Role of glial-neuronal metabolic communication in autoimmune neuroinflammation

星形胶质细胞与神经元之间的代谢交流对神经元的维持和存活至关重要。星形胶质细胞为神经元提供能量代谢物，灭活有毒废物，确保细胞外和细胞内的恒定水平衡，并在神经炎症环境中发挥调节信号通路的介质。目前尚缺乏星形细胞病模型来探索神经炎症中神经元的命运。然而，视神经脊髓炎（NMO）是一种明确的星形细胞病变的神经炎性疾病。在NMO中，患者复发严重，恢复不良，导致神经功能缺损的累积，这可能是由于神经元损伤。大多数NMO患者血清中携带一种抗水通道蛋白-4 （AQP4-Ab）的自身抗体，这是一种在中枢神经系统（CNS）中星形胶质细胞中表达的星形细胞水通道。AQP4-Ab进入中枢神经系统后，通过补体损伤星形胶质细胞，导致星形胶质细胞坏死。最后，NMO病变表现为脱髓鞘和轴突损伤。然而，NMO的病理如何扩散到最初的星形细胞病变导致神经元损伤和神经退行性变尚不清楚。所有细胞类型的参与强调了神经胶质细胞和神经元在中枢神经系统中的紧密沟通，表明一种细胞类型的细胞死亡会对其他细胞产生影响，特别是在神经炎症的背景下。在这里，我们提出了一个研究项目，以研究神经炎症小鼠模型中神经胶质-神经元代谢通讯及其可能的改变。结合创新的生物学方法和尖端的方法工具，我们希望在短期和长期范围内研究AQP4-Ab介导的神经炎症对胶质-神经元通讯的影响。因此，我们将探讨自身免疫性神经炎症条件下神经变性的代谢机制的关键问题。因此，该项目将深入了解星形细胞病驱动的神经元损伤，这将有很大的潜力揭示神经炎症的典型病理机制，从而为各种神经炎症疾病的新治疗策略提供基础。

The metabolic communication between astrocytes and neurons is crucial for neuronal maintenance and survival. Astrocytes supply neurons with energy metabolites, inactivate toxic waste, ensure a constant water equilibrium between extra- and intracellular compartments and exert mediators that modulate signaling pathways in neuroinflammatory environment. Models of astrocytopathy for exploration of neuronal fate in neuroinflammation are lacking. However, Neuromyelitis optica (NMO) is one type of neuroinflammatory disorders that represents a clear astrocytopathy disease. In NMO, patients suffer from severe relapses with poor recovery, resulting in accumulating neurological deficits that are likely due to neuronal damage. Most NMO patients carry a serum autoantibody against Aquaporin-4 (AQP4-Ab), an astrocytic water channel that in the central nervous system (CNS) is expressed in astrocytes. After entry to the CNS, AQP4-Ab damage astrocytes via complement, resulting in astrocyte necrosis. Finally, NMO lesions show demyelination and axon injury. However, how the pathology in NMO spreads beyond initial astrocytopathy leading to neuronal injury and neurodegeneration remains unclear. The involvement of all cell types emphasizes how tightly glia and neurons communicate in the CNS, suggesting that cell death of one cell type has an impact on the others, particularly in the context of neuroinflammation. Here, we propose a research project to investigate glial-neuronal metabolic communication and its possible alterations during neuroinflammation in a mouse model of NMO. Combining innovative biological approaches with cutting-edge methodological tools, we want to investigate the impact of AQP4-Ab mediated neuroinflammation on glial-neuronal communication both on a short- and long-term scale. Hereby, we will address key questions about the metabolic mechanisms underlying neurodegeneration under autoimmune neuroinflammatory conditions. Thus, this project will gain insights into astrocytopathy driven neuronal damage that have a great potential to reveal paradigmatic pathomechanisms in neuroinflammation and thus provide a basis for new therapeutic strategies for various neuroinflammatory diseases.