PFKFB2-mediated glycolysis promotes lactate-driven continual efferocytosis by macrophages. Nature metabolism 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. 10.1038/s42255-023-00736-8

FSTL1 promotes liver fibrosis by reprogramming macrophage function through modulating the intracellular function of PKM2. Gut OBJECTIVE:Follistatin-like protein 1 (FSTL1) is widely recognised as a secreted glycoprotein, but its role in modulating macrophage-related inflammation during liver fibrosis has not been documented. Herein, we aimed to characterise the roles of macrophage FSTL1 in the development of liver fibrosis. DESIGN:Expression analysis was conducted with human liver samples obtained from 33 patients with liver fibrosis and 18 individuals without fibrosis serving as controls. Myeloid-specific FSTL1-knockout (FSTL1) mice were constructed to explore the function and mechanism of macrophage FSTL1 in 3 murine models of liver fibrosis induced by carbon tetrachloride injection, bile duct ligation or a methionine-deficient and choline-deficient diet. RESULTS:FSTL1 expression was significantly elevated in macrophages from fibrotic livers of both humans and mice. Myeloid-specific FSTL1 deficiency effectively attenuated the progression of liver fibrosis. In FSTL1 mice, the microenvironment that developed during liver fibrosis showed relatively less inflammation, as demonstrated by attenuated infiltration of monocytes/macrophages and neutrophils and decreased expression of proinflammatory factors. FSTL1 macrophages exhibited suppressed proinflammatory M1 polarisation and nuclear factor kappa B pathway activation in vivo and in vitro. Furthermore, this study showed that, through its FK domain, FSTL1 bound directly to the pyruvate kinase M2 (PKM2). Interestingly, FSTL1 promoted PKM2 phosphorylation and nuclear translocation, reduced PKM2 ubiquitination to enhance PKM2-dependent glycolysis and increased M1 polarisation. Pharmacological activation of PKM2 (DASA-58) partially countered FSTL1-mediated glycolysis and inflammation. CONCLUSION:Macrophage FSTL1 promotes the progression of liver fibrosis by inducing M1 polarisation and inflammation based on the intracellular PKM2 reprogramming function of macrophages. 10.1136/gutjnl-2021-325150