Succinate is an Inflammatory Signal That Induces IL-1β Through HIF-1α

Overview

Journal Nature

Specialty Science

Date 2013 Mar 29

PMID 23535595

Citations 1825

Authors

G M Tannahill

A M Curtis

J Adamik

E M Palsson-McDermott

A F McGettrick

G Goel

C Frezza

N J Bernard

B Kelly

N H Foley

L Zheng

A Gardet

Z Tong

S S Jany

S C Corr

M Haneklaus

B E Caffrey

K Pierce

S Walmsley

F C Beasley

E Cummins

V Nizet

M Whyte

C T Taylor

H Lin

S L Masters

E Gottlieb

V P Kelly

C Clish

P E Auron

R J Xavier

L A J ONeill

Affiliations

Soon will be listed here.

Abstract

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.

Citing Articles

Gut commensals-derived succinate impels colonic inflammation in ulcerative colitis.

Dalal R, Sadhu S, Batra A, Goswami S, Dandotiya J, K V V NPJ Biofilms Microbiomes. 2025; 11(1):44.

PMID: 40082467 PMC: 11906746. DOI: 10.1038/s41522-025-00672-3.

Lipin-1 restrains macrophage lipid synthesis to promote inflammation resolution.

Bamgbose T, Schilke R, Igiehon O, Nkadi E, Binwal M, Custis D J Immunol. 2025; 214(1):85-103.

PMID: 40073265 PMC: 11844145. DOI: 10.1093/jimmun/vkae010.

Dexamethasone has profound influence on the energy metabolism of porcine blood leukocytes and prevents the LPS-induced glycolytic switch.

Ma W, Brenmoehl J, Trakooljul N, Wimmers K, Murani E Front Immunol. 2025; 16:1514061.

PMID: 40070837 PMC: 11893826. DOI: 10.3389/fimmu.2025.1514061.

The role of mA modification during macrophage metabolic reprogramming in human diseases and animal models.

Wang H, Xu P, Yin K, Wang S Front Immunol. 2025; 16:1521196.

PMID: 40066451 PMC: 11891544. DOI: 10.3389/fimmu.2025.1521196.

Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets.

Guan F, Wang R, Yi Z, Luo P, Liu W, Xie Y Signal Transduct Target Ther. 2025; 10(1):93.

PMID: 40055311 PMC: 11889221. DOI: 10.1038/s41392-025-02124-y.

References

Zhang W, Petrovic J, Callaghan D, Jones A, Cui H, Howlett C . Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1beta (IL-1beta) in astrocyte cultures. J Neuroimmunol. 2006; 174(1-2):63-73. DOI: 10.1016/j.jneuroim.2006.01.014. View

Pan H, Wu X . Hypoxia attenuates inflammatory mediators production induced by Acanthamoeba via Toll-like receptor 4 signaling in human corneal epithelial cells. Biochem Biophys Res Commun. 2012; 420(3):685-91. DOI: 10.1016/j.bbrc.2012.03.069. View

Yan Y, Dalmasso G, Sitaraman S, Merlin D . Characterization of the human intestinal CD98 promoter and its regulation by interferon-gamma. Am J Physiol Gastrointest Liver Physiol. 2006; 292(2):G535-45. DOI: 10.1152/ajpgi.00385.2006. View

Koivunen P, Hirsila M, Remes A, Hassinen I, Kivirikko K, Myllyharju J . Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem. 2006; 282(7):4524-4532. DOI: 10.1074/jbc.M610415200. View

Phillip West A, Brodsky I, Rahner C, Woo D, Erdjument-Bromage H, Tempst P . TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature. 2011; 472(7344):476-80. PMC: 3460538. DOI: 10.1038/nature09973. View

Chandel N, McClintock D, Feliciano C, Wood T, Melendez J, Rodriguez A . Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem. 2000; 275(33):25130-8. DOI: 10.1074/jbc.M001914200. View

Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel A, Johnson R, Nizet V . Cutting edge: Essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis. J Immunol. 2007; 178(12):7516-9. DOI: 10.4049/jimmunol.178.12.7516. View

Rodriguez-Prados J, Traves P, Cuenca J, Rico D, Aragones J, Martin-Sanz P . Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol. 2010; 185(1):605-14. DOI: 10.4049/jimmunol.0901698. View

Rubic T, Lametschwandtner G, Jost S, Hinteregger S, Kund J, Carballido-Perrig N . Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol. 2008; 9(11):1261-9. DOI: 10.1038/ni.1657. View

10.

Choi S, Silverman R . Inactivation and inhibition of gamma-aminobutyric acid aminotransferase by conformationally restricted vigabatrin analogues. J Med Chem. 2002; 45(20):4531-9. DOI: 10.1021/jm020134i. View

11.

Sumbayev V . LPS-induced Toll-like receptor 4 signalling triggers cross-talk of apoptosis signal-regulating kinase 1 (ASK1) and HIF-1alpha protein. FEBS Lett. 2007; 582(2):319-26. DOI: 10.1016/j.febslet.2007.12.024. View

12.

Dahia P, Ross K, Wright M, Hayashida C, Santagata S, Barontini M . A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 2005; 1(1):72-80. PMC: 1183527. DOI: 10.1371/journal.pgen.0010008. View

13.

Krawczyk C, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis R . Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood. 2010; 115(23):4742-9. PMC: 2890190. DOI: 10.1182/blood-2009-10-249540. View

14.

Masters S, Dunne A, Subramanian S, Hull R, Tannahill G, Sharp F . Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol. 2010; 11(10):897-904. PMC: 3103663. DOI: 10.1038/ni.1935. View

15.

Doyle S, Husebye H, Connolly D, Espevik T, ONeill L, Mcgettrick A . The GOLD domain-containing protein TMED7 inhibits TLR4 signalling from the endosome upon LPS stimulation. Nat Commun. 2012; 3:707. DOI: 10.1038/ncomms1706. View

16.

Selak M, Armour S, MacKenzie E, Boulahbel H, Watson D, Mansfield K . Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005; 7(1):77-85. DOI: 10.1016/j.ccr.2004.11.022. View

17.

Ghisletti S, Huang W, Ogawa S, Pascual G, Lin M, Willson T . Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. Mol Cell. 2007; 25(1):57-70. PMC: 1850387. DOI: 10.1016/j.molcel.2006.11.022. View

18.

Du J, Zhou Y, Su X, Yu J, Khan S, Jiang H . Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science. 2011; 334(6057):806-9. PMC: 3217313. DOI: 10.1126/science.1207861. View

19.

MacKenzie E, Selak M, Tennant D, Payne L, Crosby S, Frederiksen C . Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol Cell Biol. 2007; 27(9):3282-9. PMC: 1899954. DOI: 10.1128/MCB.01927-06. View

20.

Gimenez-Roqueplo A, Favier J, Rustin P, Mourad J, Plouin P, Corvol P . The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet. 2001; 69(6):1186-97. PMC: 1235531. DOI: 10.1086/324413. View