TY - JOUR
T1 - D-2-Hydroxyglutarate is an anti-inflammatory immunometabolite that accumulates in macrophages after TLR4 activation
AU - de Goede, Kyra E.
AU - Harber, Karl J.
AU - Gorki, Friederike S.
AU - Verberk, Sanne G. S.
AU - Groh, Laszlo A.
AU - Keuning, Eelco D.
AU - Struys, Eduard A.
AU - van Weeghel, Michel
AU - Haschemi, Arvand
AU - de Winther, Menno P. J.
AU - van Dierendonck, Xanthe A. M. H.
AU - van den Bossche, Jan
N1 - Funding Information: We thank dr. Thomas Weichhart and dr. Jayne Louise Wilson for the kind gift of the bone marrow from Phgdh l/fl and Phgdh Cx3cr1-Cre mice. AH was funded by grants of the Austrian Science Fund (SFB F83 and I 4646). JVdB and AH were both funded by a consortia grant from European Research Area Network on Cardiovascular Diseases ( ERA-CVD 2019T108 ). JVdB received a Netherlands Heart Foundation senior fellowship (2017T048) and an Enw-Klein-1 grant from NWO (OCENW.KLEIN.268). Lastly, we acknowledge support from Cancer Center Amsterdam . Publisher Copyright: © 2022 The Authors
PY - 2022/9/1
Y1 - 2022/9/1
N2 - 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.
AB - 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.
KW - 2-HG
KW - 2-hydroxyglutarate
KW - Immunometabolism
KW - Immunometabolite
KW - Innate immunity
KW - Macrophage
UR - http://www.scopus.com/inward/record.url?scp=85129729064&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bbadis.2022.166427
DO - https://doi.org/10.1016/j.bbadis.2022.166427
M3 - Article
C2 - 35526742
SN - 0925-4439
VL - 1868
JO - Biochimica et Biophysica Acta-Molecular Basis of Disease
JF - Biochimica et Biophysica Acta-Molecular Basis of Disease
IS - 9
M1 - 166427
ER -