Metabolic Programming Drives Protective and Inflammatory Monocyte Fates in Viral Encephalitis

Abstract 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.