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04-05-2023 | Immunomodulator | REVIEW

Itaconate: A Potent Macrophage Immunomodulator

Authors: Zeyu Li, Wenbin Zheng, Wen Kong, Tianshu Zeng

Published in: Inflammation | Issue 4/2023

Abstract

With advances in immunometabolic studies, more and more evidence has shown that metabolic changes profoundly affect the immune function of macrophages. The tricarboxylic acid cycle is a central metabolic pathway of cells. Itaconate, a byproduct of the tricarboxylic acid cycle, is an emerging metabolic small molecule that regulates macrophage inflammation and has received much attention for its potent anti-inflammatory effects in recent years. Itaconate regulates macrophage function through multiple mechanisms and has demonstrated promising therapeutic potential in a variety of immune and inflammatory diseases. New progress in the mechanism of itaconate continues to be made, but it also implies complexity in its action and a need for a more comprehensive understanding of its role in macrophages. In this article, we review the primary mechanisms and current research progress of itaconate in regulating macrophage immune metabolism, hoping to provide new insights and directions for future research and disease treatment.

Mosser, D.M., and J.P. Edwards. 2008. Exploring the full spectrum of macrophage activation. Nature Reviews Immunology. https://doi.org/10.1038/nri2448.CrossRefPubMedPubMedCentral

Saha, S., I.N. Shalova, and S.K. Biswas. 2017. Metabolic regulation of macrophage phenotype and function. Immunological Reviews. https://doi.org/10.1111/imr.12603.CrossRefPubMed

Funes, S.C., M. Rios, J. Escobar-Vera, et al. 2018. Implications of macrophage polarization in autoimmunity. Immunology. https://doi.org/10.1111/imm.12910.CrossRefPubMedPubMedCentral

Mills, C.D. 2015. Anatomy of a discovery: M1 and m2 macrophages. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2015.00212.CrossRefPubMedPubMedCentral

O’Neill, L.A.J., and M.N. Artyomov. 2019. Itaconate: The poster child of metabolic reprogramming in macrophage function. Nature Reviews Immunology. https://doi.org/10.1038/s41577-019-0128-5.CrossRefPubMed

Williams, J.O., T.E. Roche, and B.A. McFadden. 1971. Mechanism of action of isocitrate lyase from Pseudomonas indigofera. Biochemistry. https://doi.org/10.1021/bi00784a017.CrossRefPubMed

Rittenhouse, J.W., and B.A. McFadden. 1974. Inhibition of isocitrate lyase from Pseudomonas indigofera by itaconate. Archives of Biochemistry and Biophysics. https://doi.org/10.1016/0003-9861(74)90456-1.CrossRefPubMed

McFadden, B.A., and S. Purohit. 1977. Itaconate, an isocitrate lyase-directed inhibitor in Pseudomonas indigofera. Journal of Bacteriology. https://doi.org/10.1128/jb.131.1.136-144.1977.CrossRefPubMedPubMedCentral

Strelko, C.L., W. Lu, F.J. Dufort, et al. 2011. Itaconic acid is a mammalian metabolite induced during macrophage activation. Journal of the American Chemical Society. https://doi.org/10.1021/ja2070889.CrossRefPubMedPubMedCentral

10.

Michelucci, A., T. Cordes, J. Ghelfi, et al. 2013. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proceedings of the National Academy of Sciences USA. https://doi.org/10.1073/pnas.1218599110.CrossRef

11.

Cordes, T., M. Wallace, A. Michelucci, et al. 2016. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.M115.685792.CrossRefPubMedPubMedCentral

12.

Lampropoulou, V., A. Sergushichev, M. Bambouskova, et al. 2016. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metabolism. https://doi.org/10.1016/j.cmet.2016.06.004.CrossRefPubMedPubMedCentral

13.

Chen, M., H. Sun, M. Boot, et al. 2020. Itaconate is an effector of a Rab GTPase cell-autonomous host defense pathway against Salmonella. Science. https://doi.org/10.1126/science.aaz1333.CrossRefPubMedPubMedCentral

14.

ElAzzouny, M., C.T. Tom, C.R. Evans, et al. 2017. Dimethyl itaconate is not metabolized into itaconate intracellularly. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.C117.775270.CrossRefPubMedPubMedCentral

15.

Shen, H., G.C. Campanello, D. Flicker, et al. 2017. The human knockout gene CLYBL connects itaconate to vitamin B(12). Cell. https://doi.org/10.1016/j.cell.2017.09.051.CrossRefPubMedPubMedCentral

16.

Mills, E.L., D.G. Ryan, H.A. Prag, et al. 2018. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature. https://doi.org/10.1038/nature25986.CrossRefPubMedPubMedCentral

17.

Swain, A., M. Bambouskova, H. Kim, et al. 2020. Comparative evaluation of itaconate and its derivatives reveals divergent inflammasome and type I interferon regulation in macrophages. Nature Metabolism. https://doi.org/10.1038/s42255-020-0210-0.CrossRefPubMedPubMedCentral

18.

He, W., A. Henne, M. Lauterbach, et al. 2022. Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages. Nature Metabolism. https://doi.org/10.1038/s42255-022-00565-1.CrossRefPubMedPubMedCentral

19.

Bambouskova, M., L. Gorvel, V. Lampropoulou, et al. 2018. Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis. Nature. https://doi.org/10.1038/s41586-018-0052-z.CrossRefPubMedPubMedCentral

20.

Chen, F., W.A.M. Elgaher, M. Winterhoff, et al. 2022. Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism. Nature Metabolism. https://doi.org/10.1038/s42255-022-00577-x.CrossRefPubMedPubMedCentral

21.

Kornberg, M.D., P. Bhargava, P.M. Kim, et al. 2018. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science. https://doi.org/10.1126/science.aan4665.CrossRefPubMedPubMedCentral

22.

Ryan, D.G., M.P. Murphy, C. Frezza, et al. 2019. Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nature Metabolism. https://doi.org/10.1038/s42255-018-0014-7.CrossRefPubMedPubMedCentral

23.

Hadrava Vanova, K., M. Kraus, J. Neuzil, et al. 2020. Mitochondrial complex II and reactive oxygen species in disease and therapy. Redox Report. https://doi.org/10.1080/13510002.2020.1752002.CrossRefPubMedPubMedCentral

24.

Mills, E.L., B. Kelly, A. Logan, et al. 2016. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell. https://doi.org/10.1016/j.cell.2016.08.064.CrossRefPubMedPubMedCentral

25.

Garaude, J., R. Acín-Pérez, S. Martínez-Cano, et al. 2016. Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense. Nature Immunology. https://doi.org/10.1038/ni.3509.CrossRefPubMedPubMedCentral

26.

Chouchani, E.T., V.R. Pell, A.M. James, et al. 2016. A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury. Cell Metabolism. https://doi.org/10.1016/j.cmet.2015.12.009.CrossRefPubMedPubMedCentral

27.

Ackermann, W.W., and V.R. Potter. 1949. Enzyme inhibition in relation to chemotherapy. Proceedings of the Society for Experimental Biology and Medicine. https://doi.org/10.3181/00379727-72-17313.CrossRefPubMed

28.

Booth, A. N., J. Taylor, R. H. Wilson, et al. 1952. The inhibitory effects of itaconic acid in vitro and in vivo. Journal of Biological Chemistry.

29.

Dervartanian, D. V., and C. Veeger. 1964. Studies on succinate dehydrogenase. I. Spectral properties of the purified enzyme and formation of enzyme-competitive inhibitor complexes. Biochim Biophys Acta.

30.

Cordes, T., A. Lucas, A.S. Divakaruni, et al. 2020. Itaconate modulates tricarboxylic acid and redox metabolism to mitigate reperfusion injury. Mol Metab. https://doi.org/10.1016/j.molmet.2019.11.019.CrossRefPubMed

31.

Zhang, D., Z. Lu, Z. Zhang, et al. 2019. A likely protective effect of dimethyl itaconate on cerebral ischemia/reperfusion injury. International Immunopharmacology. https://doi.org/10.1016/j.intimp.2019.105924.CrossRefPubMedPubMedCentral

32.

Domínguez-Andrés, J., B. Novakovic, Y. Li, et al. 2019. The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metabolism. https://doi.org/10.1016/j.cmet.2018.09.003.CrossRefPubMed

33.

Medzhitov, R., D.S. Schneider, and M.P. Soares. 2012. Disease tolerance as a defense strategy. Science. https://doi.org/10.1126/science.1214935.CrossRefPubMedPubMedCentral

34.

Netea, M.G., L.A. Joosten, E. Latz, et al. 2016. Trained immunity: A program of innate immune memory in health and disease. Science. https://doi.org/10.1126/science.aaf1098.CrossRefPubMedPubMedCentral

35.

Battino, M., F. Giampieri, F. Pistollato, et al. 2018. Nrf2 as regulator of innate immunity: A molecular Swiss army knife! Biotechnology Advances. https://doi.org/10.1016/j.biotechadv.2017.12.012.CrossRefPubMed

36.

Itoh, K., N. Wakabayashi, Y. Katoh, et al. 1999. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes & Development. https://doi.org/10.1101/gad.13.1.76.CrossRef

37.

Burness, C.B., and E.D. Deeks. 2014. Dimethyl fumarate: A review of its use in patients with relapsing-remitting multiple sclerosis. CNS Drugs. https://doi.org/10.1007/s40263-014-0155-5.CrossRefPubMed

38.

Yi, Z., M. Deng, M.J. Scott, et al. 2020. Immune-responsive gene 1/itaconate activates nuclear factor erythroid 2-related factor 2 in hepatocytes to protect against liver ischemia-reperfusion injury. Hepatology. https://doi.org/10.1002/hep.31147.CrossRefPubMed

39.

Li, R., W. Yang, Y. Yin, et al. 2021. 4-OI attenuates carbon tetrachloride-induced hepatic injury via regulating oxidative stress and the inflammatory response. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2021.651444.CrossRefPubMedPubMedCentral

40.

Li, R., W. Yang, Y. Yin, et al. 2021. Protective role of 4-octyl itaconate in murine LPS/D-GalN-induced acute liver failure via inhibiting inflammation, oxidative stress, and apoptosis. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2021/9932099.CrossRefPubMedPubMedCentral

41.

Yang, W., Y. Wang, P. Zhang, et al. 2022. Immune-responsive gene 1 protects against liver injury caused by concanavalin A via the activation Nrf2/HO-1 pathway and inhibition of ROS activation pathways. Free Radical Biology & Medicine. https://doi.org/10.1016/j.freeradbiomed.2022.02.030.CrossRefPubMedPubMedCentral

42.

Azzimato, V., P. Chen, E. Barreby, et al. 2021. Hepatic miR-144 drives fumarase activity preventing NRF2 activation during obesity. Gastroenterology. https://doi.org/10.1053/j.gastro.2021.08.030.CrossRefPubMed

43.

Chu, X., L. Li, W. Yan, et al. 2022. 4-octyl itaconate prevents free fatty acid-induced lipid metabolism disorder through activating Nrf2-AMPK signaling pathway in hepatocytes. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2022/5180242.CrossRefPubMedPubMedCentral

44.

Chen, X., C. Li, X. Cao, et al. 2022. Mitochondria-targeted supramolecular coordination container encapsulated with exogenous itaconate for synergistic therapy of joint inflammation. Theranostics. https://doi.org/10.7150/thno.70623.CrossRefPubMedPubMedCentral

45.

Ni, L., Z. Lin, S. Hu, et al. 2022. Itaconate attenuates osteoarthritis by inhibiting STING/NF-κB axis in chondrocytes and promoting M2 polarization in macrophages. Biochemical Pharmacology. https://doi.org/10.1016/j.bcp.2022.114935.CrossRefPubMed

46.

Zhang, P., X. Wang, Q. Peng, et al. 2022. Four-octyl itaconate protects chondrocytes against H(2)O(2)-induced oxidative injury and attenuates osteoarthritis progression by activating Nrf2 signaling. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2022/2206167.CrossRefPubMedPubMedCentral

47.

Zhang, Q., X. Bai, R. Wang, et al. 2022. 4-octyl Itaconate inhibits lipopolysaccharide (LPS)-induced osteoarthritis via activating Nrf2 signalling pathway. Journal of Cellular and Molecular Medicine. https://doi.org/10.1111/jcmm.17185.CrossRefPubMedPubMedCentral

48.

Ni, L., J. Xiao, D. Zhang, et al. 2022. Immune-responsive gene 1/itaconate activates nuclear factor erythroid 2-related factor 2 in microglia to protect against spinal cord injury in mice. Cell Death & Disease. https://doi.org/10.1038/s41419-022-04592-4.CrossRef

49.

Liu, H., Y. Feng, M. Xu, et al. 2018. Four-octyl itaconate activates Keap1-Nrf2 signaling to protect neuronal cells from hydrogen peroxide. Cell Communication and Signaling: CCS. https://doi.org/10.1186/s12964-018-0294-2.CrossRefPubMedPubMedCentral

50.

Song, H., T. Xu, X. Feng, et al. 2020. Itaconate prevents abdominal aortic aneurysm formation through inhibiting inflammation via activation of Nrf2. eBioMedicine. https://doi.org/10.1016/j.ebiom.2020.102832.CrossRefPubMedPubMedCentral

51.

Nakkala, J.R., Y. Yao, Z. Zhai, et al. 2021. Dimethyl itaconate-loaded nanofibers rewrite macrophage polarization, reduce inflammation, and enhance repair of myocardic infarction. Small (Weinheim an der Bergstrasse, Germany). https://doi.org/10.1002/smll.202006992.CrossRefPubMed

52.

Tang, C., X. Wang, Y. Xie, et al. 2018. 4-octyl itaconate activates Nrf2 signaling to inhibit pro-inflammatory cytokine production in peripheral blood mononuclear cells of systemic lupus erythematosus patients. Cellular Physiology and Biochemistry. https://doi.org/10.1159/000495400.CrossRefPubMed

53.

Xie, Y., Z. Chen, and Z. Wu. 2022. Four-octyl itaconate attenuates UVB-induced melanocytes and keratinocytes apoptosis by Nrf2 activation-dependent ROS inhibition. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2022/9897442.CrossRefPubMedPubMedCentral

54.

Xin, L., F. Zhou, C. Zhang, et al. 2022. Four-octyl itaconate ameliorates periodontal destruction via Nrf2-dependent antioxidant system. International Journal of Oral Science. https://doi.org/10.1038/s41368-022-00177-1.CrossRefPubMedPubMedCentral

55.

Gu, L., J. Lin, Q. Wang, et al. 2020. Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO-1 signaling pathway. Immunology and Cell Biology. https://doi.org/10.1111/imcb.12316.CrossRefPubMedPubMedCentral

56.

Ding, Q., X. Jing, S. Yao, et al. 2022. Multifunctional hydrogel loaded with 4-octyl itaconate exerts antibacterial, antioxidant and angiogenic properties for diabetic wound repair. Biomater Adv. https://doi.org/10.1016/j.bioadv.2022.212979.CrossRefPubMedPubMedCentral

57.

Swanson, K.V., M. Deng, and J.P. Ting. 2019. The NLRP3 inflammasome: Molecular activation and regulation to therapeutics. Nature Reviews Immunology. https://doi.org/10.1038/s41577-019-0165-0.CrossRefPubMedPubMedCentral

58.

Hooftman, A., S. Angiari, S. Hester, et al. 2020. The immunomodulatory metabolite itaconate modifies NLRP3 and inhibits inflammasome activation. Cell Metabolism. https://doi.org/10.1016/j.cmet.2020.07.016.CrossRefPubMedPubMedCentral

59.

Bambouskova, M., L. Potuckova, T. Paulenda, et al. 2021. Itaconate confers tolerance to late NLRP3 inflammasome activation. Cell Reports. https://doi.org/10.1016/j.celrep.2021.108756.CrossRefPubMed

60.

HoyMahmoud ElAzzounyle, C., J.P. Green, S.M. Allan, et al. 2022. Itaconate and fumarate derivatives inhibit priming and activation of the canonical NLRP3 inflammasome in macrophages. Immunology. https://doi.org/10.1111/imm.13454.CrossRef

61.

Lin, J., J. Ren, B. Zhu, et al. 2022. Dimethyl itaconate attenuates CFA-induced inflammatory pain via the NLRP3/ IL-1β signaling pathway. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2022.938979.CrossRefPubMedPubMedCentral

62.

Zhou, H., N. Li, Y. Yuan, et al. 2018. Activating transcription factor 3 in cardiovascular diseases: A potential therapeutic target. Basic Research in Cardiology. https://doi.org/10.1007/s00395-018-0698-6.CrossRefPubMed

63.

Ghosh, S., and M.S. Hayden. 2008. New regulators of NF-kappaB in inflammation. Nature Reviews Immunology. https://doi.org/10.1038/nri2423.CrossRefPubMed

64.

Kim, E.Y., H.Y. Shin, J.Y. Kim, et al. 2010. ATF3 plays a key role in Kdo2-lipid A-induced TLR4-dependent gene expression via NF-κB activation. PLoS ONE. https://doi.org/10.1371/journal.pone.0014181.CrossRefPubMedPubMedCentral

65.

Muromoto, R., T. Hirao, K. Tawa, et al. 2016. IL-17A plays a central role in the expression of psoriasis signature genes through the induction of IκB-ζ in keratinocytes. International Immunology. https://doi.org/10.1093/intimm/dxw011.CrossRefPubMed

66.

Johansen, C., M. Mose, P. Ommen, et al. 2015. IκBζ is a key driver in the development of psoriasis. Proceedings of the National Academy of Sciences USA. https://doi.org/10.1073/pnas.1509971112.CrossRef

67.

Okuma, A., K. Hoshino, T. Ohba, et al. 2013. Enhanced apoptosis by disruption of the STAT3-IκB-ζ signaling pathway in epithelial cells induces Sjögren’s syndrome-like autoimmune disease. Immunity. https://doi.org/10.1016/j.immuni.2012.11.016.CrossRefPubMed

68.

Tsoi, L.C., S.L. Spain, E. Ellinghaus, et al. 2015. Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci. Nature Communications. https://doi.org/10.1038/ncomms8001.CrossRefPubMed

69.

McNab, F., K. Mayer-Barber, A. Sher, et al. 2015. Type I interferons in infectious disease. Nature Reviews Immunology. https://doi.org/10.1038/nri3787.CrossRefPubMedPubMedCentral

70.

Olagnier, D., A.M. Brandtoft, C. Gunderstofte, et al. 2018. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nature Communications. https://doi.org/10.1038/s41467-018-05861-7.CrossRefPubMedPubMedCentral

71.

Olagnier, D., E. Farahani, J. Thyrsted, et al. 2020. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nature Communications. https://doi.org/10.1038/s41467-020-18764-3.CrossRefPubMedPubMedCentral

72.

Ryan, D. G., E. V. Knatko, A. M. Casey, et al. 2022. Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response. iScience. https://doi.org/10.1016/j.isci.2022.103827.

73.

De Souza, D.P., A. Achuthan, M.K. Lee, et al. 2019. Autocrine IFN-I inhibits isocitrate dehydrogenase in the TCA cycle of LPS-stimulated macrophages. The Journal of Clinical Investigation. https://doi.org/10.1172/jci127597.CrossRefPubMedPubMedCentral

74.

Russell, D.G., L. Huang, and B.C. VanderVen. 2019. Immunometabolism at the interface between macrophages and pathogens. Nature Reviews Immunology. https://doi.org/10.1038/s41577-019-0124-9.CrossRefPubMedPubMedCentral

75.

Sakai, A., A. Kusumoto, Y. Kiso, et al. 2004. Itaconate reduces visceral fat by inhibiting fructose 2,6-bisphosphate synthesis in rat liver. Nutrition. https://doi.org/10.1016/j.nut.2004.08.007.CrossRefPubMed

76.

Liao, S.T., C. Han, D.Q. Xu, et al. 2019. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects. Nature Communications. https://doi.org/10.1038/s41467-019-13078-5.CrossRefPubMedPubMedCentral

77.

Qin, W., K. Qin, Y. Zhang, et al. 2019. S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate. Nature Chemical Biology. https://doi.org/10.1038/s41589-019-0323-5.CrossRefPubMed

78.

Zhu, Z., T. Umehara, N. Tsujita, et al. 2020. Itaconate regulates the glycolysis/pentose phosphate pathway transition to maintain boar sperm linear motility by regulating redox homeostasis. Free Radical Biology & Medicine. https://doi.org/10.1016/j.freeradbiomed.2020.07.008.CrossRefPubMedCentral

79.

Wynn, T.A., and K.M. Vannella. 2016. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. https://doi.org/10.1016/j.immuni.2016.02.015.CrossRefPubMedPubMedCentral

80.

Ogger, P.P., G.J. Albers, R.J. Hewitt, et al. 2020. Itaconate controls the severity of pulmonary fibrosis. Sci Immunol. https://doi.org/10.1126/sciimmunol.abc1884.CrossRefPubMedPubMedCentral

81.

Han, Y.Y., X. Gu, C.Y. Yang, et al. 2021. Protective effect of dimethyl itaconate against fibroblast-myofibroblast differentiation during pulmonary fibrosis by inhibiting TXNIP. Journal of Cellular Physiology. https://doi.org/10.1002/jcp.30456.CrossRefPubMedPubMedCentral

82.

Henderson, J., S. Dayalan Naidu, A.T. Dinkova-Kostova, et al. 2021. The cell-permeable derivative of the immunoregulatory metabolite itaconate, 4-octyl itaconate, is anti-fibrotic in systemic sclerosis. Cells. https://doi.org/10.3390/cells10082053.CrossRefPubMedPubMedCentral

83.

Maassen, S., B. Coenen, M. Ioannidis, et al. 2023. Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages. Redox Biology. https://doi.org/10.1016/j.redox.2022.102591.CrossRefPubMed

84.

Ke, Q., C. Shi, Y. Lv, et al. 2022. SGLT2 inhibitor counteracts NLRP3 inflammasome via tubular metabolite itaconate in fibrosis kidney. The FASEB Journal. https://doi.org/10.1096/fj.202100909RR.CrossRefPubMed

85.

Italiani, P., and D. Boraschi. 2014. From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2014.00514.

86.

Faas, M., N. Ipseiz, J. Ackermann, et al. 2021. IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation. Immunity. https://doi.org/10.1016/j.immuni.2021.09.010.CrossRefPubMed

87.

Xiao, H., Y. Dong, D. Wan, et al. 2023. Injectable hydrogel loaded with 4-octyl itaconate enhances cartilage regeneration by regulating macrophage polarization. Biomater Sci. https://doi.org/10.1039/d2bm01894b.CrossRefPubMed

88.

Ganta, V.C., M.H. Choi, A. Kutateladze, et al. 2017. A MicroRNA93-interferon regulatory factor-9-immunoresponsive gene-1-itaconic acid pathway modulates M2-like macrophage polarization to revascularize ischemic muscle. Circulation. https://doi.org/10.1161/circulationaha.116.025490.CrossRefPubMedPubMedCentral

89.

Nelson, V.L., H.C.B. Nguyen, J.C. Garcìa-Cañaveras, et al. 2018. PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism. Genes & Development. https://doi.org/10.1101/gad.312355.118.CrossRefPubMedPubMedCentral

90.

Runtsch, M.C., S. Angiari, A. Hooftman, et al. 2022. Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages. Cell Metabolism. https://doi.org/10.1016/j.cmet.2022.02.002.CrossRefPubMed

91.

Hedrich, C.M., T. Rauen, S.A. Apostolidis, et al. 2014. Stat3 promotes IL-10 expression in lupus T cells through trans-activation and chromatin remodeling. Proceedings of the National Academy of Sciences USA. https://doi.org/10.1073/pnas.1408023111.CrossRef

92.

Blanco, L.P., E. Patino-Martinez, S. Nakabo, et al. 2022. Modulation of the itaconate pathway attenuates murine lupus. Arthritis & Rhematology. https://doi.org/10.1002/art.42284.CrossRef

93.

Nair, S., J. P. Huynh, V. Lampropoulou, et al. 2018. Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection. Journal of Experimental Medicine. https://doi.org/10.1084/jem.20180118.

94.

Chen, L.L., C. Morcelle, Z.L. Cheng, et al. 2022. Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses. Nature Cell Biology. https://doi.org/10.1038/s41556-022-00853-8.CrossRefPubMedPubMedCentral

95.

Cong, B., Q. Zhang, and X. Cao. 2021. The function and regulation of TET2 in innate immunity and inflammation. Protein & Cell. https://doi.org/10.1007/s13238-020-00796-6.CrossRefPubMedCentral

96.

Naujoks, J., C. Tabeling, B.D. Dill, et al. 2016. IFNs modify the proteome of legionella-containing vacuoles and restrict infection via IRG1-derived itaconic acid. PLoS Pathogens. https://doi.org/10.1371/journal.ppat.1005408.CrossRefPubMedPubMedCentral

97.

Ruetz, M., G.C. Campanello, M. Purchal, et al. 2019. Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair. Science. https://doi.org/10.1126/science.aay0934.CrossRefPubMedPubMedCentral

98.

Schuster, E.M., M.W. Epple, K.M. Glaser, et al. 2022. TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages. Nature Metabolism. https://doi.org/10.1038/s42255-022-00605-w.CrossRefPubMedPubMedCentral

99.

Zhang, Z., C. Chen, F. Yang, et al. 2022. Itaconate is a lysosomal inducer that promotes antibacterial innate immunity. Molecular Cell. https://doi.org/10.1016/j.molcel.2022.05.009.CrossRefPubMedPubMedCentral

100.

Spanò, S., and J.E. Galán. 2012. A Rab32-dependent pathway contributes to Salmonella typhi host restriction. Science. https://doi.org/10.1126/science.1229224.CrossRefPubMedPubMedCentral

101.

Scheurlen, K.M., A.T. Billeter, S.J. O’Brien, et al. 2020. Metabolic dysfunction and early-onset colorectal cancer - how macrophages build the bridge. Cancer Medicine. https://doi.org/10.1002/cam4.3315.CrossRefPubMedPubMedCentral

102.

Marcero, J.R., J.E. Cox, H.A. Bergonia, et al. 2021. The immunometabolite itaconate inhibits heme synthesis and remodels cellular metabolism in erythroid precursors. Blood Advances. https://doi.org/10.1182/bloodadvances.2021004750.CrossRefPubMedPubMedCentral

Title: Itaconate: A Potent Macrophage Immunomodulator
Authors: Zeyu Li
Wenbin Zheng
Wen Kong
Tianshu Zeng
Publication date: 04-05-2023
Publisher: Springer US
Keywords: Immunomodulator
Interferon
Published in: Inflammation / Issue 4/2023
Print ISSN: 0360-3997
Electronic ISSN: 1573-2576
DOI: https://doi.org/10.1007/s10753-023-01819-0

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Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

2024 ASCO Annual Meeting

Springer Medicine

Abstract

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Effect of the Non-steroidal Anti-inflammatory Drug Diclofenac on Ischemia–Reperfusion Injury in Rat Liver: A Nitric Oxide-Dependent Mechanism

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials