Age-related impairment in anti-HMGB1 IgM response potentiates type 2 diabetes

年龄相关的抗 HMGB1 IgM 反应受损会加剧 2 型糖尿病

基本信息

批准号：
10665749
负责人：
AOSHUANG CHEN
金额：
$ 19.99万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665749
关键词：
Adjuvant Age Aging Agonist Anti-Inflammatory Agents Antibodies Apolipoprotein E Autoantibodies B-Lymphocytes Binding Biochemical Blood donor CXCR4 gene Cardiovascular Diseases Cell Aging Cells Chemotaxis Chronic Data Defect Development Disease Elderly Enzyme-Linked Immunosorbent Assay Epitopes FDA approved Fatty acid glycerol esters Feedback Female Flow Cytometry Food HMGB1 gene Healthy Eating High Fat Diet Homeostasis Human Immune Immunization Immunoglobulin M Immunotherapy Impairment In Vitro Inflammaging Inflammation Inflammatory Infusion procedures Ingestion Injectable Insulin Resistance Life Link Lipid A MAPK8 gene Mammalian Cell Mammals Metabolic Metabolic stress Molecular Mus NF-kappa B Names Non-Insulin-Dependent Diabetes Mellitus Nuclear Protein Pathogenesis Pathogenicity Pathway interactions Pattern Peritoneal Pharmaceutical Preparations Phosphorylation Play Reporting Risk Risk Factors Role Serine Serum Signal Transduction Stains Sterility Stress TLR4 gene Testing Therapeutic Western Blotting Wild Type Mouse acute infection age group age related aged cell age cell injury cytokine diabetogenic dysbiosis extracellular food challenge gain of function in vivo insight insulin receptor substrate 1 protein insulin signaling loss of function male microbiome middle age mitochondrial dysfunction neutralizing antibody novel novel therapeutics pathogen receptor response self-renewal tissue regeneration tissue repair

项目摘要

PROJECT SUMMARY Type 2 diabetes (T2D) is a common disease in older adults and also a risk factor for other age-related diseases. A common link of these diseases is age-related increase in low-grade chronic inflammation (known as “inflammaging”). Chronic inflammation is triggered partly by damage-associated molecular patterns (DAMPs). HMGB1 (High-Mobility Group Box 1) is a prototypical DAMP that is evolutionarily conserved, and it is implicated in the pathogenesis of several age-related diseases including T2D and cardiovascular disease (CVD). Recently, in both normal mice and healthy human blood donors, we identified an endogenous anti- HMGB1 IgM antibody (Ab) that neutralizes the proinflammatory activity of HMGB1, via binding to a highly conserved epitope of HMGB1, namely HMW4. This anti-HMW4 IgM was upregulated in mice in response to challenge with high fat diet (HFD). Critically, the ability to upregulate anti-HMW4 IgM (upon HFD challenge) was impaired in middle-aged (9-month-old) male and older (14-month-old) female mice, which correlated with the increase in vulnerability (or decrease in tolerance) to the diabetogenic effect of HFD, as reflected by more rapid onset of insulin resistance (IR). These data compel us now to test our hypothesis that anti-HMW4 IgM plays a diabeto-protective role, and the age-related impairment in raising this IgM represents one of the factors contributing to the increase in vulnerability to the diabetogenic effect of HFD and, thus, the risk of IR/T2D. We propose two specific aims. Specific Aim #1 is to determine whether anti-HMW4 IgM is diabeto- protective. We will use two complementary approaches: 1) Determining whether infusion of anti-HMW4 IgM into young, middle-aged, and age mice (“gain-of-function”) confers protection against HFD-induced IR and inflammation. 2) Determining whether diminishing this IgM response by depletion of anti-HMW4 IgM-producing B-1 cells in young mice (“loss-of-function”) impairs their tolerance to HFD. Specific Aim #2 is to identify age- related defects in HMW4-reactive B-1 cells that impair the anti-HMW4 IgM response, with the focus on the TLR4 signaling axis. We will use two approaches: 1) Analyzing TLR4 activation in peritoneal HMW4-reactive B-1 cells from young, middle-aged, and aged mice to determine whether middle-aged and aged mice have a defect in TLR4 signaling. 2) Treating middle-aged and aged mice with the TLR4 agonist MPLA to determine whether enhanced TLR4 stimulation restores their anti-HMW4 IgM response and tolerance to HFD. The significance of our studies lies in a few aspects. The studies will identify an age-related mechanism for regulating chronic inflammation and the body’s tolerance to fatty foods. They will provide valuable insight into the immune-metabolic interplay in metabolic challenge. They are expected to yield a novel target for immunotherapy (i.e., anti-HMW4 IgM-producing B cells) and an “injectable” therapeutic (i.e., anti- HMW4 IgM) for age-related diseases including T2D and CVD.

项目概要 2 型糖尿病 (T2D) 是老年人的常见疾病，也是其他与年龄相关的疾病的危险因素这些疾病的一个共同联系是与年龄相关的低度慢性炎症（已知）的增加。慢性炎症部分是由损伤相关的分子模式引发的。（DAMP）。HMGB1（高迁移率组盒 1）是一种进化保守的原型 DAMP，它与多种年龄相关疾病（包括 T2D 和心血管疾病）的发病机制有关最近，我们在正常小鼠和健康人类献血者中发现了一种内源性抗体。 HMGB1 IgM 抗体 (Ab) 通过与高度结合来中和 HMGB1 的促炎活性 HMGB1 的保守表位，即 HMW4，这种抗 HMW4 IgM 在小鼠体内表达上调。至关重要的是，能够上调抗 HMW4 IgM（在 HFD 挑战后）。中年（9 个月大）雄性小鼠和老年（14 个月大）雌性小鼠中的神经功能受损，这与对 HFD 致糖尿病作用的脆弱性增加（或耐受性降低），更多反映胰岛素抵抗 (IR) 的快速发生迫使我们现在检验我们的假设：抗 HMW4 IgM。发挥糖尿病保护作用，与年龄相关的 IgM 升高受损是因素之一导致 HFD 导致糖尿病的风险增加，从而增加 IR/T2D 的风险。我们提出了两个具体目标。具体目标#1 是确定抗 HMW4 IgM 是否为糖尿病。我们将使用两种互补的方法： 1) 确定是否输注抗 HMW4 IgM。给年轻、中年和老年小鼠（“功能获得”）提供针对 HFD 诱导的 IR 和 2) 确定是否通过消除抗 HMW4 IgM 产生来减弱这种 IgM 反应。年轻小鼠的 B-1 细胞（“功能丧失”）会损害它们对 HFD 的耐受性，具体目标#2 是确定年龄。 HMW4 反应性 B-1 细胞中的相关缺陷会损害抗 HMW4 IgM 反应，重点是我们将使用两种方法：1) 分析腹膜 HMW4 反应性中的 TLR4 激活。来自年轻、中年和老年小鼠的 B-1 细胞，以确定中年和老年小鼠是否具有 2）用TLR4激动剂MPLA治疗中老年小鼠以确定TLR4信号传导缺陷。增强的 TLR4 刺激是否可以恢复其抗 HMW4 IgM 反应和对 HFD 的耐受性。我们研究的意义在于几个方面。这些研究将确定一个与年龄相关的因素。它们将提供调节慢性炎症和身体对脂肪食物的耐受性的机制。他们有望对代谢挑战中的免疫代谢相互作用产生有价值的见解。免疫治疗（即产生抗 HMW4 IgM 的 B 细胞）和“注射”治疗（即抗 HMW4 IgM 的 B 细胞）的目标 HMW4 IgM）用于治疗与年龄相关的疾病，包括 T2D 和 CVD。