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

Mechanistic or mammalian target of rapamycin complex 1 (mTORC1) is an important regulator of effector functions, proliferation and cellular metabolism in macrophages. However, the biochemical processes that are controlled by mTORC1 remain ill-defined. Here, we demonstrate that multiomics in conjunction with a data-driven inverse modelling approach, termed COVRECON, identifies causal biochemical nodes that influence 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 LPS-stimulated macrophages repressed Phgdh activity, IL-4-stimulated macrophages increased the activity of the enzyme, which was required for the expression of key anti-inflammatory molecules and macrophage proliferation. Thus, we identify Phgdh as a metabolic signature of M2 macrophages, accentuating the critical role of metabolic checkpoints in immunometabolism.