasms; Memory; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Population; Property; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Research; Role; Shapes; Signal Transduction; Stimulus; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Visceral; Work; adaptive immunity; bariatric surgery; base; clinically relevant; in vivo; innovation; insight; macrophage; male; mouse model; new therapeutic target; novel; nutrient metabolism; pre-clinical; preclinical study; public health relevance; response; sex; subcutaneous

 DESCRIPTION (provided by applicant): Obesity threatens the health of children and adults in the U.S. based on its strong association with metabolic syndrome and Type 2 diabetes. The pro-inflammatory state induced by obesity has been directly linked to metabolic disease and is driven by inflammatory changes in adipose tissue. This is driven by adipose tissue leukocytes such as macrophages (ATM) and T cells that provide signals that can both positively and negatively influence nutrient metabolism by regulating adipocyte function. The mechanisms that govern the choice to either promote metabolic homeostasis or dysregulation are not well delineated. Revealing the mechanisms that govern the immune balance in adipose tissue will provide insight into new pathways that can be modified for new treatments for diabetes and other cardiometabolic disease. Antigen presenting cells (APCs) sit at the interface between innate and adaptive immune responses and associations between antigen presentation pathways and metabolic disease are well documented. We have discovered that direct communication between macrophages and CD4+ T cells in adipose tissue is a critical control point in the decision to generate regulatory/protective or immunostimulatory/pro-inflammatory signals. The identity of the signals that shape the adipose tissue immune response, when is regulation favored over immunity, which antigen presenting cells should be targeted for new therapeutics, and how these functions differ between metabolically healthy and unhealthy obese patients are unknown. This proposal will address these questions in pursuit of our long term goal of identifying the features of the adipose tissue immune system that contribute metabolic disease. This study will examine the hypothesis that ATM and adipose tissue dendritic cells (ATDC) control the phenotype of CD4+ T lymphocytes via APC function. This hypothesis is supported by our work in the prior funding cycle, but is enhanced by our recent unambiguous identification of ATDC, demonstration that ATM and ATDC differentially control metabolism and regulatory T cells, and identification of associations between MHCIIhi populations of ATMs in obese patients with diabetes. These findings drive the specific aims of the proposal which are: (1) To delineate the roles of ATMs and ATDCs in obesity-induced adipose tissue inflammation and T cell activation. (2) To assess the effects of weight loss on adipose tissue antigen presentation cell function. (3) To evaluate the association between ATM and ATDCs and diabetes status in obese humans. Completing our aims will have a significant impact on identifying the important communication pathways that shape the range of responses that can be generated by adipose tissue leukocytes. This is a required step in understanding how the adipose tissue immune system may be manipulated to either promote immune "tolerance" to obesity or block immunostimulatory signals. It will use innovative complementary studies to close the gap between our understanding of adipose tissue leukocyte biology in pre-clinical and clinical studies.

 描述（由申请人提供）：肥胖与代谢综合征和2型糖尿病密切相关，威胁着美国儿童和成人的健康。由肥胖引起的促炎状态与代谢疾病直接相关，并由脂肪组织中的炎症变化驱动。这是由脂肪组织白细胞如巨噬细胞（ATM）和T细胞驱动的，它们提供的信号可以通过调节脂肪细胞功能对营养代谢产生积极和消极的影响。控制选择促进代谢稳态或失调的机制还没有很好地描述。揭示控制脂肪组织中免疫平衡的机制将为糖尿病和其他心脏代谢疾病的新治疗方法提供新的途径。抗原呈递细胞（APC）位于先天性和适应性免疫应答之间的界面，并且抗原呈递途径和代谢疾病之间的关联被充分记录。我们已经发现，脂肪组织中巨噬细胞和CD 4 + T细胞之间的直接通信是决定产生调节/保护或免疫刺激/促炎信号的关键控制点。塑造脂肪组织免疫反应的信号的身份，什么时候调节优于免疫，新疗法应该靶向哪些抗原呈递细胞，以及代谢健康和不健康的肥胖患者之间这些功能的差异是未知的。这项提案将解决这些问题，以追求我们的长期目标，确定脂肪组织免疫系统的特点，有助于代谢疾病。本研究将检验ATM和脂肪组织树突状细胞（ATDC）通过APC功能控制CD 4 + T淋巴细胞表型的假设。这一假设得到了我们在前一个资助周期中的工作的支持，但我们最近明确鉴定了ATDC，证明了ATM和ATDC差异控制代谢和调节性T细胞，并鉴定了肥胖糖尿病患者中ATM的MHCIIhi群体之间的关联。这些发现推动了该提案的具体目标，即：（1）描述ATMs和ATDC在肥胖诱导的脂肪组织炎症和T细胞活化中的作用。(2)评估体重减轻对脂肪组织抗原呈递细胞功能的影响。(3)评估肥胖人群中ATM和ATDC与糖尿病状态之间的关系。完成我们的目标将对确定重要的通信途径产生重大影响，这些途径形成了脂肪组织白细胞可以产生的反应范围。这是理解脂肪组织免疫系统如何被操纵以促进对肥胖的免疫“耐受”或阻断免疫刺激信号的必要步骤。它将使用创新的补充研究来缩小我们在临床前和临床研究中对脂肪组织白细胞生物学的理解之间的差距。