The Cell Autonomous and Non-autonomous Roles of Itaconate in Immune Response

Overview

Journal Cell Insight

Date 2025 Jan 29

PMID 39877254

Authors

Chao Chen

Xinjian Li

Affiliations

Soon will be listed here.

Abstract

Itaconate which is discovered as a mammalian metabolite possessing antimicrobial and immunoregulatory activity has attracted much attention in the field of immunometabolism. Itaconate is synthesized by myeloid cells under conditions of pathogen infection and sterile inflammation. In addition to regulating immune response of myeloid cells, itaconate secreted from myeloid cells can also be taken up by non-myeloid cells to exert immunoregulatory effects in a cell non-autonomous manner. In this review, we recap the discovery of itaconate as a distinct immunologic regulator and effector, describe the development of itaconate biosensor, and detail the recent findings that decipher the mechanism underlying intercellular transport of itaconate. Based on these knowledges, we propose itaconate is a messenger transmitting immunologic signals from myeloid cells to other types of cells during host inflammation and immune defense.

References

Okabe M, Lies D, Kanamasa S, Park E . Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl Microbiol Biotechnol. 2009; 84(4):597-606. DOI: 10.1007/s00253-009-2132-3. View

Daniels B, Kofman S, Smith J, Norris G, Snyder A, Kolb J . 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. PMC: 6342485. DOI: 10.1016/j.immuni.2018.11.017. View

Mills E, Ryan D, Prag H, Dikovskaya D, Menon D, Zaslona Z . Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature. 2018; 556(7699):113-117. PMC: 6047741. DOI: 10.1038/nature25986. View

Cordes T, Wallace M, Michelucci A, Divakaruni A, Sapcariu S, Sousa C . Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels. J Biol Chem. 2016; 291(27):14274-14284. PMC: 4933182. DOI: 10.1074/jbc.M115.685792. View

Weiss J, Davies L, Karwan M, Ileva L, Ozaki M, Cheng R . Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors. J Clin Invest. 2018; 128(9):3794-3805. PMC: 6118601. DOI: 10.1172/JCI99169. View

Wang S, Adler J, LARDY H . The pathway of itaconate metabolism by liver mitochondria. J Biol Chem. 1961; 236:26-30. View

Chen M, Sun H, Boot M, Shao L, Chang S, Wang W . Itaconate is an effector of a Rab GTPase cell-autonomous host defense pathway against . Science. 2020; 369(6502):450-455. PMC: 8020367. DOI: 10.1126/science.aaz1333. View

Ruetz M, Campanello G, Purchal M, Shen H, Mcdevitt L, Gouda H . Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair. Science. 2019; 366(6465):589-593. PMC: 7070230. DOI: 10.1126/science.aay0934. View

Chen C, Liu C, Sun P, Zhang Z, Wang Z, Liu P . Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity. Dev Cell. 2024; 59(21):2807-2817.e8. DOI: 10.1016/j.devcel.2024.07.011. View

10.

Sun P, Zhang Z, Wang B, Liu C, Chen C, Liu P . A genetically encoded fluorescent biosensor for detecting itaconate with subcellular resolution in living macrophages. Nat Commun. 2022; 13(1):6562. PMC: 9636186. DOI: 10.1038/s41467-022-34306-5. View

11.

Su C, Cheng T, Huang J, Zhang T, Yin H . 4-Octyl itaconate restricts STING activation by blocking its palmitoylation. Cell Rep. 2023; 42(9):113040. DOI: 10.1016/j.celrep.2023.113040. View

12.

Bambouskova M, Potuckova L, Paulenda T, Kerndl M, Mogilenko D, Lizotte K . Itaconate confers tolerance to late NLRP3 inflammasome activation. Cell Rep. 2021; 34(10):108756. PMC: 8039864. DOI: 10.1016/j.celrep.2021.108756. View

13.

Gu X, Wei H, Suo C, Shen S, Zhu C, Chen L . Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8 T-cell exhaustion. Nat Commun. 2023; 14(1):8154. PMC: 10710408. DOI: 10.1038/s41467-023-43988-4. View

14.

OCarroll S, Peace C, Toller-Kawahisa J, Min Y, Hooftman A, Charki S . Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase. Nat Metab. 2024; 6(11):2060-2069. DOI: 10.1038/s42255-024-01145-1. View

15.

Chen F, Lukat P, Iqbal A, Saile K, Kaever V, van den Heuvel J . Crystal structure of -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. PMC: 6789909. DOI: 10.1073/pnas.1908770116. View

16.

Zhao Y, Liu Z, Liu G, Zhang Y, Liu S, Gan D . Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab. 2023; 35(10):1688-1703.e10. PMC: 10558089. DOI: 10.1016/j.cmet.2023.09.004. View

17.

Hooftman A, Angiari S, Hester S, Corcoran S, Runtsch M, Ling C . The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation. Cell Metab. 2020; 32(3):468-478.e7. PMC: 7422798. DOI: 10.1016/j.cmet.2020.07.016. View

18.

Liao S, Han C, Xu D, Fu X, Wang J, Kong L . 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects. Nat Commun. 2019; 10(1):5091. PMC: 6841710. DOI: 10.1038/s41467-019-13078-5. View

19.

Sohail A, Iqbal A, Sahini N, Chen F, Tantawy M, Waqas S . Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection. PLoS Pathog. 2022; 18(1):e1010219. PMC: 8846506. DOI: 10.1371/journal.ppat.1010219. View

20.

Chen Y, Li G, Li X, Wei L, Fu M, Cheng Z . Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy. Sci Adv. 2023; 9(17):eadg0654. PMC: 10146892. DOI: 10.1126/sciadv.adg0654. View