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Inflammation
Published in: Inflammation 1/2024

27-09-2023 | RESEARCH

Anti-Necroptotic Effects of Itaconate and its Derivatives

Authors: Si-tao Ni, Qing Li, Ying Chen, Fu-li Shi, Tak-sui Wong, Li-sha Yuan, Rong Xu, Ying-qing Gan, Na Lu, Ya-ping Li, Zhi-ya Zhou, Li-hui Xu, Xian-hui He, Bo Hu, Dong-yun Ouyang

Published in: Inflammation | Issue 1/2024

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Abstract

Itaconate is an unsaturated dicarboxylic acid that is derived from the decarboxylation of the Krebs cycle intermediate cis-aconitate and has been shown to exhibit anti-inflammatory and anti-bacterial/viral properties. But the mechanisms underlying itaconate’s anti-inflammatory activities are not fully understood. Necroptosis, a lytic form of regulated cell death (RCD), is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) signaling. It has been involved in the pathogenesis of organ injury in many inflammatory diseases. In this study, we aimed to explore whether itaconate and its derivatives can inhibit necroptosis in murine macrophages, a mouse MPC-5 cell line and a human HT-29 cell line in response to different necroptotic activators. Our results showed that itaconate and its derivatives dose-dependently inhibited necroptosis, among which dimethyl itaconate (DMI) was the most effective one. Mechanistically, itaconate and its derivatives inhibited necroptosis by suppressing the RIPK1/RIPK3/MLKL signaling and the oligomerization of MLKL. Furthermore, DMI promoted the nuclear translocation of Nrf2 that is a critical regulator of intracellular redox homeostasis, and reduced the levels of intracellular reactive oxygen species (ROS) and mitochondrial superoxide (mtROS) that were induced by necroptotic activators. Consistently, DMI prevented the loss of mitochondrial membrane potential induced by the necroptotic activators. In addition, DMI mitigated caerulein-induced acute pancreatitis in mice accompanied by reduced activation of the necroptotic signaling in vivo. Collectively, our study demonstrates that itaconate and its derivatives can inhibit necroptosis by suppressing the RIPK1/RIPK3/MLKL signaling, highlighting their potential applications for treating necroptosis-associated diseases.
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Literature
1.
Michelucci, A., T. Cordes, J. Ghelfi, et al. 2013. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production [J]. Proceedings of the National Academy of Sciences of the United States of America 110 (19): 7820–7825.PubMedPubMedCentralCrossRef
2.
Zhang, P., Y. Wang, W. Yang, et al. 2022. 4-octyl itaconate regulates immune balance by activating Nrf2 and negatively regulating PD-L1 in a mouse model of sepsis [J]. International journal of biological sciences 18 (16): 6189–6209.PubMedPubMedCentralCrossRef
3.
Bambouskova, M., L. Gorvel, V. Lampropoulou, et al. 2018. Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis [J]. Nature 556 (7702): 501–504.PubMedPubMedCentralCrossRef
4.
Ogger P.P, G.J. Albers, R.J. Hewitt, et al. 2020. Itaconate controls the severity of pulmonary fibrosis [J]. Science Immunology 5 (52).
5.
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 [J]. Nature communications 11 (1): 4938.PubMedPubMedCentralCrossRef
6.
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 [J]. Hepatology (Baltimore, MD) 72 (4): 1394–1411.PubMedCrossRef
7.
Song, H., T. Xu, X. Feng, et al. 2020. Itaconate prevents abdominal aortic aneurysm formation through inhibiting inflammation via activation of Nrf2 [J]. eBioMedicine 57: 102832.PubMedPubMedCentralCrossRef
8.
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 [J]. Cellular physiology and biochemistry : International journal of experimental cellular physiology, biochemistry, and pharmacology 51 (2): 979–990.PubMedCrossRef
9.
Hooftman, A., S. Angiari, S. Hester, et al. 2020. The immunomodulatory metabolite itaconate modifies NLRP3 and inhibits inflammasome activation [J]. Cell metabolism 32 (3): 468–78.e7.PubMedPubMedCentralCrossRef
10.
Liu, Y., L. Song, N. Zheng, et al. 2022. A urinary proteomic landscape of COVID-19 progression identifies signaling pathways and therapeutic options [J]. Science China Life sciences 65 (9): 1866–1880.PubMedPubMedCentralCrossRef
11.
Xie, Y., Z. Chen, and Z. Wu. 2022. Four-octyl itaconate attenuates UVB-induced melanocytes and keratinocytes apoptosis by Nrf2 activation-dependent ROS inhibition [J]. Oxidative medicine and cellular longevity 2022: 9897442.PubMedPubMedCentralCrossRef
12.
He, R., B. Liu, R. Xiong, et al. 2022. Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury [J]. Cell death discovery 8 (1): 43.PubMedPubMedCentralCrossRef
13.
Shan, Q., X. Li, M. Zheng, et al. 2019. Protective effects of dimethyl itaconate in mice acute cardiotoxicity induced by doxorubicin [J]. Biochemical and biophysical research communications 517 (3): 538–544.PubMedCrossRef
14.
Jiao, H., L. Wachsmuth, S. Kumari, et al. 2020. Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation [J]. Nature 580 (7803): 391–395.PubMedPubMedCentralCrossRef
15.
Degterev, A., Z. Huang, M. Boyce, et al. 2005. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury [J]. Nature chemical biology 1 (2): 112–119.PubMedCrossRef
16.
Chen, X., W. Li, J. Ren, et al. 2014. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death [J]. Cell Research 24 (1): 105–121.PubMedCrossRef
17.
Sun, L., H. Wang, Z. Wang, et al. 2012. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase [J]. Cell 148 (1–2): 213–227.PubMedCrossRef
18.
Zhao, J., S. Jitkaew, Z. Cai, et al. 2012. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis [J]. Proceedings of the National Academy of Sciences of the United States of America 109 (14): 5322–5327.PubMedPubMedCentralCrossRef
19.
Vandenabeele, P., L. Galluzzi, T. Vanden Berghe, et al. 2010. Molecular mechanisms of necroptosis: an ordered cellular explosion [J]. Nature reviews Molecular cell biology 11 (10): 700–714.PubMedCrossRef
20.
Tenev, T., K. Bianchi, M. Darding, et al. 2011. The ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs [J]. Molecular cell 43 (3): 432–448.PubMedCrossRef
21.
Mccomb, S., B. Shutinoski, S. Thurston, et al. 2014. Cathepsins limit macrophage necroptosis through cleavage of Rip1 kinase [J]. Journal of immunology (Baltimore, Md : 1950) 192 (12): 5671–8.
22.
Degterev, A., J. Hitomi, M. Germscheid, et al. 2008. Identification of RIP1 kinase as a specific cellular target of necrostatins [J]. Nature Chemical Biology 4 (5): 313–321.PubMedPubMedCentralCrossRef
23.
Li, D., J. Chen, J. Guo, et al. 2021. A phosphorylation of RIPK3 kinase initiates an intracellular apoptotic pathway that promotes prostaglandin(2α)-induced corpus luteum regression [J]. eLife 10.
24.
Murphy, J.M., P.E. Czabotar, J.M. Hildebrand, et al. 2013. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism [J]. Immunity 39 (3): 443–453.PubMedCrossRef
25.
Dondelinger, Y., W. Declercq, S. Montessuit, et al. 2014. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates [J]. Cell reports 7 (4): 971–981.PubMedCrossRef
26.
Quarato, G., C.S. Guy, C.R. Grace, et al. 2016. Sequential engagement of distinct MLKL phosphatidylinositol-binding sites executes necroptosis [J]. Molecular cell 61 (4): 589–601.PubMedPubMedCentralCrossRef
27.
Karki, R., B.R. Sharma, S. Tuladhar, et al. 2021. Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes [J]. Cell 184 (1): 149–68.e17.PubMedCrossRef
28.
29.
Cao, L., and W. Mu. 2021. Necrostatin-1 and necroptosis inhibition: pathophysiology and therapeutic implications [J]. Pharmacological research 163: 105297.PubMedCrossRef
30.
Cuchet-Lourenço, D., D. Eletto, C. Wu, et al. 2018. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation [J]. Science (New York, NY) 361 (6404): 810–813.CrossRef
31.
Shi, F.L., L.S. Yuan, T.S. Wong, et al. 2023. Dimethyl fumarate inhibits necroptosis and alleviates systemic inflammatory response syndrome by blocking the RIPK1-RIPK3-MLKL axis [J]. Pharmacological research 189: 106697.PubMedCrossRef
32.
Huang, Y.T., Q.Q. Liang, H.R. Zhang, et al. 2022. Baicalin inhibits necroptosis by decreasing oligomerization of phosphorylated MLKL and mitigates caerulein-induced acute pancreatitis in mice [J]. International Immunopharmacology 108: 108885.PubMedCrossRef
33.
Shi, F.L., S.T. Ni, S.Q. Luo, et al. 2022. Dimethyl fumarate ameliorates autoimmune hepatitis in mice by blocking NLRP3 inflammasome activation [J]. International Immunopharmacology 108: 108867.PubMedCrossRef
34.
Li, C.G., Q.Z. Zeng, M.Y. Chen, et al. 2019. Evodiamine augments NLRP3 inflammasome activation and anti-bacterial responses through inducing α-tubulin acetylation [J]. Frontiers in pharmacology 10: 290.PubMedPubMedCentralCrossRef
35.
Zeng, B., Y. Huang, S. Chen, et al. 2022. Dextran sodium sulfate potentiates NLRP3 inflammasome activation by modulating the KCa3.1 potassium channel in a mouse model of colitis [J]. Cellular & Molecular Immunology 19 (8): 925–43.
36.
Wu, J., Z. Huang, J. Ren, et al. 2013. Mlkl knockout mice demonstrate the indispensable role of mlkl in necroptosis [J]. Cell Research 23 (8): 994–1006.PubMedPubMedCentralCrossRef
37.
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 [J]. Journal of cellular physiology 236 (11): 7734–7744.PubMedCrossRef
38.
Bertheloot, D., E. Latz, and B.S. Franklin. 2021. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death [J]. Cellular & molecular immunology 18 (5): 1106–1121.CrossRef
39.
Baird, L., and M. Yamamoto, 2020. The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway [J]. Molecular and Cellular Biology 40 (13).
40.
Louhimo, J., M.L. Steer, and G. Perides. 2016. Necroptosis is an important severity determinant and potential therapeutic target in experimental severe pancreatitis [J]. Cellular and molecular gastroenterology and hepatology 2 (4): 519–535.PubMedPubMedCentralCrossRef
41.
Li, M., Y. Yuan, X. Han, et al. 2022. Antioxidant mitoquinone alleviates chronic pancreatitis via anti-fibrotic and antioxidant effects [J]. Journal of inflammation research 15: 4409–4420.PubMedPubMedCentralCrossRef
42.
Marciniak, A., B. Walczyna, G. Rajtar, et al. 2016. Tempol, a membrane-permeable radical scavenger, exhibits anti-inflammatory and cardioprotective effects in the cerulein-induced pancreatitis rat model [J]. Oxidative medicine and cellular longevity 2016: 4139851.PubMedCrossRef
43.
Yu, J.H., J.W. Lim, W. Namkung, et al. 2002. Suppression of cerulein-induced cytokine expression by antioxidants in pancreatic acinar cells [J]. Laboratory Investigation: A Journal of Technical Methods and Pathology 82 (10): 1359–68.
44.
Shi, J., and C. Cai. 2022. Research Progress on the mechanism of itaconate regulating macrophage immunometabolism [J]. Frontiers in immunology 13: 937247.PubMedPubMedCentralCrossRef
45.
Peace, C.G., and L.A. O'neill. 2022. The role of itaconate in host defense and inflammation [J]. The Journal of Clinical Investigation 132 (2).
46.
Hooftman, A., and L.A.J. O'Neill. 2019. The Immunomodulatory Potential of the Metabolite Itaconate [J]. Trends in Immunology 40 (8): 687–98.
47.
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 [J]. Nature metabolism 2 (7): 594–602.PubMedPubMedCentralCrossRef
48.
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 [J]. Nature 556 (7699): 113–117.PubMedPubMedCentralCrossRef
49.
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 [J]. iScience 25 (2): 103827.
50.
Waqas, S.F., A. Sohail, A.H.H. Nguyen, et al. 2022. ISG15 deficiency features a complex cellular phenotype that responds to treatment with itaconate and derivatives [J]. Clinical and translational medicine 12 (7): e931.PubMedPubMedCentralCrossRef
51.
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 [J]. Nature communications 10 (1): 5091.PubMedPubMedCentralCrossRef
52.
Qin, W., K. Qin, Y. Zhang, et al. 2019. S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate [J]. Nature Chemical Biology 15 (10): 983–991.PubMedCrossRef
53.
Qin, W., Y. Zhang, H. Tang, et al. 2020. Chemoproteomic profiling of itaconation by bioorthogonal probes in inflammatory macrophages [J]. Journal of the American Chemical Society 142 (25): 10894–10898.PubMedCrossRef
54.
Bambouskova, M., L. Potuckova, T. Paulenda, et al. 2021. Itaconate confers tolerance to late NLRP3 inflammasome activation [J]. Cell reports 34 (10): 108756.PubMedCrossRef
55.
Yang, W., Y. Wang, Y. Huang, et al. 2023. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer [J]. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 159 : 114301.
56.
Van Herreweghe, F., N. Festjens, W. Declercq, et al. 2010. Tumor necrosis factor-mediated cell death: to break or to burst, that’s the question [J]. Cellular and Molecular Life Sciences 67 (10): 1567–1579.PubMedCrossRef
57.
Zhang, Y., S.S. Su, S. Zhao, et al. 2017. RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome [J]. Nature communications 8: 14329.PubMedPubMedCentralCrossRef
58.
Yang, Z., Y. Wang, Y. Zhang, et al. 2018. RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis [J]. Nature cell biology 20 (2): 186–197.PubMedCrossRef
59.
Qiu, X., Y. Zhang, and J. Han. 2018. RIP3 is an upregulator of aerobic metabolism and the enhanced respiration by necrosomal RIP3 feeds back on necrosome to promote necroptosis [J]. Cell death and differentiation 25 (5): 821–824.PubMedPubMedCentral
60.
Sohail, A., A.A. Iqbal, N. Sahini, et al. 2022. Itaconate and derivatives reduce interferon responses and inflammation in influenza a virus infection [J]. PLoS pathogens 18 (1): e1010219.PubMedPubMedCentralCrossRef
61.
Lin, Y., S. Choksi, H.M. Shen, et al. 2004. Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation [J]. The Journal of biological chemistry 279 (11): 10822–10828.PubMedCrossRef
62.
Kamata, H., S. Honda, S. Maeda, et al. 2005. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases [J]. Cell 120 (5): 649–661.PubMedCrossRef
63.
Lampropoulou, V., A. Sergushichev, M. Bambouskova, et al. 2016. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation [J]. Cell metabolism 24 (1): 158–166.PubMedPubMedCentralCrossRef
64.
Cordes, T., M. Wallace, A. Michelucci, et al. 2016. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels [J]. The Journal of biological chemistry 291 (27): 14274–14284.PubMedPubMedCentralCrossRef
65.
Huang, S., and A.H. Millar. 2013. Succinate dehydrogenase: the complex roles of a simple enzyme [J]. Current opinion in plant biology 16 (3): 344–349.PubMedCrossRef
66.
Billingham, L.K., J.S. Stoolman, K. Vasan, et al. 2022. Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation [J]. Nature immunology 23 (5): 692–704.PubMedPubMedCentralCrossRef
67.
Wang, Y.P., A. Sharda, S.N. Xu, et al. 2021. Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis [J]. Cell metabolism 33 (5): 1027–41.e8.PubMedPubMedCentralCrossRef
68.
Hooftman, A., C.G. Peace, D.G. Ryan, et al. 2023. Macrophage fumarate hydratase restrains mtRNA-mediated interferon production [J]. Nature 615 (7952): 490–498.PubMedPubMedCentralCrossRef
69.
Spinelli, J.B., P.C. Rosen, H.G. Sprenger, et al. 2021. Fumarate is a terminal electron acceptor in the mammalian electron transport chain [J]. Science (New York, NY) 374 (6572): 1227–1237.CrossRef
70.
Leppäniemi, A., M. Tolonen, A. Tarasconi, et al. 2019. 2019 WSES guidelines for the management of severe acute pancreatitis [J]. World journal of emergency surgery : WJES 14: 27.PubMedPubMedCentralCrossRef
71.
Kuo, P.C., W.T. Weng, B.A. Scofield, et al. 2020. Dimethyl itaconate, an itaconate derivative, exhibits immunomodulatory effects on neuroinflammation in experimental autoimmune encephalomyelitis [J]. Journal of neuroinflammation 17 (1): 138.PubMedPubMedCentralCrossRef
Metadata
Title
Anti-Necroptotic Effects of Itaconate and its Derivatives
Authors
Si-tao Ni
Qing Li
Ying Chen
Fu-li Shi
Tak-sui Wong
Li-sha Yuan
Rong Xu
Ying-qing Gan
Na Lu
Ya-ping Li
Zhi-ya Zhou
Li-hui Xu
Xian-hui He
Bo Hu
Dong-yun Ouyang
Publication date
27-09-2023
Publisher
Springer US
Published in
Inflammation / Issue 1/2024
Print ISSN: 0360-3997
Electronic ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-023-01909-z

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