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Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway

  • Authors:
    • Su Yang
    • Xingxing Zhang
    • Hengli Zhang
    • Xiangxiang Lin
    • Xijun Chen
    • Ying Zhang
    • Xiao Lin
    • Lijie Huang
    • Qichuan Zhuge
  • View Affiliations / Copyright

    Affiliations: Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Operation Room, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
    Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 672
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    Published online on: July 21, 2021
       https://doi.org/10.3892/mmr.2021.12311
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Abstract

The endogenous metabolite itaconate and its cell‑permeable derivative dimethyl itaconate (DI) have been identified as anti‑inflammatory regulators of macrophages; however, their contribution to inflammasome‑mediated pyroptosis remains unknown. The present study examined the molecular mechanism of DI on NLR family pyrin domain‑containing 3 (NLRP3) inflammasome assembly and NLRP3 inflammasome‑dependent pyroptosis in microglia. Lipopolysaccharide (LPS) and ATP were used to induce microglia pyroptosis in vitro; this process was confirmed by TUNEL assay, lactate dehydrogenase (LDH) detection and gasdermin D (GSDMD) expression analysis. The regulation of microglia polarization and inflammatory cytokine expression was assessed by immunofluorescence assays and ELISA. To investigate the associated mechanism of action, the expression levels of the nuclear factor erythroid 2‑related factor 2 (Nrf‑2)/heme oxygenase‑1 (HO‑1) pathway proteins were analyzed by western blotting. Finally, the regulatory effect of DI on autophagy and its association with inflammation was determined by western blotting. The present study demonstrated that DI administration inhibited NLRP3 assembly, LDH release and GSDMD cleavage. Cotreatment of DI with LPS and ATP facilitated the transition from M1 to M2, reduced inflammatory mediator expression and impeded NF‑κB phosphorylation. In addition, DI effectively reduced reactive oxygen species production through the Nrf‑2/HO‑1 pathway. Moreover, DI induced cellular autophagy, whereas inhibition of autophagy with 3‑methyladenine markedly reversed its inhibitory effect on NLRP3‑dependent pyroptosis. Taken together, the present study suggested that DI participated in the Nrf‑2/HO‑1 pathway and served a key role in microglia inflammation and NLRP3 inflammasome‑mediated pyroptosis via induction of autophagy.
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Copy and paste a formatted citation
Spandidos Publications style
Yang S, Zhang X, Zhang H, Lin X, Chen X, Zhang Y, Lin X, Huang L and Zhuge Q: Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway. Mol Med Rep 24: 672, 2021.
APA
Yang, S., Zhang, X., Zhang, H., Lin, X., Chen, X., Zhang, Y. ... Zhuge, Q. (2021). Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway. Molecular Medicine Reports, 24, 672. https://doi.org/10.3892/mmr.2021.12311
MLA
Yang, S., Zhang, X., Zhang, H., Lin, X., Chen, X., Zhang, Y., Lin, X., Huang, L., Zhuge, Q."Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway". Molecular Medicine Reports 24.3 (2021): 672.
Chicago
Yang, S., Zhang, X., Zhang, H., Lin, X., Chen, X., Zhang, Y., Lin, X., Huang, L., Zhuge, Q."Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway". Molecular Medicine Reports 24, no. 3 (2021): 672. https://doi.org/10.3892/mmr.2021.12311
Copy and paste a formatted citation
x
Spandidos Publications style
Yang S, Zhang X, Zhang H, Lin X, Chen X, Zhang Y, Lin X, Huang L and Zhuge Q: Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway. Mol Med Rep 24: 672, 2021.
APA
Yang, S., Zhang, X., Zhang, H., Lin, X., Chen, X., Zhang, Y. ... Zhuge, Q. (2021). Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway. Molecular Medicine Reports, 24, 672. https://doi.org/10.3892/mmr.2021.12311
MLA
Yang, S., Zhang, X., Zhang, H., Lin, X., Chen, X., Zhang, Y., Lin, X., Huang, L., Zhuge, Q."Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway". Molecular Medicine Reports 24.3 (2021): 672.
Chicago
Yang, S., Zhang, X., Zhang, H., Lin, X., Chen, X., Zhang, Y., Lin, X., Huang, L., Zhuge, Q."Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway". Molecular Medicine Reports 24, no. 3 (2021): 672. https://doi.org/10.3892/mmr.2021.12311
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