Role of glial-neuronal metabolic communication in autoimmune neuroinflammation

星形胶质细胞和神经元之间的代谢通讯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，使有毒废物失活，确保细胞内外隔室之间持续的水平衡，并在神经炎性环境中发挥调节信号通路的中介作用。目前还缺乏探索神经炎症中神经元命运的星形细胞病变模型。然而，视神经脊髓炎(NMO)是一种神经炎性疾病，代表了一种明显的星形细胞病变。在NMO中，患者严重复发，康复不良，导致累积的神经缺陷，很可能是由于神经元损伤。大多数NMO患者都携带有针对AQP4的血清自身抗体(AQP4-Ab)，AQP4-Ab是一种星形细胞水通道，在中枢神经系统(CNS)中表达于星形胶质细胞。AQP4-Ab进入中枢后，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之外，导致神经元损伤和神经变性仍不清楚。所有细胞类型的参与都强调了神经胶质细胞和神经元在中枢神经系统中的紧密联系，这表明一种细胞类型的细胞死亡对其他细胞类型有影响，特别是在神经炎症的背景下。在这里，我们提出了一项研究项目，以研究神经胶质-神经元代谢通讯及其在神经炎症期间在NMO小鼠模型中的可能变化。结合创新的生物学方法和尖端的方法学工具，我们希望在短期和长期范围内研究AQP4-Ab介导的神经炎症对神经胶质细胞-神经元通讯的影响。因此，我们将解决在自身免疫性神经炎性条件下导致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变导致的神经元损伤，这将具有揭示神经炎症的聚合病理机制的巨大潜力，从而为各种神经炎症性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.