PFKFB2-mediated glycolysis promotes lactate-driven continual efferocytosis by macrophages

Schilperoort et al. explore the mechanisms underlying dynamic changes in macrophage metabolism that support efferocytosis. They show that transient glycolysis and subsequent lactate production are necessary to execute continual efferocytosis, as opposed to prolonged glycolysis observed in pro-inflammatory macrophages. Resolving-type macrophages prevent chronic inflammation by clearing apoptotic cells through efferocytosis. These macrophages are thought to rely mainly on oxidative phosphorylation, but emerging evidence suggests a possible link between efferocytosis and glycolysis. To gain further insight into this issue, we investigated molecular-cellular mechanisms involved in efferocytosis-induced macrophage glycolysis and its consequences. We found that efferocytosis promotes a transient increase in macrophage glycolysis that is dependent on rapid activation of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), which distinguishes this process from glycolysis in pro-inflammatory macrophages. Mice transplanted with activation-defective PFKFB2 bone marrow and then subjected to dexamethasone-induced thymocyte apoptosis exhibit impaired thymic efferocytosis, increased thymic necrosis, and lower expression of the efferocytosis receptors MerTK and LRP1 on thymic macrophages compared with wild-type control mice. In vitro mechanistic studies revealed that glycolysis stimulated by the uptake of a first apoptotic cell promotes continual efferocytosis through lactate-mediated upregulation of MerTK and LRP1. Thus, efferocytosis-induced macrophage glycolysis represents a unique metabolic process that sustains continual efferocytosis in a lactate-dependent manner. The differentiation of this process from inflammatory macrophage glycolysis raises the possibility that it could be therapeutically enhanced to promote efferocytosis and resolution in chronic inflammatory diseases.

Automated summary

The study reveals that transient increase in glycolysis and lactate production are essential for continual efferocytosis, contrasting with prolonged glycolysis in pro-inflammatory macrophages. This unique metabolic process depends on the activation of PFKFB2 enzyme and promotes continual efferocytosis through lactate-mediated upregulation of MerTK and LRP1. Inhibiting this process may provide a potential therapeutic pathway in chronic inflammatory diseases.