Regulation of Adipose Tissue Inflammation by Antigen Presenting Cells

描述（由申请人提供）：由于肥胖与代谢综合征和2型糖尿病等疾病密切相关，肥胖威胁着美国儿童和成人的健康。由肥胖诱导的促炎信号被认为是肥胖引起这些疾病的发病率和死亡率的机制。脂肪组织巨噬细胞（ATM）是肥胖诱导的炎症反应的重要介质。它们在肥胖脂肪中被激活，并通过干扰正常脂肪细胞功能来失调代谢。我们已经取得了关键的发现，ATM作为不同的亚型存在，根据肥胖的状态进行不同的调节。最近，研究表明，T细胞也参与脂肪组织炎症，并可能与ATM合作，导致肥胖脂肪组织炎症。一个基本的未回答的问题是：什么是信号的性质和细胞间的相互作用，引发脂肪与肥胖的炎症变化？该提案将通过检查ATM作为抗原呈递细胞与脂肪中的炎性CD4+ T细胞通信并激活其的假设来解决这个问题。这一假设是基于我们的初步数据，表明ATM可以以抗原依赖性方式激活T细胞。此外，我们已经确定了在ATM上发现的两种受体，它们是产生肥胖诱导的脂肪中T细胞变化所必需的。我们的研究将应用一些技术和概念创新来研究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细胞被脂肪中的肥胖诱导信号激活，这些信号是由ATM的居民人口传播的。随着更严重的肥胖，炎症ATM被招募到脂肪和放大T细胞炎症。我们将测试这个模型，并通过使用肥胖小鼠模型来揭示这些事件背后的机制，以解决三个特定的目标。(1)确定肥胖改变ATM激活CD4+ T细胞能力的机制。(2)了解MGL1（一种仅在常驻ATM上发现的受体）参与启动脂肪组织炎症和T细胞活化的机制。(3)评估募集的炎性ATM上的抗原呈递如何有助于维持脂肪组织炎症。这些炎症相互作用的影响将与人体健康相关的葡萄糖和脂质代谢的生理变化有关。实现这些目标将提供一个新的见解脂肪组织炎症是如何启动的。重要的是，确定调节脂肪组织炎症的细胞间通讯类型可以确定新的干预点，将肥胖与其对健康的负面影响分开。

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.