New insights on metabolic reprogramming in macrophage plasticity

Macrophages are the first line of defense in the innate immune system. Macrophages have two subtypes: classically activated macrophages (M1) and alternatively activated macrophages (M2), with different phenotypes and functions. They play a critical role in defending against pathogens and maintaining internal homeostasis. Macrophages have great plasticity in their biological characteristics. Although the regulation of macrophage plasticity has not been fully elucidated, accumulated evidence supports that microenvironmental differences are the root cause for macrophage differentiation into different subtypes. These differences alter macrophage plasticity by modulating key metabolites, activating downstream gene transcription, and influencing phagocytosis, cytokine secretion, and immune regulation. Herein, we systematically summarize metabolic reprogramming, including glucose, lipid, amino acid, ion, vitamin, nucleotide, and butyrate metabolism, as key regulators affecting macrophage polarization, providing new insights for developing targeted drugs that modulate macrophage plasticity.