Innate lymphoid cell regulation of metabolic homeostasis

先天淋巴细胞对代谢稳态的调节

• 批准号: 8709176
• 负责人: Jonathan R Brestoff
• 金额: $ 2.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8709176
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Affect; B-Lymphocytes; Cardiovascular Diseases; Cells; Child; Colon; Color; Core Facility; Data; Dendritic Cells; Development; Diet; Disease; Energy Metabolism; Exhibits; Fatty acid glycerol esters; Flow Cytometry; Frequencies; Functional disorder; Genes; Genetic; Glucose; Healthcare Systems; Heart Diseases; Homeostasis; Human; IL2RA gene; IL7R gene; Immune; Immune system; Immunology; In Vitro; Inflammation; Interferons; Interleukin Receptor; Interleukin-13; Interleukin-4; Interleukin-5; Interleukins; Killer Cells; Link; Lipids; Lung; Lymphoid Cell; Malignant Neoplasms; Measures; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular Profiling; Morbid Obesity; Mus; Natural Killer Cells; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Obesity associated disease; Pathogenesis; Pathway interactions; Pennsylvania; Phenotype; Population; Population Group; Property; Public Health; Reagent; Recombinant Interleukins; Regulation; Reporting; Research; Resources; Role; Site; Sorting - Cell Movement; Surface; T-Lymphocyte; Testing; Tissues; Triglycerides; United States; Universities; Visceral; Weight; base; cell type; comparative; cost; cytokine; eosinophil; fasting blood glucose level; feeding; gain of function; genome-wide; granulocyte; in vivo; loss of function; macrophage; novel; prevent; public health relevance; receptor; subcutaneous; transcription factor; translational study

DESCRIPTION (provided by applicant): Obesity is an increasingly prevalent disease that affects 36% of adults and 16% of children and costs the United States (U.S.) healthcare system $150-$190 billion annually. Consequently, there is an urgent need to better understand the factors that regulate the development of obesity. Recent studies indicate that white adipose tissue (WAT)-resident immune cell populations critically regulate WAT homeostasis and produce cytokines that regulate systemic metabolic homeostasis and energy expenditure. This suggests that immune cells can contribute to the development of obesity and associated metabolic dysfunction. However, despite our growing understanding of the influence of inflammation on obesity, how the immune system regulates the development of obesity remains poorly defined. In preliminary studies I have identified a population of group 2 innate lymphoid cells (ILC2s) in human and murine WAT. This recently identified cell type lacks markers for a variety of well-described cell types such as T cells, B cells, dendritic cells, macrophages, natura killer cells and granulocytes and is therefore referred to as lineage-negative (Lin-) but does express CD90, CD25 and CD127 as well as the receptors for IL-33, IL-25 and thymic stromal lymphopoeitin (TSLP). Consistent with the properties of ILC2s in other tissue sites, I found that WAT ILC2s were developmentally dependent on the transcription factors Id2 and TCF-1. Further, this cell type responded to recombinant IL-33 in vivo and in vitro and produced the TH2 cell-associated effector cytokines IL-5 and IL-13, both of which are reported to regulate energy expenditure and metabolic homeostasis. My new data demonstrate that ILC2s are dysregulated in WAT of high fat diet (HFD)-fed obese mice compared to mice fed a control diet. Mice lacking IL-33, a cytokine that is essential for ILC2 function, exhibited more severe obesity. In contrast, exogenous IL-33 increased WAT ILC2s and decreased WAT mass. Collectively, my preliminary data provoke the hypothesis that the IL-33-WAT ILC2 axis negatively regulates obesity. This hypothesis forms the basis of my two aims. In Aim 1, I will determine the phenotype of ILCs in human and murine WAT and investigate the developmental requirements and functional potential of murine WAT ILCs. In Aim 2, I will test whether WAT ILC2s are sufficient to limit the development of obesity, investigate whether IL-33 negatively regulates obesity in an ILC2-dependent manner in mice, and compare WAT ILC2 frequencies in obese vs non- obese humans. These aims will be addressed employing the intellectual and scientific resources available to me in the Artis lab, novel murine strains and ILC2-activating reagents, and a suite of metabolism and immunology core facilities at the University of Pennsylvania.

描述（由申请人提供）：肥胖是一种日益普遍的疾病，影响36％的成年人和16％的儿童，而美国（美国）医疗保健系统每年150亿美元至1900亿美元。因此，迫切需要更好地了解调节肥胖发展的因素。最近的研究表明，白色脂肪组织（WAT） - 居住的免疫细胞种群严格调节WAT稳态，并产生调节全身代谢稳态和能量消耗的细胞因子。这表明免疫细胞可以有助于肥胖和相关代谢功能障碍的发展。但是，尽管我们对炎症对肥胖的影响的了解日益了解，但免疫系统如何调节肥胖的发展仍然很差。在初步研究中，我已经确定了人类和鼠WAT中2组先天淋巴样细胞（ILC2）的人群。最近发现的细胞类型缺乏各种描述良好的细胞类型的标记，例如T细胞，B细胞，树突状细胞，巨噬细胞，巨噬细胞，自然杀伤细胞和粒细胞，因此被称为谱系阴性（Lin-） （TSLP）。与其他组织部位中ILC2的特性一致，我发现wat iLc2在发展上取决于转录因子ID2和TCF-1。此外，这种细胞类型对体内和体外的重组IL-33做出了反应，并产生了与Th2细胞相关的效应细胞因子IL-5和IL-13，据报道它们都调节能量支出和代谢性均具有调节。我的新数据表明，与喂养对照饮食的小鼠相比，高脂饮食（HFD）喂养的肥胖小鼠的ILC2在高脂肪饮食（HFD）的肥胖小鼠中失调。缺乏IL-33的小鼠是ILC2功能必不可少的细胞因子，表现出更严重的肥胖症。相反，外源IL-33增加了ILC2S和降低的WAT质量。总的来说，我的初步数据引发了这样一个假设，即IL-33-WAT ILC2轴对肥胖进行负调节。这个假设构成了我两个目标的基础。在AIM 1中，我将确定人类和鼠类WAT中ILC的表型，并研究Murine Wat ILC的发育要求和功能潜力。在AIM 2中，我将测试ILC2是否足以限制肥胖的发展，研究IL-33是否在小鼠中以ILC2依赖性方式对肥胖进行负调节，并比较肥胖与非肥胖人的wat wat wat ILC2频率。这些目标将采用我在工匠实验室中使用的智力和科学资源，新颖的鼠菌株和ILC2激活试剂以及一套套件来解决 宾夕法尼亚大学的代谢和免疫学核心设施。