The Role of B Cells and B Cell Toll-like Receptors in Glucose Intolerance

B 细胞和 B 细胞 Toll 样受体在葡萄糖耐受不良中的作用

• 批准号: 7976476
• 负责人: Barbara Nikolajczyk
• 金额: $ 24.38万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7976476
• 关键词: Ablation; Adipose tissue; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; B-Lymphocytes; Cells; Chronic; Data; Diet; Disease; Endotoxemia; Endotoxins; Epidemic; Equilibrium; Etiology; Family; Fatty acid glycerol esters; Genetic; Genetic Polymorphism; Glucose; Glucose Intolerance; Hematopoietic; Human; Human Subject Research; Immune; Immune system; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Interleukin-10; Investigation; Knockout Mice; Lead; Ligands; Link; Measurement; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Modeling; Mus; Muscle Cells; Mutation; Myeloid Cells; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obese Mice; Obesity; Outcome; Pathogenesis; Patients; Phenotype; Plasma; Play; Process; Production; Publishing; Regulation; Role; Serum; Severities; Source; Surface; TLR2 gene; TLR4 gene; Testing; Time; Toll-like receptors; Work; cell type; cytokine; glucose monitor; glucose tolerance; in vivo; insulin sensitivity; insulin sensitivity/resistance; member; monocyte; mouse model; novel strategies; public health relevance; receptor; receptor function; reconstitution; research study; response; standard measure; stem

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is associated with chronic inflammation that predominantly originates from immune system cells. These cells are chronically activated by the in vivo milieu of T2D patients, which includes elevated plasma levels of free fatty acids (FFAs) and endotoxin. Both of FFAs and endotoxin are ligands for toll-like receptors (TLRs), and both generally activate pro-inflammatory cytokine production upon TLR engagement. These cytokines likely play important roles in the chronic systemic inflammation characterizing T2D and other metabolic syndromes. Multiple studies show that controlling inflammation in obese mice by blocking TLR function decreases the incidence of insulin resistance, a hallmark of T2D. Although many cell types are sources of inflammatory cytokines, immune cell cytokines are required for insulin resistance. Taken together, these analyses indicate that TLR-activated inflammation from immune system cells is a key process that promotes T2D and other metabolic diseases. Although monocytes are generally considered the most important immune cell type for pro-inflammatory cytokine production, B cells also produce significant levels of cytokines. Our new data on B cells from T2D patients demonstrate that B cell TLR2 and TLR4 activation generally results in production of pro-inflammatory cytokines. However, TLR4 ligand decreases TLR2- mediated production of TNF-1. This anti-inflammatory effect may be balanced by the complete inability of B cells from T2D patients to secrete IL-10, a critical anti-inflammatory cytokine. The discoveries of an elevated percentage of TLR4-positive B cells in T2D patients and the mixed inflammatory responses of these B cells to TLR ligands lead to the hypothesis that B cells and B cell TLRs play important roles in T2D by regulating inflammation thus insulin resistance and glucose tolerance. Because the general endotoxemia and elevated free fatty acids in T2D patients provide innumerable TLR ligands, our preliminary data predict that B cell TLRs influence T2D through cytokine regulation in vivo. Although additional studies on human B cell TLR function are likely to be mechanistically and clinically important, the next critical step in this line of investigation is to unequivocally demonstrate B cells and B cell TLRs play roles in T2D inflammation and pathogenesis. These studies will be undertaken in a diet-induced obesity mouse model of T2D that takes advantage of available genetically altered mice. This project will test the effects of 1. the absence of B cells; 2. TLR function only on B cells; and 3. B cell-specific TLR inactivation on inflammatory and metabolic outcomes of high fat diet in vivo. These studies will define the role of B cells in metabolic imbalance, and predict the likely efficacy of using approved B cell ablation therapies as new treatments for metabolic syndrome and T2D. PUBLIC HEALTH RELEVANCE: Type 2 diabetes (T2D) is increasing at epidemic rates world-wide, and the treatment arsenal for this disease is limited. Inflammation plays an important role in the etiology and complications of T2D. Inflammation stemming from immune cell cytokine production plays a demonstrated role in insulin resistance, one of the key features of T2D. The role of myeloid cell cytokines in T2D is relatively well understood. Our new work in T2D patients demonstrates that B cells may be another major source of cytokines in T2D. However, our human subjects research, by its nature, cannot definitively link B cells to disease pathogenesis. The project proposes to test the role of B cells and their surface receptors in T2D using model organisms. Importantly, this work will determine whether existing B cell ablation therapies can be used as fundamentally new treatments for T2D.

描述（由申请人提供）：2型糖尿病（T2 D）与主要源自免疫系统细胞的慢性炎症相关。这些细胞被T2 D患者的体内环境慢性激活，包括游离脂肪酸（FFA）和内毒素的血浆水平升高。FFA和内毒素两者都是Toll样受体（TLR）的配体，并且两者通常在TLR接合时激活促炎细胞因子产生。这些细胞因子可能在以T2 D和其他代谢综合征为特征的慢性全身性炎症中发挥重要作用。多项研究表明，通过阻断TLR功能来控制肥胖小鼠的炎症，可以降低胰岛素抵抗的发生率，胰岛素抵抗是T2 D的标志。虽然许多细胞类型是炎性细胞因子的来源，但免疫细胞细胞因子是胰岛素抵抗所必需的。总之，这些分析表明，免疫系统细胞的TLR激活炎症是促进T2 D和其他代谢疾病的关键过程。尽管单核细胞通常被认为是促炎细胞因子产生的最重要的免疫细胞类型，但B细胞也产生显著水平的细胞因子。我们对来自T2 D患者的B细胞的新数据表明，B细胞TLR 2和TLR 4活化通常导致促炎细胞因子的产生。然而，TLR 4配体降低TLR 2介导的TNF-1的产生。这种抗炎作用可以通过来自T2 D患者的B细胞完全不能分泌IL-10（一种关键的抗炎细胞因子）来平衡。T2 D患者中TLR 4阳性B细胞百分比升高以及这些B细胞对TLR配体的混合炎症反应的发现导致了以下假设：B细胞和B细胞TLR通过调节炎症从而调节胰岛素抵抗和葡萄糖耐量在T2 D中起重要作用。由于T2 D患者普遍的内毒素血症和升高的游离脂肪酸提供了无数的TLR配体，我们的初步数据预测B细胞TLR通过体内细胞因子调节影响T2 D。尽管对人B细胞TLR功能的其他研究可能在机制和临床上具有重要意义，但这一系列研究的下一个关键步骤是明确证明B细胞和B细胞TLR在T2 D炎症和发病机制中发挥作用。这些研究将在饮食诱导的肥胖T2 D小鼠模型中进行，该模型利用了可用的遗传改变小鼠。该项目将测试1.缺乏B细胞; 2. TLR仅在B细胞上起作用;和3. B细胞特异性TLR失活对体内高脂饮食炎症和代谢结果的影响这些研究将确定B细胞在代谢失衡中的作用，并预测使用批准的B细胞消融疗法作为代谢综合征和T2 D的新疗法的可能疗效。 公共卫生相关性：2型糖尿病（T2 D）在世界范围内以流行率增加，这种疾病的治疗手段有限。炎症在T2 D的病因和并发症中起重要作用。源自免疫细胞细胞因子产生的炎症在胰岛素抵抗中起着证明的作用，胰岛素抵抗是T2 D的关键特征之一。骨髓细胞因子在T2 D中的作用相对较好地理解。我们在T2 D患者中的新工作表明，B细胞可能是T2 D中细胞因子的另一个主要来源。然而，我们的人类受试者研究，就其性质而言，不能明确地将B细胞与疾病发病机制联系起来。该项目建议使用模式生物来测试B细胞及其表面受体在T2 D中的作用。重要的是，这项工作将确定现有的B细胞消融疗法是否可以作为T2 D的新疗法。