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: 10609478
• 负责人: AMY S MAJOR
• 金额: $ 55.69万
• 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/10609478
• 关键词: ATP Citrate (pro-S)-Lyase; Acceleration; 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; Mediating; Medical; Metabolic; Metabolic Pathway; Metabolism; Methylation; Modeling; Modification; Mus; Nephritis; Pathway interactions; Patients; 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 Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Work; alpha ketoglutarate; anti-cancer; autoreactive B cell; chronic graft versus host disease; comorbidity; conditional knockout; cytokine; drug repurposing; effective therapy; epigenetic regulation; glucose uptake; histone methylation; in vivo Model; inhibitor; insight; mortality; mouse model; new therapeutic target; novel; pathogenic autoantibodies; programs; response; side effect; therapeutic target; transgene expression; 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.

项目摘要 全身性红斑狼疮（SLE）的特征是自身抗体产生和免疫剂量 沉积并影响全球五至七百万个人。动脉粥样硬化和心血管疾病 是SLE早期死亡率的常见原因，但免疫介导的机制导致了这一和其他机制 疾病后遗症尚不清楚。因此，需求很高，可以确定有针对性的策略 克服明显免疫抑制的不良副作用。在此应用程序中，我们建议 卵泡辅助T细胞（TFH）的细胞代谢，对于促进自动反应性B细胞反应至关重要，可能 提供新颖的SLE治疗靶标。相反，调节性T细胞（Treg）可以保护。我们的小组有 证明活化的T细胞在增殖时会增加葡萄糖和谷氨酰胺的消耗量 分化为特定的功能子集。重要的是，激活后的分化和生物合成 需要一个独特的代谢程序。迄今为止，TFH代谢仍然知之甚少，但是我们的数据 表明葡萄糖和谷氨酰胺都是必不可少的，TFH似乎具有较高的谷氨酰胺分解率 并受到葡萄糖摄取率的限制。现在很明显，这些代谢途径调节染色质 通过提供表观遗传修饰的底物，可及性和基因表达。我们的数据表明 谷氨酰胺（GLS）和ATP-citrate裂解酶（ACLY），它们调节谷氨酰胺依赖性产生α- 酮谷酸酯（αkg）和葡萄糖衍生的柠檬酸盐转化为乙酰辅酶A，调节表观遗传学 标记，基因表达和TFH功能必不可少的分化。这些观察基于我们以前的 表明GLS抑制作用导致αkg降低和组蛋白甲基化的差异改变的工作 以及CD4 TH1和TH17细胞中的染色质可及性。重要的是，GLS和缺陷型T细胞均失败 在慢性注射的体内模型中产生或维持TFH。我们还使用了一个模型进行sle- 加速了动脉粥样硬化，并表明动脉粥样硬化中的T细胞的发生率有所提高 代谢。此外，Treg的功能降低，TFH频率增加。当前的建议 将检验以下假设：TFH细胞需要谷氨酰胺和柠檬酸盐代谢来调节表观遗传标记和 染色质的可及性允许在SLE和 靶向GLS或ACLY将破坏TFH分化以治疗疾病的表观遗传调节。我们将：（1） 确定GLS和ACLY在分化，表观遗传调节和基因表达中的作用，以及 TFH细胞的代谢，（2）测试GLS或ACLY的抑制作用，以减少鼠的自身抗体产生 SLE和损害SLE患者的循环TFH，（3）确定操纵TFH代谢的影响 在SLE加速性动脉粥样硬化上。我们测试表观遗传标记和TFH代谢调节剂的建议 差异化将利用目前正在研究的两个靶标作为抗癌代谢 治疗剂，并将确定重新利用这些药物是否会在SLE中提供新的机会。