The IRG1-Itaconate axis: A regulatory hub for immunity and metabolism in macrophages

References

• Ganeshan K, Chawla A. Metabolic regulation of immune responses. Annu Rev Immunol. 2014;32:609–634. doi:10.1146/annurev-immunol-032713-120236.
   PubMed Web of Science ®Google Scholar
• Jung J, Zeng H, Horng T. Metabolism as a guiding force for immunity. Nat Cell Biol. 2019;21(1):85–93. doi:10.1038/s41556-018-0217-x.
   PubMed Web of Science ®Google Scholar
• Mills EL, O’Neill LA. Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal. Eur J Immunol. 2016;46(1):13–21. doi:10.1002/eji.201445427.
   PubMed Web of Science ®Google Scholar
• Saha S, Shalova IN, Biswas SK. Metabolic regulation of macrophage phenotype and function. Immunol Rev. 2017;280(1):102–111. doi:10.1111/imr.12603.
   PubMed Web of Science ®Google Scholar
• Van den Bossche J, O’Neill LA, Menon D. Macrophage immunometabolism: where are we (going)? Trends Immunol. 2017;38(6):395–406. doi:10.1016/j.it.2017.03.001.
   PubMed Web of Science ®Google Scholar
• Collins JM, Jones DP, Sharma A, et al. TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis. PLoS Pathog. 2021;17(9):e1009941. doi:10.1371/journal.ppat.1009941.
   PubMed Web of Science ®Google Scholar
• Ryan DG, Murphy MP, Frezza C, et al. Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nat Metab. 2019;1:16–33. doi:10.1038/s42255-018-0014-7.
   PubMedGoogle Scholar
• Bambouskova M, Gorvel L, Lampropoulou V, et al. Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis. Nature. 2018;556(7702):501–504. doi:10.1038/s41586-018-0052-z.
   PubMed Web of Science ®Google Scholar
• Mills EL, Kelly B, Logan A, et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell. 2016;167(2):457–470.e13. doi:10.1016/j.cell.2016.08.064.
   PubMed Web of Science ®Google Scholar
• Lampropoulou V, Sergushichev A, Bambouskova M, et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 2016;24(1):158–166. doi:10.1016/j.cmet.2016.06.004.
   PubMed Web of Science ®Google Scholar
• Yu XH, Zhang DW, Zheng XL, et al. Itaconate: an emerging determinant of inflammation in activated macrophages. Immunol Cell Biol. 2019;97(2):134–141. doi:10.1111/imcb.12218.
   PubMed Web of Science ®Google Scholar
• Wu R, Chen F, Wang N, et al. ACOD1 in immunometabolism and disease. Cell Mol Immunol. 2020;17(8):822–833. doi:10.1038/s41423-020-0489-5.
   PubMed Web of Science ®Google Scholar
• Michelucci A, Cordes T, Ghelfi J, et al. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci U S A. 2013;110(19):7820–7825. doi:10.1073/pnas.1218599110.
   PubMed Web of Science ®Google Scholar
• Mills EL, Ryan DG, Prag HA, et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature. 2018;556(7699):113–117. doi:10.1038/nature25986.
   PubMed Web of Science ®Google Scholar
• Hooftman A, Angiari S, Hester S, et al. The immunomodulatory metabolite itaconate modifies NLRP3 and inhibits inflammasome activation. Cell Metab. 2020;32(3):468–478.e7. doi:10.1016/j.cmet.2020.07.016.
   PubMed Web of Science ®Google Scholar
• Bambouskova M, Potuckova L, Paulenda T, et al. Itaconate confers tolerance to late NLRP3 inflammasome activation. Cell Rep. 2021;34(10):108756. doi:10.1016/j.celrep.2021.108756.
   PubMed Web of Science ®Google Scholar
• Daniels BP, Kofman SB, Smith JR, et al. The nucleotide sensor ZBP1 and kinase RIPK3 induce the enzyme IRG1 to promote an antiviral metabolic state in neurons. Immunity. 2019;50(1):64–76.e4. doi:10.1016/j.immuni.2018.11.017.
   PubMed Web of Science ®Google Scholar
• Liu R, Li X, Ma H, et al. Spermidine endows macrophages anti-inflammatory properties by inducing mitochondrial superoxide-dependent AMPK activation, Hif-1α upregulation and autophagy. Free Radic Biol Med. 2020;161:339–350. doi:10.1016/j.freeradbiomed.2020.10.029.
   PubMed Web of Science ®Google Scholar
• Jamal Uddin M, Joe Y, Kim SK, et al. IRG1 induced by heme oxygenase-1/carbon monoxide inhibits LPS-mediated sepsis and pro-inflammatory cytokine production. Cell Mol Immunol. 2016;13(2):170–179. doi:10.1038/cmi.2015.02.
   PubMed Web of Science ®Google Scholar
• Cordes T, Wallace M, Michelucci A, et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J Biol Chem. 2016;291(27):14274–14284. doi:10.1074/jbc.M115.685792.
   PubMed Web of Science ®Google Scholar
• Cordes T, Metallo CM. Itaconate alters succinate and coenzyme a metabolism via inhibition of mitochondrial complex II and methylmalonyl-CoA mutase. Metabolites. 2021;11(2):117. doi:10.3390/metabo11020117.
   PubMed Web of Science ®Google Scholar
• Liao ST, Han C, Xu DQ, et al. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects. Nat Commun. 2019;10(1):5091. doi:10.1038/s41467-019-13078-5.
   PubMedGoogle Scholar
• Cordes T, Michelucci A, Hiller K. Itaconic acid: the surprising role of an industrial compound as a mammalian antimicrobial metabolite. Annu Rev Nutr. 2015;35:451–473. doi:10.1146/annurev-nutr-071714-034243.
   PubMed Web of Science ®Google Scholar
• Luan HH, Medzhitov R. Food fight: role of itaconate and other metabolites in antimicrobial defense. Cell Metab. 2016;24(3):379–387. doi:10.1016/j.cmet.2016.08.013.
   PubMed Web of Science ®Google Scholar
• Li R, Zhang P, Wang Y, Tao K. Itaconate: a metabolite regulates inflammation response and oxidative stress. Oxid Med Cell Longev. 2020;2020:5404780. doi:10.1155/2020/5404780.
   PubMed Web of Science ®Google Scholar
• Kanamasa S, Dwiarti L, Okabe M, Park EY. Cloning and functional characterization of the cis-aconitic acid decarboxylase (CAD) gene from Aspergillus terreus. Appl Microbiol Biotechnol. 2008;80(2):223–229. doi:10.1007/s00253-008-1523-1.
   PubMed Web of Science ®Google Scholar
• Lee CG, Jenkins NA, Gilbert DJ, et al. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics. 1995;41(5):263–270. doi:10.1007/BF00172150.
   PubMed Web of Science ®Google Scholar
• Chun HL, Lee SY, Kim K-H, et al. The crystal structure of mouse IRG1 suggests that cis-aconitate decarboxylase has an open and closed conformation. PLoS One. 2020;15(12):e0242383. doi:10.1371/journal.pone.0242383.
   PubMed Web of Science ®Google Scholar
• Chen F, Lukat P, Iqbal AA, et al. Crystal structure of cis-aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis. Proc Natl Acad Sci U S A. 2019;116(41):20644–20654. doi:10.1073/pnas.1908770116.
   PubMed Web of Science ®Google Scholar
• Gidon A, Louet C, Røst LM, et al. The tumor necrosis factor alpha and interleukin 6 auto-paracrine signaling loop controls Mycobacterium avium infection via induction of IRF1/IRG1 in human primary macrophages. mBio. 2021;12(5):e0212121. doi:10.1128/mBio.02121-21.
   PubMed Web of Science ®Google Scholar
• Chen M, Sun H, Boot M, et al. Itaconate is an effector of a Rab GTPase cell-autonomous host defense pathway against Salmonella. Science. 2020;369(6502):450–455. doi:10.1126/science.aaz1333.
   PubMed Web of Science ®Google Scholar
• Baup S. Ueber eine neue Brenz - Citronensäure und über die Nomenclatur der Brenzkörper überhaupt. J Prakt Chem. 2004;8(1):418–424. doi:10.1002/prac.18360080162.
   Google Scholar
• Willke T, Vorlop KD. Biotechnological production of itaconic acid. Appl Microbiol Biotechnol. 2001;56(3–4):289–295. doi:10.1007/s002530100685.
   PubMed Web of Science ®Google Scholar
• Strelko CL, Lu W, Dufort FJ, et al. Itaconic acid is a mammalian metabolite induced during macrophage activation. J Am Chem Soc. 2011;133(41):16386–16389. doi:10.1021/ja2070889.
   PubMed Web of Science ®Google Scholar
• ElAzzouny M, Tom CT, Evans CR, et al. Dimethyl itaconate is not metabolized into itaconate intracellularly. J Biol Chem. 2017;292(12):4766–4769. doi:10.1074/jbc.C117.775270.
   PubMed Web of Science ®Google Scholar
• Swain A, Bambouskova M, Kim H, et al. Comparative evaluation of itaconate and its derivatives reveals divergent inflammasome and type I interferon regulation in macrophages. Nat Metab. 2020;2(7):594–602. doi:10.1038/s42255-020-0210-0.
   PubMedGoogle Scholar
• Winterhoff M, Chen F, Sahini N, et al. Establishment, validation, and initial application of a sensitive LC-MS/MS assay for quantification of the naturally occurring isomers itaconate, mesaconate, and citraconate. Metabolites. 2021;11(5):270. doi:10.3390/metabo11050270.
   PubMed Web of Science ®Google Scholar
• Gautam A, Dixit S, Philipp MT, et al. Interleukin-10 alters effector functions of multiple genes induced by Borrelia burgdorferi in macrophages to regulate Lyme disease inflammation. Infect Immun. 2011;79(12):4876–4892. doi:10.1128/IAI.05451-11.
   PubMed Web of Science ®Google Scholar
• Tallam A, Perumal TM, Antony PM, et al. Gene regulatory network inference of immunoresponsive gene 1 (IRG1) identifies interferon regulatory factor 1 (IRF1) as its transcriptional regulator in mammalian macrophages. PLoS One. 2016;11(2):e0149050. doi:10.1371/journal.pone.0149050.
   PubMed Web of Science ®Google Scholar
• Degrandi D, Hoffmann R, Beuter-Gunia C, Pfeffer K. The proinflammatory cytokine-induced IRG1 protein associates with mitochondria. J Interferon Cytokine Res. 2009;29(1):55–67. doi:10.1089/jir.2008.0013.
   PubMed Web of Science ®Google Scholar
• Sasikaran J, Ziemski M, Zadora PK, et al. Bacterial itaconate degradation promotes pathogenicity. Nat Chem Biol. 2014;10(5):371–377. doi:10.1038/nchembio.1482.
   PubMed Web of Science ®Google Scholar
• McFadden BA, Williams JO, Roche TE. Mechanism of action of isocitrate lyase from Pseudomonas indigofera. Biochemistry. 1971;10(8):1384–1390. doi:10.1021/bi00784a017.
   PubMed Web of Science ®Google Scholar
• van Schaik EJ, Tom M, Woods DE. Burkholderia pseudomallei isocitrate lyase is a persistence factor in pulmonary melioidosis: implications for the development of isocitrate lyase inhibitors as novel antimicrobials. Infect Immun. 2009;77(10):4275–4283. doi:10.1128/IAI.00609-09.
   PubMed Web of Science ®Google Scholar
• Tomlinson KL, Lung TWF, Dach F, et al. Staphylococcus aureus induces an itaconate-dominated immunometabolic response that drives biofilm formation. Nat Commun. 2021;12(1):1399. doi:10.1038/s41467-021-21718-y.
   PubMed Web of Science ®Google Scholar
• Singh S, Singh PK, Jha A, et al. Integrative metabolomics and transcriptomics identifies itaconate as an adjunct therapy to treat ocular bacterial infection. Cell Rep Med. 2021;2(5):100277. doi:10.1016/j.xcrm.2021.100277.
   PubMedGoogle Scholar
• Nair S, Huynh JP, Lampropoulou V, et al. Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection. J Exp Med. 2018;215(4):1035–1045. doi:10.1084/jem.20180118.
   PubMed Web of Science ®Google Scholar
• Zhu D, Zhao Y, Luo Y, et al. Irg1-itaconate axis protects against acute kidney injury via activation of Nrf2. Am J Transl Res. 2021;13(3):1155–1169.
   PubMed Web of Science ®Google Scholar
• Li Y, Zhang P, Wang C, et al. Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species. J Biol Chem. 2013;288(23):16225–16234. doi:10.1074/jbc.M113.454538.
   PubMed Web of Science ®Google Scholar
• Van Quickelberghe E, Martens A, Goeminne LJE, et al. Identification of immune-responsive gene 1 (IRG1) as a target of A20. J Proteome Res. 2018;17(6):2182–2191. doi:10.1021/acs.jproteome.8b00139.
   PubMed Web of Science ®Google Scholar
• Hall CJ, Boyle RH, Astin JW, et al. Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating β-oxidation-dependent mitochondrial ROS production. Cell Metab. 2013;18(2):265–278. doi:10.1016/j.cmet.2013.06.018.
   PubMed Web of Science ®Google Scholar
• Konishi H, Tanaka M, Takemura Y, et al. Activation of protein kinase C by tyrosine phosphorylation in response to H2O2. Proc Natl Acad Sci U S A. 1997;94(21):11233–11237. doi:10.1073/pnas.94.21.11233.
   PubMed Web of Science ®Google Scholar
• Hoshino K, Kaisho T, Iwabe T, et al. Differential involvement of IFN-beta in Toll-like receptor-stimulated dendritic cell activation. Int Immunol. 2002;14(10):1225–1231. doi:10.1093/intimm/dxf089.
   PubMed Web of Science ®Google Scholar
• Rodríguez N, Mages J, Dietrich H, et al. MyD88-dependent changes in the pulmonary transcriptome after infection with Chlamydia pneumoniae. Physiol Genomics. 2007;30(2):134–145. doi:10.1152/physiolgenomics.00011.2007.
   PubMed Web of Science ®Google Scholar
• Ganta VC, Choi MH, Kutateladze A, et al. A MicroRNA93-interferon regulatory factor-9-immunoresponsive gene-1-itaconic acid pathway modulates M2-like macrophage polarization to revascularize ischemic muscle. Circulation. 2017;135(24):2403–2425. doi:10.1161/CIRCULATIONAHA.116.025490.
   PubMed Web of Science ®Google Scholar
• Shi S, Blumenthal A, Hickey CM, et al. Expression of many immunologically important genes in Mycobacterium tuberculosis-infected macrophages is independent of both TLR2 and TLR4 but dependent on IFN-alphabeta receptor and STAT1. J Immunol. 2005;175(5):3318–3328. doi:10.4049/jimmunol.175.5.3318.
   PubMed Web of Science ®Google Scholar
• Kawai T, Takeuchi O, Fujita T, et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol. 2001;167(10):5887–5894. doi:10.4049/jimmunol.167.10.5887.
   PubMed Web of Science ®Google Scholar
• Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev. 2018;98(3):1169–1203. doi:10.1152/physrev.00023.2017.
   PubMed Web of Science ®Google Scholar
• Yu C, Xiao J-H. The Keap1-Nrf2 system: a mediator between oxidative stress and aging. Oxid Med Cell Longev. 2021;2021:6635460. doi:10.1155/2021/6635460.
   PubMed Web of Science ®Google Scholar
• Mornata F, Pepe G, Sfogliarini C, et al. Reciprocal interference between the NRF2 and LPS signaling pathways on the immune-metabolic phenotype of peritoneal macrophages. Pharmacol Res Perspect. 2020;8(4):e00638. doi:10.1002/prp2.638.
   PubMed Web of Science ®Google Scholar
• Olagnier D, Brandtoft AM, Gunderstofte C, et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat Commun. 2018;9(1):3506. doi:10.1038/s41467-018-05861-7.
   PubMedGoogle Scholar
• Li Y, Chen X, Zhang H, et al. 4-octyl itaconate alleviates lipopolysaccharide-induced acute lung injury in mice by inhibiting oxidative stress and inflammation. DDDT. 2020;14:5547–5558. doi:10.2147/DDDT.S280922.
   PubMed Web of Science ®Google Scholar
• Kuo PC, Weng WT, Scofield BA, et al. Dimethyl itaconate, an itaconate derivative, exhibits immunomodulatory effects on neuroinflammation in experimental autoimmune encephalomyelitis. J Neuroinflammation. 2020;17(1):138. doi:10.1186/s12974-020-01768-7.
   PubMed Web of Science ®Google Scholar
• Zhang S, Jiao Y, Li C, et al. Dimethyl itaconate alleviates the inflammatory responses of macrophages in sepsis. Inflammation. 2021;44(2):549–557. doi:10.1007/s10753-020-01352-4.
   PubMed Web of Science ®Google Scholar
• Song H, Xu T, Feng X, et al. Itaconate prevents abdominal aortic aneurysm formation through inhibiting inflammation via activation of Nrf2. EBioMedicine. 2020;57:102832. doi:10.1016/j.ebiom.2020.102832.
   PubMed Web of Science ®Google Scholar
• Yi Z, Deng M, Scott MJ, et al. Immune-responsive gene 1/itaconate activates nuclear factor erythroid 2-related factor 2 in hepatocytes to protect against liver ischemia-reperfusion injury. Hepatology. 2020;72(4):1394–1411. doi:10.1002/hep.31147.
   PubMed Web of Science ®Google Scholar
• Xu Y, Li Z, Lu S, et al. Integrative analysis of the roles of lncRNAs and mRNAs in itaconate-mediated protection against liver ischemia-reperfusion injury in mice. J Inflamm Res. 2021;14:4519–4536. doi:10.2147/JIR.S327467.
   PubMed Web of Science ®Google Scholar
• Coll RC, Robertson AA, Chae JJ, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21(3):248–255. doi:10.1038/nm.3806.
   PubMed Web of Science ®Google Scholar
• Paik S, Kim JK, Silwal P, et al. An update on the regulatory mechanisms of NLRP3 inflammasome activation. Cell Mol Immunol. 2021;18(5):1141–1160. doi:10.1038/s41423-021-00670-3.
   PubMed Web of Science ®Google Scholar
• Yang Y, Wang H, Kouadir M, et al. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis. 2019;10(2):128. doi:10.1038/s41419-019-1413-8.
   PubMed Web of Science ®Google Scholar
• Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 2019;26(1):99–114. doi:10.1038/s41418-018-0212-6.
   PubMed Web of Science ®Google Scholar
• Xia S, Hollingsworth L, Wu H. Mechanism and regulation of gasdermin-mediated cell death. Cold Spring Harb Perspect Biol. 2020;12(3):a036400. doi:10.1101/cshperspect.a036400.
   PubMed Web of Science ®Google Scholar
• De Nardo D, Labzin LI, Kono H, et al. High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3. Nat Immunol. 2014;15(2):152–160. doi:10.1038/ni.2784.
   PubMed Web of Science ®Google Scholar
• Bordon Y. Itaconate charges down inflammation. Nat Rev Immunol. 2018;18(6):360–361. doi:10.1038/s41577-018-0016-4.
   PubMed Web of Science ®Google Scholar
• Zhang M, Peng LL, Wang Y, et al. Roles of A20 in autoimmune diseases. Immunol Res. 2016;64(2):337–344. doi:10.1007/s12026-015-8677-6.
   PubMed Web of Science ®Google Scholar
• Duong BH, Onizawa M, Oses-Prieto JA, et al. A20 restricts ubiquitination of pro-interleukin-1β protein complexes and suppresses NLRP3 inflammasome activity. Immunity. 2015;42(1):55–67. doi:10.1016/j.immuni.2014.12.031.
   PubMed Web of Science ®Google Scholar
• Zhu X, Guo Y, Liu Z, et al. Itaconic acid exerts anti-inflammatory and antibacterial effects via promoting pentose phosphate pathway to produce ROS. Sci Rep. 2021;11(1):18173. doi:10.1038/s41598-021-97352-x.
   PubMed Web of Science ®Google Scholar
• Naujoks J, Tabeling C, Dill BD, et al. IFNs modify the proteome of legionella-containing vacuoles and restrict infection via IRG1-derived itaconic acid. PLoS Pathog. 2016;12(2):e1005408. doi:10.1371/journal.ppat.1005408.
   PubMed Web of Science ®Google Scholar
• Zheng Y, Chen Z, She C, et al. Four-octyl itaconate activates Nrf2 cascade to protect osteoblasts from hydrogen peroxide-induced oxidative injury. Cell Death Dis. 2020;11(9):772. doi:10.1038/s41419-020-02987-9.
   PubMed Web of Science ®Google Scholar
• Jha AK, Huang SC, Sergushichev A, et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 2015;42(3):419–430. doi:10.1016/j.immuni.2015.02.005.
   PubMed Web of Science ®Google Scholar
• Shen H, Campanello GC, Flicker D, et al. The human knockout gene CLYBL connects itaconate to vitamin B12. Cell. 2017;171(4):771–782.e11. doi:10.1016/j.cell.2017.09.051.
   PubMed Web of Science ®Google Scholar
• Domínguez-Andrés J, Novakovic B, Li Y, et al. The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metab. 2019;29(1):211–220.e5. doi:10.1016/j.cmet.2018.09.003.
   PubMed Web of Science ®Google Scholar
• Taylor PR, Tsoni SV, Willment JA, et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat Immunol. 2007;8(1):31–38. doi:10.1038/ni1408.
   PubMed Web of Science ®Google Scholar
• Qin W, Qin K, Zhang Y, et al. S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate. Nat Chem Biol. 2019;15(10):983–991. doi:10.1038/s41589-019-0323-5.
   PubMed Web of Science ®Google Scholar
• Weiss JM, Davies LC, Karwan M, et al. Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors. J Clin Invest. 2018;128(9):3794–3805. doi:10.1172/JCI99169.
   PubMed Web of Science ®Google Scholar
• Kelly B, O’Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015;25(7):771–784. doi:10.1038/cr.2015.68.
   PubMed Web of Science ®Google Scholar
• Meiser J, Krämer L, Sapcariu SC, et al. Pro-inflammatory macrophages sustain pyruvate oxidation through pyruvate dehydrogenase for the synthesis of itaconate and to enable cytokine expression. J Biol Chem. 2016;291(8):3932–3946. doi:10.1074/jbc.M115.676817.
   PubMed Web of Science ®Google Scholar
• Sakai A, Kusumoto A, Kiso Y, Furuya E. Itaconate reduces visceral fat by inhibiting fructose 2,6-bisphosphate synthesis in rat liver. Nutrition. 2004;20(11–12):997–1002. doi:10.1016/j.nut.2004.08.007.
   PubMed Web of Science ®Google Scholar
• Neinast M, Murashige D, Arany Z. Branched chain amino acids. Annu Rev Physiol. 2019;81:139–164. doi:10.1146/annurev-physiol-020518-114455.
   PubMed Web of Science ®Google Scholar
• Lerin C, Goldfine AB, Boes T, et al. Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism. Mol Metab. 2016;5(10):926–936. doi:10.1016/j.molmet.2016.08.001.
   PubMed Web of Science ®Google Scholar
• Ruetz M, Campanello GC, Purchal M, et al. Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair. Science. 2019;366(6465):589–593. doi:10.1126/science.aay0934.
   PubMed Web of Science ®Google Scholar
• Papathanassiu AE, Ko JH, Imprialou M, et al. BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases. Nat Commun. 2017;8:16040. doi:10.1038/ncomms16040.
   PubMed Web of Science ®Google Scholar
• Gonzalez-Pena D, Nixon SE, Southey BR, et al. Differential transcriptome networks between IDO1-knockout and wild-type mice in brain microglia and macrophages. PLoS One. 2016;11(6):e0157727. doi:10.1371/journal.pone.0157727.
   PubMed Web of Science ®Google Scholar
• Liu X, Shi B, Suo R, et al. Itaconate regulates macrophage function through stressful iron-sulfur cluster disrupting and iron metabolism rebalancing. Faseb J. 2021;35(10):e21936. doi:10.1096/fj.202100726RR.
   PubMed Web of Science ®Google Scholar
• Lin J, Ren J, Gao DS, et al. The emerging application of itaconate: promising molecular targets and therapeutic opportunities. Front Chem. 2021;9:669308. doi:10.3389/fchem.2021.669308.
   PubMed Web of Science ®Google Scholar
• Daly R, Blackburn G, Best C, et al. Changes in plasma itaconate elevation in early rheumatoid arthritis patients elucidates disease activity associated macrophage activation. Metabolites. 2020;10(6):241. doi:10.3390/metabo10060241.
   PubMed Web of Science ®Google Scholar
• Cordes T, Lucas A, Divakaruni AS, et al. Itaconate modulates tricarboxylic acid and redox metabolism to mitigate reperfusion injury. Mol Metab. 2020;32:122–135. doi:10.1016/j.molmet.2019.11.019.
   PubMed Web of Science ®Google Scholar
• Kuo PC, Weng WT, Scofield BA, et al. Immunoresponsive gene 1 modulates the severity of brain injury in cerebral ischaemia. Brain Commun. 2021;3(3):fcab187. doi:10.1093/braincomms/fcab187.
   PubMedGoogle Scholar
• Wang Q, Li XL, Mei Y, et al. The anti-inflammatory drug dimethyl itaconate protects against colitis-associated colorectal cancer. J Mol Med (Berl). 2020;98(10):1457–1466. doi:10.1007/s00109-020-01963-2.
   PubMed Web of Science ®Google Scholar
• Wang HG, Zhang MN, Wen X, Yang XZ. Itaconate aggravates experimental colitis. Clin Res Hepatol Gastroenterol. 2021;45(2):101629. doi:10.1016/j.clinre.2021.101629.
   PubMed Web of Science ®Google Scholar
• Benveniste EN. Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med (Berl). 1997;75(3):165–173. doi:10.1007/s001090050101.
   PubMed Web of Science ®Google Scholar