TGFβ macrophage reprogramming: a new dimension of macrophage plasticity

Abstract The August 2023 article in Science Signaling, “TGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis,” challenges the traditional M1/M2 macrophage classification by investigating the impact of transforming growth factor β on macrophage metabolism and function. Despite its conventional anti-inflammatory role, transforming growth factor β–treated macrophages exhibit a distinct phenotype marked by heightened glycolysis, suppressed proinflammatory cytokines, and increased coagulation factor expression. The study identifies phosphofructokinase, liver type as a crucial glycolytic enzyme regulated by transforming growth factor β via the mTOR–c-MYC pathway. Epigenetic changes induced by transforming growth factor β, such as increased Smad3 activation and reduced proinflammatory transcription factor motif enrichment, contribute to the anti-inflammatory profile. The research extends its implications to sepsis, revealing the role of transforming growth factor β in exacerbating coagulation and reducing survival in mouse models. This effect involves upregulation of coagulation factor F13A1, dependent on phosphofructokinase, liver type activity and glycolysis in macrophages. Connections to COVID-19 pathology are drawn, as transforming growth factor β–treated macrophages and SARS-CoV-2 E protein-exposed cells display similar metabolic profiles. Bioinformatic analysis of COVID-19 patient data suggests correlations between myeloid expression of TGFβR1, PFKL, and F13A1 with disease severity. The study challenges the M1/M2 classification, emphasizing the complexity of macrophage responses influenced by transforming growth factor β, proposing transforming growth factor β as a potential therapeutic target for conditions like sepsis and COVID-19 where dysregulated coagulation is significant. Overall, the research provides valuable insights into transforming growth factor β–mediated immunometabolic regulation, paving the way for future investigations and potential therapeutic interventions.