Skip to main content
SpringerLink
Log in

Immune Response Gene-1 [IRG1]/itaconate protect against multi-organ injury via inhibiting gasdermin D-mediated pyroptosis and inflammatory response

  • Original Article
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

Sepsis is a multiple organ dysfunction syndrome due to a dysregulated response to infection with unacceptably high mortality. Currently, no effective treatment exists for sepsis. IRG1/itaconate has been considered to play a protective role for various inflammatory diseases. In the present study, we explored the protective role and mechanisms of IRG1/itaconate on lipopolysaccharide (LPS)-induced multi-organ injury. The LPS-induced sepsis model was used. IRG1−/− and wild type mice were used to explore the protective role of IRG1/itaconate on multi-organ injury. GSDMD−/− mice were used to explore the effect of GSDMD-mediated pyroptosis on LPS-induced model. RAW264.7 cells and bone-marrow-derived macrophages (BMDMs) were used for in vitro studies. In vivo experiments, we found IRG1 deficiency aggravated LPS-induced multi-organ injury especially lung injury. 4-Octyl itaconate (4-OI), a derivative of itaconate, significantly ameliorated LPS-induced acute lung, liver, and kidney injury. Furthermore, IRG1/4-OI decreased serum interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α) level, macrophage infiltration, and TUNEL-positive cells in lung and liver tissue. Western blot showed IRG1/itaconate decreased the expressions of p-ERK, p-P38, p-JNK, and p-P65 and increased the expression of Nrf2/HO-1 in lung tissue. Meanwhile, 4-OI inhibited the expression of GSDMD-N. In vitro experiments, 4-OI inhibited ROS production and promoted apoptosis under LPS stimulation in RAW264.7 cells. Furthermore, 4-OI inhibited nuclear factor-kappaB/mitogen-activated protein kinase pathways and GSDMD-medicated pyroptosis in BMDMs. Finally, we used GSDMD−/− mice to explore the effect of pyroptosis on LPS-induced multi-organ injury. The results showed that GSDMD deficiency significantly ameliorated lung injury. In conclusion, our data demonstrated that IRG1/itaconate protect against multi-organ injury via inhibiting inflammation response and GSDMD-indicated pyroptosis, which may be a promising agent for protecting against sepsis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The data used to support the findings of this study are available from the corresponding authors upon request.

Abbreviations

BMDMs:

Bone-marrow-derived macrophages

GSDMD-N:

N-terminal domain of GSDMD

LPS:

Lipopolysaccharide

IL-1β:

Interleukin-1β

IRG1:

Immune responsive gene 1

MAPK:

Mitogen-activated protein kinase

NF-κb:

Nuclear factor kappaB

NLRP3:

NOD-like receptor protein 3

Nrf2:

Nuclear factor erythroid 2-related factor 2

ROS:

Reactive oxygen species

TLR4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor-α

4-OI:

4-Octyl itaconate

References

  • Ahmad FM, AAB M, Bani Hani A, Abu Abeeleh M, Abu-Humaidan AHA (2022) Complement Terminal Pathway Activation is Associated with Organ Failure in Sepsis Patients. J Inflammat Res 15:153–162

    Article  Google Scholar 

  • Ahmed SM, Luo L, Namani A, Wang XJ, Tang X (2017) Nrf2 signaling pathway: Pivotal roles in inflammation. Biochim Biophys Acta 1863(2):585–597

    Article  CAS  Google Scholar 

  • An Y, Zhang H, Wang C et al (2019) Activation of ROS/MAPKs/NF-κB/NLRP3 and inhibition of efferocytosis in osteoclast-mediated diabetic osteoporosis. FASEB J off Publ Fed Am Soc Exp Biol 33(11):12515–12527

    CAS  Google Scholar 

  • Babolmorad G, Latif A, Domingo IK et al (2021) Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity. EMBO Rep 22(5):e51280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bauer M, Gerlach H, Vogelmann T, Preissing F, Stiefel J, Adam D (2020) Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019- results from a systematic review and meta-analysis. Critical Care (london, England) 24(1):239

    Article  PubMed  Google Scholar 

  • Brink A, Alsma J, Verdonschot R et al (2019) Predicting mortality in patients with suspected sepsis at the Emergency Department; A retrospective cohort study comparing qSOFA, SIRS and National Early Warning Score. PLoS ONE 14(1):e0211133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burdette BE, Esparza AN, Zhu H, Wang S (2021) Gasdermin D in pyroptosis. Acta Pharmaceutica Sinica b 11(9):2768–2782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cadenas S (2018) ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radical Biol Med 117:76–89

    Article  CAS  Google Scholar 

  • Cecconi M, Evans L, Levy M, Rhodes A (2018) Sepsis and septic shock. Lancet (london, England) 392(10141):75–87

    Article  PubMed  Google Scholar 

  • Cochet F, Peri F (2017) The Role of Carbohydrates in the Lipopolysaccharide (LPS)/Toll-Like Receptor 4 (TLR4) Signalling. Int J Mol Sci 18:11

    Article  Google Scholar 

  • Deng C, Zhao L, Yang Z et al (2022) Targeting HMGB1 for the treatment of sepsis and sepsis-induced organ injury. Acta Pharmacol Sin 43(3):520–528

    Article  CAS  PubMed  Google Scholar 

  • Efferth T, Oesch F (2021) The immunosuppressive activity of artemisinin-type drugs towards inflammatory and autoimmune diseases. Med Res Rev 41(6):3023–3061

    Article  CAS  PubMed  Google Scholar 

  • Gambhir L, Checker R, Thoh M et al (2014) 1,4-Naphthoquinone, a pro-oxidant, suppresses immune responses via KEAP-1 glutathionylation. Biochem Pharmacol 88(1):95–105

    Article  CAS  PubMed  Google Scholar 

  • Gao F, Qian M, Liu G, Ao W, Dai D, Yin C (2021) USP10 alleviates sepsis-induced acute kidney injury by regulating Sirt6-mediated Nrf2/ARE signaling pathway. Journal of Inflammation (london, England) 18(1):25

    Article  CAS  PubMed  Google Scholar 

  • Ge X, Tang P, Rong Y et al (2021) Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-κB signaling pathway in vascular endothelial cells after traumatic spinal cord injury. Redox Biol 41:101932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henderson J, Dayalan Naidu S, Dinkova-Kostova AT, Przyborski S, Stratton R, Or S (2021) The Cell-Permeable Derivative of the Immunoregulatory Metabolite Itaconate, 4-Octyl Itaconate. Is Anti-Fibrotic in Systemic Sclerosis. Cells 10:8

    Article  Google Scholar 

  • Hong MK, Hu LL, Zhang YX et al (2020) 6-Gingerol ameliorates sepsis-induced liver injury through the Nrf2 pathway. Int Immunopharmacol 80:106196

    Article  CAS  PubMed  Google Scholar 

  • Hooftman A, Angiari S, Hester S et al (2020) The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation. Cell Metab 32(3):468-478.e467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu Q, Zhang W, Wu Z et al (2021) Baicalin and the liver-gut system: Pharmacological bases explaining its therapeutic effects. Pharmacol Res 165:105444

    Article  CAS  PubMed  Google Scholar 

  • Kang R, Zeng L, Zhu S et al (2018) Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis. Cell Host Microbe 24(1):97-108.e104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SR, Ha YM, Kim YM et al (2015) Ascorbic acid reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and improves survival rate in septic mice by activation of Nrf2/HO-1 signals. Biochem Pharmacol 95(4):279–289

    Article  CAS  PubMed  Google Scholar 

  • Lelubre C, Vincent JL (2018) Mechanisms and treatment of organ failure in sepsis. Nat Rev Nephrol 14(7):417–427

    Article  PubMed  Google Scholar 

  • Li MY, Zhu XL, Zhao BX et al (2019a) Adrenomedullin alleviates the pyroptosis of Leydig cells by promoting autophagy via the ROS-AMPK-mTOR axis. Cell Death Dis 10(7):489

    Article  PubMed  PubMed Central  Google Scholar 

  • Li Z, Jia Y, Feng Y et al (2019b) Methane alleviates sepsis-induced injury by inhibiting pyroptosis and apoptosis: in vivo and in vitro experiments. Aging 11(4):1226–1239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li N, Wang W, Zhou H et al (2020a) Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury. Free Radical Biol Med 160:303–318

    Article  CAS  Google Scholar 

  • Li Y, Chen X, Zhang H et al (2020b) 4-Octyl Itaconate Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice by Inhibiting Oxidative Stress and Inflammation. Drug Des Dev Ther 14:5547–5558

    Article  CAS  Google Scholar 

  • Li R, Yu L, Qin Y et al (2021a) Protective effects of rare earth lanthanum on acute ethanol-induced oxidative stress in mice via Keap 1/Nrf2/p62 activation. The Science of the Total Environment 758:143626

    Article  ADS  CAS  PubMed  Google Scholar 

  • Li G, Zhang P, You Y et al (2021b) Qiangjing Tablets Regulate Apoptosis and Oxidative Stress via Keap/Nrf2 Pathway to Improve the Reproductive Function in Asthenospermia Rats. Front Pharmacol 12:714892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin Q, Li S, Jiang N et al (2019) PINK1-parkin pathway of mitophagy protects against contrast-induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation. Redox Biol 26:101254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liochev SI (2013) Reactive oxygen species and the free radical theory of aging. Free Radical Biol Med 60:1–4

    Article  CAS  Google Scholar 

  • Liu Z, Yao X, Sun B et al (2021) Pretreatment with kaempferol attenuates microglia-mediate neuroinflammation by inhibiting MAPKs-NF-κB signaling pathway and pyroptosis after secondary spinal cord injury. Free Radical Biol Med 168:142–154

    Article  CAS  Google Scholar 

  • Mills EL, Ryan DG, Prag HA et al (2018) Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556(7699):113–117

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Newton K, Dixit VM, Kayagaki N (2021) Dying cells fan the flames of inflammation. Science (new York, NY) 374(6571):1076–1080

    Article  ADS  CAS  Google Scholar 

  • Ren Q, Guo F, Tao S, Huang R, Ma L, Fu P (2020) Flavonoid fisetin alleviates kidney inflammation and apoptosis via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways in septic AKI mice. Biomed Pharm Biomed Pharm 122:109772

    Article  CAS  Google Scholar 

  • Song P, Shen DF, Meng YY et al (2020) Geniposide protects against sepsis-induced myocardial dysfunction through AMPKα-dependent pathway. Free Radical Biol Med 152:186–196

    Article  CAS  Google Scholar 

  • Tu W, Wang H, Li S, Liu Q, Sha H (2019) The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases. Aging Dis 10(3):637–651

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang Q, Li XL, Mei Y et al (2020) The anti-inflammatory drug dimethyl itaconate protects against colitis-associated colorectal cancer. J Mol Med (berl) 98(10):1457–1466

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Zhang H, Qi W et al (2018) Nicotine promotes atherosclerosis via ROS-NLRP3-mediated endothelial cell pyroptosis. Cell Death Dis 9(2):171

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu R, Chen F, Wang N, Tang D, Kang R (2020) ACOD1 in immunometabolism and disease. Cell Mol Immunol 17(8):822–833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu B, Jiang M, Chu Y et al (2018) Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice. J Hepatol 68(4):773–782

    Article  CAS  PubMed  Google Scholar 

  • Yang W, Tao K, Zhang P, Chen X, Sun X, Li R (2022a) Maresin 1 protects against lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting macrophage pyroptosis and inflammatory response. Biochem Pharmacol 195:114863

    Article  CAS  PubMed  Google Scholar 

  • Yang W, Wang Y, Zhang P et al (2022b) 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 Biol Med 182:108–118

    Article  CAS  Google Scholar 

  • Youm YH, Nguyen KY, Grant RW et al (2015) The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 21(3):263–269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu C, Xiao JH (2021) The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging. Oxid Med Cell Longev 2021:6635460

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang S, Jiao Y, Li C et al (2021) Dimethyl Itaconate Alleviates the Inflammatory Responses of Macrophages in Sepsis. Inflammation 44(2):549–557

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (No. 81701883, 82072736, and 82172171) and Science Foundation of Union Hospital (2022xhyn051).

Author information

Author notes

  1. Wenchang Yang, Yaxin Wang, and Yongzhou Huang contributed equally to this paper.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China

    Wenchang Yang, Yongzhou Huang, Tao Wang, Chengguo Li, Peng Zhang, Weizhen Liu, Yuping Yin, Ruidong Li & Kaixiong Tao

  2. Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Yaxin Wang

  3. Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, People’s Republic of China

    Yongzhou Huang

Authors
  1. Wenchang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yaxin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yongzhou Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chengguo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weizhen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuping Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ruidong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kaixiong Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors helped to perform the research; WY: conceptualization, data curation, investigation, software, roles/writing—original draft. YW: methodology, validation, funding acquisition. YH: formal analysis. TW: validation. CL: formal analysis. PZ: methodology, validation. WL: methodology, resources, supervision. YY: methodology, validation, supervision. RL: funding acquisition, project administration, resources, supervision, visualization, writing—review and editing. KT: funding acquisition, project administration, resources, supervision, visualization, writing—review and editing. All authors approved the final version for publication.

Corresponding authors

Correspondence to Ruidong Li or Kaixiong Tao.

Ethics declarations

Conflict of interests

The authors declare that they have no competing interests.

Ethics approval

This study was approved by the Institutional Animal Use and Care Committee of Huazhong University of Science and Technology.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, W., Wang, Y., Huang, Y. et al. Immune Response Gene-1 [IRG1]/itaconate protect against multi-organ injury via inhibiting gasdermin D-mediated pyroptosis and inflammatory response. Inflammopharmacol 32, 419–432 (2024). https://doi.org/10.1007/s10787-023-01278-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-023-01278-x

Keywords

Search

Navigation