TGFβ macrophage reprogramming: A new dimension of macrophage plasticity.

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 (TGFβ) on macrophage metabolism and function. Despite its conventional anti-inflammatory role, TGFβ-treated macrophages exhibit a distinct phenotype marked by heightened glycolysis, suppressed proinflammatory cytokines, and increased coagulation factor expression. The study identifies phosphofructokinase-liver type (PFKL) as a crucial glycolytic enzyme regulated by TGFβ via the mTOR-c-MYC pathway. Epigenetic changes induced by TGFβ, 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 TGFβ's role in exacerbating coagulation and reducing survival in mouse models. This effect involves upregulation of coagulation factor F13A1, dependent on PFKL activity and glycolysis in macrophages. Connections to COVID-19 pathology are drawn, as TGFβ-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 M1/M2 classification, emphasizing the complexity of macrophage responses influenced by TGFβ, proposing TGFβ as a potential therapeutic target for conditions like sepsis and COVID-19 where dysregulated coagulation is significant. Overall, the research provides valuable insights into TGFβ-mediated immunometabolic regulation, paving the way for future investigations and potential therapeutic interventions.