Regulation of Adipose Tissue Inflammation By Antigen Presenting Cells

 描述(申请人提供)：肥胖威胁着美国儿童和成人的健康，因为它与代谢综合征和2型糖尿病密切相关。肥胖引起的促炎状态与代谢性疾病直接相关，并由脂肪组织的炎性变化驱动。这是由脂肪组织白细胞，如巨噬细胞(ATM)和T细胞驱动的，这些细胞提供的信号可以通过调节脂肪细胞的功能对营养代谢产生积极和消极的影响。控制选择促进代谢动态平衡或调节失调的机制没有被很好地描绘出来。揭示控制脂肪组织免疫平衡的机制将为糖尿病和其他心脏代谢性疾病的新治疗方法提供新的途径。抗原提呈细胞(APC)位于先天免疫反应和获得性免疫反应之间的交界处，抗原提呈途径与代谢性疾病之间的联系已有很好的文献记载。我们发现，脂肪组织中巨噬细胞和CD4+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。形成脂肪组织免疫反应的信号的一致性，何时调节优先于免疫，哪些抗原提呈细胞应该作为新的治疗方法的靶点，以及代谢健康和不健康的肥胖患者之间这些功能的差异尚不清楚。这项建议将解决这些问题，以追求我们的长期目标，即确定导致代谢性疾病的脂肪组织免疫系统的特征。本研究将验证ATM和脂肪组织树突状细胞(ATDC)通过APC功能控制CD4+T淋巴细胞表型的假设。这一假说得到了我们在前一个资金周期中工作的支持，但我们最近对ATDC的明确识别、证明ATM和ATDC不同地控制新陈代谢和调节T细胞，以及确定肥胖症合并糖尿病患者的MHCIII人群之间的关联，加强了这一假说。这些发现推动了该提案的具体目标：(1)阐明ATM和ATDC在肥胖诱导的脂肪组织炎症和T细胞激活中的作用。(2)评价减肥对脂肪组织抗原提呈细胞功能的影响。(3)探讨肥胖人群中ATM和ATDC与糖尿病的关系。完成我们的目标将对确定重要的沟通途径产生重大影响，这些途径塑造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“耐受性”或阻断免疫刺激信号的必要步骤。它将使用创新的互补性研究来弥合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。

 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.