Microglial Phenotypic Polarization via CSF1R-Mediated Metabolic Reprogramming

The molecular foundation of microglial phenotypic polarization during perinatal immune activation centers on colony-stimulating factor-1 receptor (CSF1R) and its role in orchestrating metabolic reprogramming rather than cellular replacement. Under homeostatic conditions, yolk sac-derived microglia maintain a surveillance phenotype supported by oxidative phosphorylation and fatty acid oxidation. However, perinatal immune activation triggers CSF1R-mediated signaling cascades that fundamentally rewire microglial metabolism toward glycolysis and pentose phosphate pathway activation. Pattern recognition receptor activation by PAMPs or DAMPs leads to CSF1R dimerization and autophosphorylation, activating downstream PI3K/AKT and mTORC1 pathways. This metabolic shift is characterized by upregulation of glycolytic enzymes including hexokinase-2 (HK2), phosphofructokinase-1 (PFK1), and pyruvate kinase M2 (PKM2), while simultaneously downregulating oxidative metabolism through inhibition of carnitine palmitoyltransferase-1 (CPT1) and pyruvate dehydrogenase complex. The metabolic reprogramming enables enhanced phagocytic capacity, increased reactive oxygen species production, and sustained pro-inflammatory cytokine synthesis. Crucially, CSF1R signaling also activates hypoxia-inducible factor-1α (HIF-1α) even under normoxic conditions, stabilizing the glycolytic phenotype and promoting expression of inflammatory mediators. This metabolic polarization creates distinct microglial subpopulations with altered functional capacities, including enhanced antigen presentation through upregulated MHC-II expression and modified synaptic pruning activities that persist into postnatal development, potentially underlying neurodevelopmental disorders.