Macrophage polarization and immunometabolic reprogramming in sepsis: mechanisms and therapeutic implications

Dysregulated host immune responses to infection cause sepsis, a potentially fatal organ failure condition. The primary characteristic is an imbalance between pro-inflammatory and anti-inflammatory responses, which ultimately results in multiple organ dysfunction syndrome (MODS). Its high prevalence and death are caused by intricate pathophysiological pathways. Macrophages have a high degree of phenotypic plasticity and are key regulators of the inflammatory response in sepsis. The development of the disease depends on the balance between M1 and M2 polarization. In order to sustain proinflammatory activity, M1 macrophages increase glycolytic metabolism and secrete proinflammatory molecules including TNF-α and IL-1β to eradicate infections. However, excessive stimulation of these macrophages might result in tissue injury. In order to mediate immune suppression and tissue healing, M2 macrophages secrete anti-inflammatory molecules such as TGF-β and IL-10 through oxidative phosphorylation and fatty acid oxidation. Immune dysregulation in sepsis is mostly caused by an imbalance in this polarization. Significant metabolic reprogramming occurs in conjunction with macrophage polarization; immunological function is reshaped by dysregulated glycolysis, mitochondrial function, lactate metabolism, itaconic acid metabolism, lipid metabolism, and amino acid metabolism. Macrophage function is further regulated concurrently by epigenetic changes (histone alterations, DNA methylation) and intercellular contacts (with T cells, neutrophils, mesenchymal stem cells, etc.). Clinical diagnosis relies on biomarkers such as procalcitonin, lactate, and presepsin, while therapeutic approaches include antibiotics, anti-inflammatory drugs, and vasoactive agents, yet numerous challenges persist. This review systematically elucidates macrophage phenotypic functions, metabolic reprogramming, epigenetic regulation, and intercellular interaction mechanisms in sepsis. It summarizes current clinical diagnostic and therapeutic approaches, providing theoretical foundations and potential targets for precision interventions in sepsis management.