2. Academic Validation
  3. d-2-Hydroxyglutarate is an anti-inflammatory immunometabolite that accumulates in macrophages after TLR4 activation

d-2-Hydroxyglutarate is an anti-inflammatory immunometabolite that accumulates in macrophages after TLR4 activation

  • Biochim Biophys Acta Mol Basis Dis. 2022 Sep 1;1868(9):166427. doi: 10.1016/j.bbadis.2022.166427.
Kyra E de Goede 1,  Karl J Harber 2,  Friederike S Gorki 3,  Sanne G S Verberk 1,  Laszlo A Groh 1,  Eelco D Keuning 1,  Eduard A Struys 4,  Michel van Weeghel 5,  Arvand Haschemi 6,  Menno P J de Winther 7,  Xanthe A M H van Dierendonck 1,  Jan Van den Bossche 8
Affiliations

Affiliations

  • 1 Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Institute for Infection and Immunity, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • 2 Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Institute for Infection and Immunity, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, 1105, AZ, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Cardiovascular Sciences, 1105, AZ, Amsterdam, the Netherlands.
  • 3 Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Institute for Infection and Immunity, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn 53127, Germany.
  • 4 Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Amsterdam, the Netherlands.
  • 5 Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Cardiovascular Sciences, 1105, AZ, Amsterdam, the Netherlands.
  • 6 Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
  • 7 Amsterdam UMC, University of Amsterdam, Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, 1105, AZ, Amsterdam, the Netherlands.
  • 8 Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Institute for Infection and Immunity, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. Electronic address: [email protected].
PMID: 35526742 DOI: 10.1016/j.bbadis.2022.166427
Abstract

Macrophages undergo extensive metabolic rewiring upon activation which assist the cell in roles beyond energy production and synthesis of anabolic building blocks. So-called immunometabolites that accumulate upon immune activation can serve as co-factors for enzymes and can act as signaling molecules to modulate cellular processes. As such, the Krebs-cycle-associated metabolites succinate, itaconate and alpha-ketoglutarate (αKG) have emerged as key regulators of macrophage function. Here, we describe that 2-hydroxyglutarate (2HG), which is structurally similar to αKG and exists as two enantiomers, accumulates during later stages of LPS-induced inflammatory responses in mouse and human macrophages. D-2HG was the most abundant enantiomer in macrophages and its LPS-induced accumulation followed the induction of Hydroxyacid-Oxoacid Transhydrogenase (HOT). HOT interconverts αKG and gamma-hydroxybutyrate into D-2HG and succinic semialdehyde, and we here identified this Enzyme as being immune-responsive and regulated during the course of macrophage activation. The buildup of D-2HG may be further explained by reduced expression of D-2HG Dehydrogenase (D2HGDH), which converts D-2HG back into αKG, and showed inverse kinetics with HOT and D-2HG levels. We tested the immunomodulatory effects of D-2HG during LPS-induced inflammatory responses by transcriptomic analyses and functional profiling of D-2HG-pre-treated macrophages in vitro and mice in vivo. Together, these data suggest a role for D-2HG in the negative feedback regulation of inflammatory signaling during late-stage LPS-responses in vitro and as a regulator of local and systemic inflammatory responses in vivo. Finally, we show that D-2HG likely exerts distinct anti-inflammatory effects, which are in part independent of αKG-dependent dioxygenase inhibition. Together, this study reveals an immunometabolic circuit resulting in the accumulation of the immunomodulatory metabolite D-2HG that can inhibit inflammatory macrophage responses.

Keywords

2-HG; 2-hydroxyglutarate; Immunometabolism; Immunometabolite; Innate immunity; Macrophage.

Figures
Products