Targeting Tfh Cell Metabolic Regulation in SLE and SLE-Associated Atherosclerosis

针对 SLE 和 SLE 相关动脉粥样硬化的 Tfh 细胞代谢调节

• 批准号: 10029497
• 负责人: AMY S MAJOR
• 金额: $ 58.19万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-20 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10029497
• 关键词: ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Acetylation; Address; Affect; Affinity; Anabolism; Animal Model; Antigen-Antibody Complex; Arthritis; Atherosclerosis; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bioenergetics; Bone Marrow; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cause of Death; Cells; Cellular Metabolic Process; Characteristics; Chimera organism; Chromatin; Chronic; Citrates; Clinical Trials; Consumption; Coronary Arteriosclerosis; DNA; Data; Defect; Deposition; Disease; Epigenetic Process; Event; Frequencies; Gene Expression; Genetic; Glucose; Glucose Transporter; Glutaminase; Glutamine; Helper-Inducer T-Lymphocyte; Histone Acetylation; Histones; Immune; Immunosuppression; Impairment; Individual; Inflammation; Inflammatory; Investigation; Knock-out; Lead; Mediating; Medical; Metabolic; Metabolic Pathway; Metabolism; Methylation; Modeling; Modification; Mus; Nephritis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Play; Production; Proliferating; Publishing; Regulation; Regulatory T-Lymphocyte; Role; SLEB1 gene; Signal Transduction; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T cell differentiation; T cell regulation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Transgenic Organisms; Work; alpha ketoglutarate; anti-cancer; autoreactive B cell; base; chronic graft versus host disease; comorbidity; conditional knockout; cytokine; effective therapy; epigenetic regulation; glucose uptake; histone methylation; in vivo Model; inhibitor/antagonist; insight; mortality; mouse model; new therapeutic target; novel; programs; response; side effect; therapeutic target; tumor metabolism; vascular inflammation

PROJECT SUMMARY Systemic lupus erythematosus (SLE) is characterized by autoantibody production and immune complex deposition and affects five to seven million individuals worldwide. Atherosclerosis and cardiovascular disease are common causes of early mortality in SLE, but immune-mediated mechanisms leading to this and other disease sequelae are not well understood. Therefore, demand is high to identify targeted strategies to overcome the undesirable side-effects of overt immunosuppression. In this application, we propose that the cellular metabolism of follicular helper T cells (Tfh), critical in promoting autoreactive B cell responses, may provide novel SLE therapeutic targets. Conversely, regulatory T cells (Treg) may protect. Our group has demonstrated that activated T cells increase glucose and glutamine consumption as they proliferate and differentiate into specific functional subsets. Importantly, differentiation and biosynthesis following activation requires a distinct metabolic program. To date, Tfh metabolism remains poorly understood, but our data suggest that both glucose and glutamine are essential and that Tfh appear to have high rates of glutaminolysis and are limited by rates of glucose uptake. It is now clear that these metabolic pathways regulate chromatin accessibility and gene expression by providing substrates for epigenetic modifications. Our data suggest that Glutaminase (GLS) and ATP-Citrate Lyase (ACLY), which regulate glutamine-dependent production of α- ketoglutarate (αKG) and conversion of glucose-derived citrate to acetyl-CoA, respectively, regulate epigenetic marks, gene expression and differentiation essential for Tfh function. These observations build on our previous work demonstrating that GLS-inhibition led to reduced αKG and differential alterations to histone methylation and chromatin accessibility in CD4 Th1 and Th17 cells. Importantly, both GLS and ACLY-deficient T cells failed to generate or maintain Tfh in an in vivo model of chronic inflammation. We have also used a model for SLE- accelerated atherosclerosis and shown that T cells in atherosclerosis have increased rates of metabolism. Further, Treg had reduced function and Tfh frequencies were increased. The current proposal will test the hypothesis that Tfh cells require glutamine and citrate metabolism to regulate epigenetic marks and chromatin accessibility to allow gene expression for germinal centers and autoantibody production in SLE and that targeting GLS or ACLY will disrupt epigenetic regulation of Tfh differentiation to treat disease. We will: (1) Establish the role of GLS and ACLY in differentiation, epigenetic regulation and gene expression, and metabolism of Tfh cells, and (2) Test inhibition of GLS or ACLY to decrease autoantibody production in murine SLE and impair circulating Tfh from SLE patients, and (3) determine the effect of manipulating Tfh metabolism on SLE-accelerated atherosclerosis. Our proposal to test the metabolic regulators of epigenetic marks and Tfh differentiation will leverage two targets that are currently under investigation as anti-cancer metabolism therapeutics and will determine if repurposing these drugs may offer new opportunities in SLE.

项目概要 系统性红斑狼疮 (SLE) 的特点是自身抗体产生和免疫复合物 沉积并影响全世界五到七百万人。动脉粥样硬化和心血管疾病 是 SLE 早期死亡的常见原因，但导致这种情况和其他情况的免疫介导机制 疾病后遗症尚不清楚。因此，迫切需要确定有针对性的策略 克服明显的免疫抑制的不良副作用。在本申请中，我们建议 滤泡辅助 T 细胞 (Tfh) 的细胞代谢对于促进自身反应性 B 细胞反应至关重要，可能 提供新的 SLE 治疗靶点。相反，调节性 T 细胞 (Treg) 可能会起到保护作用。我们组有 证明激活的 T 细胞在增殖和增殖时会增加葡萄糖和谷氨酰胺的消耗 分化成特定的功能子集。重要的是，激活后的分化和生物合成 需要独特的代谢程序。迄今为止，人们对 Tfh 代谢的了解仍知之甚少，但我们的数据 表明葡萄糖和谷氨酰胺都是必需的，并且 Tfh 似乎具有很高的谷氨酰胺分解率 并受到葡萄糖摄取率的限制。现在已经清楚这些代谢途径调节染色质 通过提供表观遗传修饰的底物来实现可及性和基因表达。我们的数据表明 谷氨酰胺酶 (GLS) 和 ATP-柠檬酸裂解酶 (ACLY)，调节谷氨酰胺依赖性 α- 的产生 酮戊二酸 (αKG) 和葡萄糖衍生的柠檬酸向乙酰辅酶A的转化分别调节表观遗传 Tfh 功能所必需的标记、基因表达和分化。这些观察建立在我们之前的基础上 证明 GLS 抑制导致 αKG 减少和组蛋白甲基化差异改变的工作 CD4 Th1 和 Th17 细胞中的染色质可及性。重要的是，GLS 和 ACLY 缺陷的 T 细胞都失败了 在慢性炎症体内模型中产生或维持 Tfh。我们还使用了 SLE 模型—— 加速动脉粥样硬化，并表明动脉粥样硬化中的 T 细胞增加了动脉粥样硬化的发生率 代谢。此外，Treg 功能降低，Tfh 频率增加。目前的提案 将检验 Tfh 细胞需要谷氨酰胺和柠檬酸代谢来调节表观遗传标记的假设， 染色质可及性允许 SLE 和 SLE 生发中心的基因表达和自身抗体的产生 靶向 GLS 或 ACLY 将破坏 Tfh 分化的表观遗传调控，从而治疗疾病。我们将：（1） 确定 GLS 和 ACLY 在分化、表观遗传调控和基因表达中的作用，以及 Tfh 细胞的代谢，以及 (2) 测试 GLS 或 ACLY 的抑制以减少小鼠自身抗体的产生 SLE 和损害 SLE 患者的循环 Tfh，以及 (3) 确定操纵 Tfh 代谢的效果 系统性红斑狼疮（SLE）加速动脉粥样硬化。我们建议测试表观遗传标记和 Tfh 的代谢调节因子 分化将利用目前正在研究的两个目标作为抗癌代谢 疗法，并将确定重新利用这些药物是否可以为 SLE 提供新的机会。