TGFβ macrophage reprogramming: a new dimension of macrophage plasticity

J Leukoc Biol. 2024 Feb 23;115(3):411-414. doi: 10.1093/jleuko/qiae001.


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.

Keywords: TGFβ; immunometabolism; inflammation; macrophage; sepsis.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / metabolism
  • Blood Coagulation Factors / metabolism
  • COVID-19* / pathology
  • Humans
  • Macrophage Activation
  • Macrophages / metabolism
  • Mice
  • Phosphofructokinases / metabolism
  • Sepsis* / metabolism
  • Transforming Growth Factor beta


  • Transforming Growth Factor beta
  • Anti-Inflammatory Agents
  • Phosphofructokinases
  • Blood Coagulation Factors