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.

项目总结 系统性红斑狼疮(SLE)以自身抗体产生和免疫复合体为特征 并影响到全世界500万至700万人。动脉粥样硬化与心血管疾病 是SLE早期死亡的常见原因，但免疫介导的机制导致了这一点和其他 疾病的后遗症还没有得到很好的了解。因此，确定有针对性的战略的需求很高 克服公开免疫抑制的不良副作用。在此应用程序中，我们建议 滤泡辅助T细胞(TFH)的细胞代谢，在促进自身反应性B细胞反应中起关键作用，可能 提供新的系统性红斑狼疮治疗靶点。相反，调节性T细胞(Treg)可以起到保护作用。我们的团队已经 证明了激活的T细胞在增殖时增加了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 需要一个独特的新陈代谢程序。到目前为止，TFH的代谢仍然知之甚少，但我们的数据 提示葡萄糖和谷氨酰胺都是必需的，而转铁蛋白似乎有很高的谷氨酰胺分解速度 并受到葡萄糖摄取率的限制。现在已经很清楚，这些代谢途径调节染色质。 通过为表观遗传修饰提供底物来实现可获得性和基因表达。我们的数据表明 谷氨酰胺酶和三磷酸腺苷-柠檬酸裂解酶调节谷氨酰胺依赖的α- 酮戊二酸(αKG)和葡萄糖衍生的柠檬酸到乙酰辅酶A的转化分别调节表观遗传学 Tfh功能所必需的标记、基因表达和分化。这些观察结果建立在我们之前的基础上 研究表明，Gls抑制导致αKG减少和组蛋白甲基化的差异改变 以及CD4Th1和Th17细胞中染色质的可及性。重要的是，GLS和ACLY缺陷的T细胞都失败了 在慢性炎症的体内模型中产生或维持转铁蛋白。我们还对SLE使用了一个模型- 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 新陈代谢。此外，Treg的功能降低，Tfh频率增加。目前的提案 将测试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，并 染色质可及性允许生发中心的基因表达和SLE和自身抗体的产生 靶向GLS或ACLY将扰乱Tfh分化治疗疾病的表观遗传调控。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，以及(2)GLS或ACLY抑制小鼠自身抗体产生的实验 SLE和损害SLE患者的循环Tfh，以及(3)确定干预Tfh代谢的效果 系统性红斑狼疮加速的动脉粥样硬化。我们建议测试表观遗传标记和转铁蛋白的代谢调节 分化将利用两个目前正在研究的抗癌新陈代谢靶点 并将确定改变这些药物的用途是否会为SLE提供新的机会。