CCR2-Mediated Microglial Replacement Drives mTOR-HIF1α Metabolic Reprogramming…

This hypothesis proposes that perinatal immune activation triggers a two-phase pathogenic cascade where CCR2-mediated recruitment of bone marrow-derived monocytes leads to metabolic reprogramming through the mTOR-HIF1α axis. During the initial recruitment phase, TLR activation upregulates CCL2 production and compromises blood-brain barrier integrity through MMP-2/MMP-9 activation, enabling CCR2+ Ly6C+ inflammatory monocytes to infiltrate the CNS and differentiate into metabolically distinct microglia-like cells. These infiltrating monocyte-derived cells exhibit fundamentally different metabolic programming compared to resident yolk sac-derived microglia. In the subsequent metabolic reprogramming phase, sustained inflammatory signaling in these newly recruited cells activates mTORC1 through PI3K/AKT pathways, leading to HIF1α stabilization independent of oxygen availability. The mTORC1-mediated phosphorylation prevents HIF1α degradation by the VHL ubiquitin ligase complex, causing nuclear translocation and binding to hypoxia response elements. This drives expression of glycolytic enzymes including GLUT1, HK2, and PFKL, establishing a persistent pro-inflammatory metabolic state. The metabolic reprogramming becomes self-perpetuating as enhanced glycolysis generates lactate and other metabolites that further stabilize HIF1α and maintain mTORC1 activation. This creates a pathological population of metabolically trained monocyte-derived microglia that persist throughout development, fundamentally altering the neuroinflammatory landscape and predisposing to neurodevelopmental disorders through sustained metabolic dysregulation rather than transient inflammatory responses.