Regulation of Adipose Tissue Inflammation by Antigen Presenting Cells

描述（由申请人提供）：肥胖与代谢综合征和2型糖尿病等疾病密切相关，威胁着美国儿童和成人的健康。肥胖引起的促炎信号被认为是肥胖导致这些疾病发病率和死亡率的机制。脂肪组织巨噬细胞（ATMs）是肥胖诱导炎症的重要介质。它们在肥胖脂肪中被激活，通过干扰正常的脂肪细胞功能而失调代谢。我们已经有了关键的发现，atm以不同的亚型存在，这些亚型根据肥胖状态受到不同的调节。最近的研究表明，T细胞也参与脂肪组织炎症，并可能与atm一起引起肥胖脂肪组织炎症。一个悬而未决的基本问题是：引发肥胖脂肪炎症变化的信号和细胞间相互作用的本质是什么？本研究将通过检验ATMs作为抗原呈递细胞与脂肪中的炎症性CD4+ T细胞交流和激活的假设来解决这个问题。这一假设是基于我们的初步数据，证明atm可以以抗原依赖的方式激活T细胞。此外，我们已经确定了在atm上发现的两种受体，它们需要在脂肪中的T细胞中产生肥胖诱导的变化。我们的研究将应用一些技术和概念上的创新来研究atm和T细胞之间的相互作用。我们提出了一个模型，在肥胖的早期阶段，T细胞被肥胖诱导的脂肪信号激活，这些信号由atm的常驻人群传递。随着肥胖程度的加重，炎症性atm被募集到脂肪中，并放大T细胞炎症。我们将测试这一模型，并通过使用小鼠肥胖模型来揭示这些事件背后的机制，以解决三个具体目标。(1)确定肥胖改变atm激活CD4+ T细胞能力的机制。(2)了解MGL1这一仅在常驻atm上发现的受体参与脂肪组织炎症和T细胞激活的机制。(3)评估在募集的炎症atm上抗原呈递如何有助于脂肪组织炎症的维持。这些炎症相互作用的影响将与与人体健康相关的糖脂代谢的生理变化有关。实现这些目标将为脂肪组织炎症如何启动提供新的见解。重要的是，识别调节脂肪组织炎症的细胞-细胞通讯类型，可以确定新的干预点，将肥胖从其对健康的负面影响中分离出来。

DESCRIPTION (provided by applicant): Obesity threatens the health of children and adults in the U.S. due its strong association with diseases such as metabolic syndrome and Type 2 diabetes. The pro-inflammatory signals induced by obesity are recognized as a mechanism by which obesity causes morbidity and mortality from these diseases. Adipose tissue macrophages (ATMs) are important mediators of obesity-induced inflammation. They are activated in obese fat and dysregulate metabolism by interfering with normal fat cell function. We have made the key discovery that ATMs exist as distinct subtypes that are regulated differently depending on the state of obesity. Recently, studies have demonstrated that T cells also participate in adipose tissue inflammation and may partner with ATMs to cause inflammation in obese adipose tissue. A fundamental unanswered question is: what is the nature of the signals and cell-cell interactions that initiate the inflammatory changes in fat with obesity? This proposal will address this question by examining the hypothesis that ATMs function as antigen presenting cells to communicate with and activate inflammatory CD4+ T cells in fat. This hypothesis is based on our preliminary data demonstrating that ATMs can activate T cells in an antigen-dependent manner. Furthermore, we have identified two receptors found on ATMs that are required to generate the obesity-induced changes in T cells in fat. Our study will apply several technical and conceptual innovations to study the interaction between ATMs and T cells. We propose a model where, in the early stages of obesity, T cells are activated by obesity-induced signals in fat that are transmitted by the resident population of ATMs. With more severe obesity, inflammatory ATMs are recruited to fat and amplify T cell inflammation. We will test this model and reveal the mechanisms behind these events by using mouse models of obesity to address three specific aims. (1) To identify the mechanisms by which obesity alters the ability of ATMs to activate CD4+ T cells. (2) To understand the mechanisms by which MGL1, a receptor found only on resident ATMs, participates in the initiation of adipose tissue inflammation and T cell activation. (3) To assess how antigen presentation on recruited inflammatory ATMs contributes to the maintenance of adipose tissue inflammation. The impact of these inflammatory interactions will be related to the physiologic changes in glucose and lipid metabolism that are relevant to human health. Accomplishing these aims will provide a novel insight into how adipose tissue inflammation is initiated. Importantly, identification of the types of cell-cell communications that regulate inflammation in adipose tissue can identify novel points for intervention to uncouple obesity from its negative effects on health. PUBLIC HEALTH RELEVANCE: Inflammatory activation in obesity contributes to the development of insulin resistance and diabetes. This inflammation is largely generated by the activity of inflammatory cells found in fat tissue that change as fat mass increases. This proposal will investigate how two important inflammatory cells in fat, macrophages and T cells, communicate in adipose tissue. Results of this study could lead to novel therapies for type 2 diabetes that are directed towards blocking obesity-induced inflammation.