The influence of mitochondrial lymphocyte metabolism on the onset of RA

线粒体淋巴细胞代谢对RA发病的影响

• 批准号: 418296086
• 负责人: Professor Dr. Dirk Mielenz
• 金额: --
• 依托单位: Medizinische Klinik 3 - Rheumatologie und Immunologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418296086?language=en
• 关键词: influence; mitochondrial; lymphocyte; metabolism; onset

Mechanisms driving the progression of rheumatoid arthritis (RA) from early pre-symptomatic autoimmune stages to full-blown inflammatory disease remain enigmatic. During the previous funding period, we have shown that small endogenous metabolites such as acetate as well as energetic reprogramming of cells critically affect the action of T cells and the development of RA. Although energetic reprogramming and metabolic dysfunction of T cells and B cells likely impact both on the break of tolerance and the onset of inflammation, underlying mechanisms are incompletely defined, especially due to the absence of appropriate technologies. In the proposed project, we therefore aim to dissect the checkpoints controlling metabolic reprogramming of T- and B cells in the pre-clinical phase of RA using new methods allowing to study their specific contribution to the onset of RA. We will therefore use three novel technologies based on flow cytometry methods (SCENITH, Met-Flow) or microscopy (NADH-FLIM) that allow high throughput assessment of metabolism in single cells. A particular focus will be on the changes in the metabolism of B cells and T cells in the earliest stages of murine experimental arthritis and human rheumatoid arthritis. In this setting, metabolic analyses will not be confined to T- and B cell subsets only but will also specifically address the metabolism of activated autoreactive T- and B cells in experimental arthritis and human RA. Following up on these experiments, we will determine whether and how mitochondrial dysfunction controls metabolic T- and B-cell function during the transition from the pre-symptomatic to the inflammatory phase of arthritis. To achieve this aim, we will establish a surrogate premature lymphocyte aging phenotype by specific induction of mitochondrial dysfunction in T- and B cells through expression of a dominant negative mutant of the mitochondrial helicase TWINKLE. In summary, this project will provide a translational approach that defines the nature of early changes of the metabolism of activated adaptive immune cells in arthritis, in search for new possibilities for early preventive interference for disease progression.

驱动类风湿性关节炎（RA）从早期症状前自身免疫阶段发展到全面炎症性疾病的机制仍然是谜。在之前的资助期间，我们已经证明了小的内源性代谢物，如醋酸盐以及细胞的能量重编程对T细胞的作用和RA的发展有重要影响。尽管T细胞和B细胞的能量重编程和代谢功能障碍可能影响耐受性的破坏和炎症的发生，但潜在的机制尚不完全明确，特别是由于缺乏适当的技术。因此，在拟议的项目中，我们的目标是在RA的临床前阶段剖析控制T细胞和B细胞代谢重编程的检查点，使用新的方法来研究它们对RA发病的特定贡献。因此，我们将使用基于流式细胞术方法（SCENITH, Met-Flow）或显微镜（NADH-FLIM）的三种新技术，这些技术允许对单细胞的代谢进行高通量评估。特别关注的是B细胞和T细胞代谢在小鼠实验性关节炎和人类类风湿关节炎早期阶段的变化。在这种情况下，代谢分析将不仅仅局限于T细胞和B细胞亚群，还将专门研究实验性关节炎和人类RA中活化的自身反应性T细胞和B细胞的代谢。在这些实验的后续研究中，我们将确定线粒体功能障碍是否以及如何控制关节炎从症状前期到炎症期的代谢T细胞和b细胞功能。为了实现这一目标，我们将通过表达线粒体解旋酶TWINKLE的显性负突变体，在T细胞和B细胞中特异性诱导线粒体功能障碍，建立替代的淋巴细胞过早衰老表型。总之，该项目将提供一种转化方法，定义关节炎中活化的适应性免疫细胞代谢早期变化的本质，为疾病进展的早期预防性干预寻找新的可能性。