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

Autor: Wilson JL; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria., Nägele T; Department of Ecogenomics and Systems Biology, University of Vienna, Vienna 1090, Austria; Vienna Metabolomics Center (VIME), University of Vienna, Vienna 1090, Austria; Department Biology I, Ludwig Maximilians University Munich, 82152 Planegg-Martinsried, Germany., Linke M; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria., Demel F; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria., Fritsch SD; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria., Mayr HK; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria., Cai Z; Department of Ecogenomics and Systems Biology, University of Vienna, Vienna 1090, Austria., Katholnig K; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria., Sun X; Vienna Metabolomics Center (VIME), University of Vienna, Vienna 1090, Austria., Fragner L; Department of Ecogenomics and Systems Biology, University of Vienna, Vienna 1090, Austria; Vienna Metabolomics Center (VIME), University of Vienna, Vienna 1090, Austria., Miller A; Department of Laboratory Medicine, Medical University of Vienna, Vienna 1090, Austria., Haschemi A; Department of Laboratory Medicine, Medical University of Vienna, Vienna 1090, Austria., Popa A; CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna 1090, Austria., Bergthaler A; CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna 1090, Austria., Hengstschläger M; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria., Weichhart T; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria. Electronic address: thomas.weichhart@meduniwien.ac.at., Weckwerth W; Department of Ecogenomics and Systems Biology, University of Vienna, Vienna 1090, Austria; Vienna Metabolomics Center (VIME), University of Vienna, Vienna 1090, Austria. Electronic address: wolfram.weckwerth@univie.ac.at.
Jazyk: angličtina
Zdroj: Cell reports [Cell Rep] 2020 Feb 04; Vol. 30 (5), pp. 1542-1552.e7.
DOI: 10.1016/j.celrep.2020.01.011
Abstrakt: 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.
Competing Interests: Declaration of Interests The authors declare no competing interest.
(Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE