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

This hypothesis proposes that perinatal immune activation triggers CCR2-dependent recruitment of bone marrow-derived monocytes that replace resident microglia and undergo sustained metabolic reprogramming through the mTOR-HIF1α axis. During critical neurodevelopmental windows, pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) activate microglial TLR4/TLR2 receptors, leading to NF-κB-mediated upregulation of CCL2 and blood-brain barrier disruption through MMP-2/MMP-9 activation. The resulting CCL2 gradient recruits CCR2+ Ly6C+ inflammatory monocytes from bone marrow, which transmigrate across compromised neurovascular barriers and differentiate into brain-resident microglia-like cells. Critically, these monocyte-derived microglia retain distinct metabolic programming compared to yolk sac-derived resident microglia. Upon CNS colonization, recruited monocytes maintain elevated mTORC1 activity through persistent PI3K/AKT signaling, leading to constitutive phosphorylation of S6K1 and 4E-BP1. Activated mTORC1 stabilizes HIF1α protein by preventing VHL-mediated degradation and promoting HIF1α mRNA translation. Nuclear HIF1α/HIF1β heterodimers bind hypoxia response elements in glycolytic enzyme promoters, upregulating GLUT1, HK2, PFKL, and ALDOA expression. This metabolic shift toward aerobic glycolysis (Warburg effect) persists long after initial immune resolution, creating a population of hypermetabolic, pro-inflammatory microglia that disrupts synaptic pruning, promotes neuroinflammation, and impairs neurodevelopmental processes underlying autism spectrum disorders. The CCR2-mTOR-HIF1α axis thus represents a mechanistic link between early-life immune activation and sustained microglial dysfunction in neurodevelopmental disorders.