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