Inverse Data-Driven Modeling and Multiomics Analysis Reveals Phgdh as a Metabolic Checkpoint of Macrophage Polarization and Proliferation

Cell Rep. 2020 Feb 4;30(5):1542-1552.e7. doi: 10.1016/j.celrep.2020.01.011.


Mechanistic or mammalian target of rapamycin complex 1 (mTORC1) is an important regulator of effector functions, proliferation, and cellular metabolism in macrophages. The biochemical processes that are controlled by mTORC1 are still being defined. Here, we demonstrate that integrative multiomics in conjunction with a data-driven inverse modeling approach, termed COVRECON, identifies a biochemical node that influences overall metabolic profiles and reactions of mTORC1-dependent macrophage metabolism. Using a combined approach of metabolomics, proteomics, mRNA expression analysis, and enzymatic activity measurements, we demonstrate that Tsc2, a negative regulator of mTORC1 signaling, critically influences the cellular activity of macrophages by regulating the enzyme phosphoglycerate dehydrogenase (Phgdh) in an mTORC1-dependent manner. More generally, while lipopolysaccharide (LPS)-stimulated macrophages repress Phgdh activity, IL-4-stimulated macrophages increase the activity of the enzyme required for the expression of key anti-inflammatory molecules and macrophage proliferation. Thus, we identify Phgdh as a metabolic checkpoint of M2 macrophages.

Keywords: Phgdh; Tsc2; biochemical Jacobian; cancer; mTOR; macrophage polarization; macrophage proliferation; metabolic modeling; metabolomics; serine/glycine pathway; tumor-associated macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Polarity* / drug effects
  • Cell Proliferation / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Genomics*
  • Glutamic Acid / metabolism
  • Glycine / metabolism
  • Interleukin-4 / pharmacology
  • Ketoglutaric Acids / metabolism
  • Kinetics
  • Macrophages / cytology*
  • Macrophages / drug effects
  • Macrophages / enzymology
  • Macrophages / metabolism*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice, Inbred C57BL
  • Models, Biological*
  • Phosphoglycerate Dehydrogenase / genetics
  • Phosphoglycerate Dehydrogenase / metabolism*
  • Principal Component Analysis
  • Serine / metabolism
  • Tuberous Sclerosis Complex 2 Protein / metabolism


  • Ketoglutaric Acids
  • Tuberous Sclerosis Complex 2 Protein
  • Interleukin-4
  • Glutamic Acid
  • Serine
  • Phosphoglycerate Dehydrogenase
  • Mechanistic Target of Rapamycin Complex 1
  • Glycine