Integrated metabolic-transcriptomic network identifies immunometabolic modulations in human macrophages

Cell Reports, vol. 43, pp. 114741

Abstract

Macrophages exhibit diverse phenotypes and respond flexibly to environmental cues through metabolic remodeling. In this study, we present a comprehensive multi-omics dataset integrating intra- and extracellular metabolomes with transcriptomic data to investigate the metabolic impact on human macrophage function. Our analysis establishes a metabolite-gene correlation network that characterizes macrophage activation. We find that the concurrent inhibition of tryptophan catabolism by IDO1 and IL4I1 inhibitors suppresses the macrophage pro-inflammatory response, whereas single inhibition leads to pro-inflammatory activation. We find that a subset of anti-inflammatory macrophages activated by Fc receptor signaling promotes glycolysis, challenging the conventional concept of reduced glycolysis preference in anti-inflammatory macrophages. We demonstrate that cholesterol accumulation suppresses macrophage IFN-γ responses. Our integrated network enables the discovery of immunometabolic features, provides insights into macrophage functional metabolic reprogramming, and offers valuable resources for researchers exploring macrophage immunometabolic characteristics and potential therapeutic targets for immune-related disorders.

Authors 14

1. Hung‐Jen Chen

   Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Department of Medical Biochemistry, Experimental Vascular Biology, Atherosclerosis and Ischemic Syndromes, Amsterdam Cardiovascular Sciences, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam University Medical Center, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands

2. Daniel C. Sévin

   GlaxoSmithKline (Germany)

   Affiliation as printed

   Cellzome, GSK R&D, 69117 Heidelberg, Germany

3. Guillermo R. Griffith

   Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Department of Medical Biochemistry, Experimental Vascular Biology, Atherosclerosis and Ischemic Syndromes, Amsterdam Cardiovascular Sciences, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam University Medical Center, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands

4. Johanna Vappiani

   GlaxoSmithKline (Germany)

   Affiliation as printed

   Cellzome, GSK R&D, 69117 Heidelberg, Germany

5. Lee M. Booty

   GlaxoSmithKline (United Kingdom)

   Affiliation as printed

   Immunology Network, Immunology Research Unit, GSK, SG1 2NY Stevenage, UK

6. Cindy P. A. A. van Roomen

   Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Department of Medical Biochemistry, Experimental Vascular Biology, Atherosclerosis and Ischemic Syndromes, Amsterdam Cardiovascular Sciences, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam University Medical Center, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands

7. Johan Kuiper Aachen Division of BioTherapeutics, Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of BioTherapeutics, Leiden Academic Centre for Drug Research, 2333 CL Leiden, the Netherlands

8. Jeroen den Dunnen

   Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · University of Amsterdam

   Affiliation as printed

   Center for Experimental and Molecular Medicine, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam University Medical Center, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands

9. Wouter J. de Jonge

   Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam

   Affiliation as printed

   Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center, Location AMC, University of Amsterdam, 1105 BK Amsterdam, the Netherlands

10. Rab K. Prinjha

    GlaxoSmithKline (United Kingdom)

    Affiliation as printed

    Immunology Research Unit, GSK Medicines Research Centre, SG1 2NY Stevenage, UK

11. Palwinder K. Mander

    GlaxoSmithKline (United Kingdom)

    Affiliation as printed

    Immunology Research Unit, GSK Medicines Research Centre, SG1 2NY Stevenage, UK

12. Paola Grandi

    GlaxoSmithKline (Germany)

    Affiliation as printed

    Cellzome, GSK R&D, 69117 Heidelberg, Germany

13. Beata S. Wyspianska

    GlaxoSmithKline (United Kingdom)

    Affiliation as printed

    Immunology Research Unit, GSK Medicines Research Centre, SG1 2NY Stevenage, UK

14. Menno P.J. de Winther corresponding

    Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

    Department of Medical Biochemistry, Experimental Vascular Biology, Atherosclerosis and Ischemic Syndromes, Amsterdam Cardiovascular Sciences, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam University Medical Center, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands. Electronic address: m.dewinther@amsterdamumc.nl