Elucidating the function of antioxidants and ROS on metabolism and inflammation in macrophages and B cells

阐明抗氧化剂和 ROS 对巨噬细胞和 B 细胞代谢和炎症的功能

• 批准号: 413710817
• 负责人: Professor Dr. Karsten Hiller
• 金额: --
• 依托单位: Département Infection et Immunité
• 依托单位国家: 德国
• 项目类别: Research Grants
• 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/413710817?language=en
• 关键词: Elucidating; function; antioxidants; ROS; metabolism

Immune-mediated diseases such as autoimmunity and infections are driven by a deregulated immune system that involves regulatory mechanisms in lymphocytes, but also innate immune cells like macrophages. In multiple sclerosis, an autoimmune disease that affects the central nervous system, immunopathology evident by axon demyelination and neurodegeneration that has severe consequences for the affected patients and is the most frequent cause of non-reversible disabilities in young adults. However, treatment options are limited and either lack effectiveness or have tremendous side effects. An attractive approach might be the interference with metabolic cascades that are implicated in immune cell functionality. Increased levels of reactive oxygen species (ROS) are found in metabolic active cells and in inflammatory diseases. There is evidence that ROS regulate macrophage/microglia pro-inflammatory/anti-inflammatory capacities, which are cellular key drivers of neuroinflammation. Increased ROS in human multiple sclerosis are a typical observed pathological feature. This indicates a disturbed cellular redox state in the disease context and that redox regulation is crucial for the maintenance of normal cellular functions and cellular homeostasis. Our previous work has identified that controlling ROS by the antioxidant glutathione (GSH) is fundamental for the metabolic control of inflammatory T cells and thus has opened up a new perspective to cope with disordered cells in vivo. However, whether this is a unified function of GSH is currently unknown, especially as different immune cell types have different metabolic requirements. Our aim is to discover novel subset-specific pathways and targets that may offer new therapeutic options for inflammatory diseases and/or neurodegenerative disorders such as MS. Therefore we will will interfere with ROS-scavenging by the use of genetic approaches in mice to target redox homeostasis in combination with in vivo disease models that are relevant for human autoimmune diseases and infections. We will focus on inflammatory cells in the innate immune system, mainly macrophages and B cells, which are crucial for adaptive immunity. We will metabolically profile both macrophages and B cells in the specific disease context and will align these changes to the observed phenotypes. We will identify, characterize and manipulate cell specific intrinsic metabolic and signaling pathways that are associated with a protective or detrimental immune response. Thus, identification of cell or disease specific metabolic signatures or pathway specificities will be an important step for the further development of immune-metabolism targeted therapeutic strategies.

免疫介导的疾病，如自身免疫和感染，是由一种失控的免疫系统驱动的，这种免疫系统涉及淋巴细胞的调节机制，但也包括巨噬细胞等先天免疫细胞。多发性硬化症是一种影响中枢神经系统的自身免疫性疾病，免疫病理学表现为轴突脱髓鞘和神经变性，对受影响的患者具有严重后果，是年轻人中最常见的不可逆转残疾的原因。然而，治疗选择有限，要么缺乏有效性，要么有巨大的副作用。一个有吸引力的方法可能是干扰与免疫细胞功能有关的代谢级联反应。在代谢活性细胞和炎症性疾病中发现活性氧簇(ROS)水平升高。有证据表明，ROS调节巨噬细胞/小胶质细胞的促炎/抗炎能力，这是神经炎症的细胞关键驱动因素。在人类多发性硬化症中，ROS升高是一个典型的观察病理特征。这表明在疾病的背景下，细胞氧化还原状态紊乱，氧化还原调节对于维持正常的细胞功能和细胞内稳态至关重要。我们以前的工作已经证实，抗氧化剂谷胱甘肽(GSH)对ROS的控制是炎性T细胞代谢控制的基础，从而为处理体内紊乱的细胞开辟了新的视角。然而，这是否是GSH的统一功能目前尚不清楚，特别是不同的免疫细胞类型有不同的代谢要求。我们的目标是发现新的亚群特异的途径和靶点，可能为炎症性疾病和/或神经退行性疾病(如MS)提供新的治疗选择。因此，我们将通过使用小鼠的遗传方法来干扰ROS的清除，结合与人类自身免疫性疾病和感染相关的体内疾病模型。我们将关注先天免疫系统中的炎性细胞，主要是巨噬细胞和B细胞，它们对适应性免疫至关重要。我们将在特定的疾病背景下对巨噬细胞和B细胞进行代谢分析，并将这些变化与观察到的表型相一致。我们将识别、描述和操纵与保护性或有害免疫反应相关的细胞特有的内在代谢和信号通路。因此，识别细胞或疾病特异性代谢信号或途径特异性将是进一步发展免疫代谢靶向治疗策略的重要一步。