Wishart Claire L, Spiteri Alanna G, Tan Jian, Macia Laurence, King Nicholas J C
Infection, Immunity, Inflammation Research Theme, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, NSW 2006, Australia.
Charles Perkins Centre, The University of Sydney, Sydney, NSW, NSW 2006, Australia.
Adv Sci (Weinh). 2025 Sep;12(33):e05844. doi: 10.1002/advs.202505844. Epub 2025 Jul 14.
Infiltrating monocytes can exert both protective and pathogenic effects during central nervous system (CNS) inflammation. However, the metabolic mechanisms that govern these divergent roles remain poorly understood, limiting opportunities for therapeutic intervention. Single-cell RNA-sequencing and metabolic flow analysis of brain and bone marrow (BM) is used to map the metabolic signatures of monocyte-derived cells (MCs) during lethal West Nile virus encephalitis. Trajectory analysis shows that BM monocytes progress through three metabolic profiles before migrating to the brain and differentiating into a pro-inflammatory HIF1-α⁺ MC population. This population further diverges into an inflammatory, iNOS⁺ MC subset with high glycolysis and amino acid metabolism, and a protective, glycolytically quiescent, antigen-presenting MC subset. Daily in vivo glycolysis inhibition reduces neuroinflammation and disease signs without increasing viral load. This effect does not reflect a broad reduction in myelopoiesis but rather a selective decrease in iNOS⁺ MC migration, revealing distinct glycolytic dependencies among MC subsets. HIF1-α activity remains independent of glycolysis, enabling functional differentiation of antigen-presenting MCs without impairing antiviral responses by cervical lymph node T cells. This study identifies key metabolic drivers of MC function in viral CNS disease, in which selective metabolic reprogramming reduces severe neuroinflammation, demonstrating a promising therapeutic strategy.
浸润的单核细胞在中枢神经系统（CNS）炎症期间可发挥保护和致病作用。然而，调控这些不同作用的代谢机制仍知之甚少，限制了治疗干预的机会。利用脑和骨髓（BM）的单细胞RNA测序和代谢流分析来描绘致死性西尼罗河病毒脑炎期间单核细胞衍生细胞（MCs）的代谢特征。轨迹分析表明，BM单核细胞在迁移至脑并分化为促炎性HIF1-α⁺ MC群体之前会经历三种代谢状态。该群体进一步分化为具有高糖酵解和氨基酸代谢的炎性iNOS⁺ MC亚群，以及具有保护性、糖酵解静止的抗原呈递MC亚群。每日体内糖酵解抑制可减轻神经炎症和疾病症状，而不增加病毒载量。这种效应并非反映骨髓生成的广泛减少，而是iNOS⁺ MC迁移的选择性降低，揭示了MC亚群之间不同的糖酵解依赖性。HIF1-α活性仍独立于糖酵解，可实现抗原呈递MC的功能分化，而不损害颈淋巴结T细胞的抗病毒反应。本研究确定了病毒CNS疾病中MC功能的关键代谢驱动因素，其中选择性代谢重编程可减轻严重神经炎症，证明了一种有前景的治疗策略。
