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

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

Blog Article

Summary: 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 Pushbutton Switches 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.

: Wilson et al.show that Tsc2, a negative regulator of mTORC1 signaling, critically influences the metabolome of macrophages.Inverse data-driven modeling and multiomics data reveal that Phgdh is an mTORC1-dependent metabolic checkpoint of macrophage proliferation and polarization.

Phgdh is required for the expression of key anti-inflammatory molecules and GENTLE FACE CLEANSER M2 proliferation.Keywords: Tsc2, mTOR, serine/glycine pathway, Phgdh, macrophage polarization, macrophage proliferation, metabolomics, metabolic modeling, biochemical Jacobian, cancer, tumor-associated macrophages.