Skip to main content

Advertisement

SpringerLink
Log in

Silence of MLK3 alleviates lipopolysaccharide-induced lung epithelial cell injury via inhibiting p53-mediated ferroptosis

  • Original Paper
  • Published:
Journal of Molecular Histology Aims and scope Submit manuscript

Abstract

Acute lung injury (ALI) is characterized with a high rate of morbidity and mortality. The injury and apoptosis of lung epithelial cells play crucial roles in the progression of ALI. Mixed lineage kinase 3 (MLK3) has been reported to be involved in the regulation of cellular biological functions, such as cell proliferation, apoptosis and ferroptosis. However, the effect of MLK3 exerted on ALI has not been reported. Here, LPS-stimulated MLE12 pulmonary epithelial cells were used as an in vitro model for ALI. In this research, LPS elevated the expression of MLK3 in MLE12 cells. The silence of MLK3 alleviated LPS-induced cell injury. Notably, LPS promoted ferroptosis through enhancing GSH depletion and the productions of MDA and iron, which was attenuated by MLK3 knockdown. Moreover, the silence of MLK3 inhibited p53 expression in LPS-induced cells along with a decrease in the expressions of p21 and Bax, while overexpressing p53 reversed these effects of MLK3 silence. Meanwhile, p53 overexpression reversed the positive effects of MLK3 knockdown on LPS-induced cell ferroptosis and injury. Together, our results confirmed that the silence of MLK3 alleviated LPS-induced lung epithelial cell injury by inhibiting p53-mediated ferroptosis.

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

Similar content being viewed by others

Availability of data and material

The data and materials used to support the findings of this study are available from the corresponding author on reasonable request.

References

  • Chu B, Kon N, Chen D, Li TY, Liu T, Jiang L et al (2019) ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat Cell Biol 21(5):579–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Desmet EA, Hollenbaugh JA, Sime PJ, Wright TW, Topham DJ, Sant AJ et al (2010) Mixed Lineage Kinase 3 deficiency delays viral clearance in the lung and is associated with diminished influenza-induced cytopathic effect in infected cells. Virology 400(2):224–232

    Article  CAS  PubMed  Google Scholar 

  • Dong H, Qiang ZZ, Chai DD, Peng JL, Xia YY, Hu R et al (2020) Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1. Aging 12(13):12943–12959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gai CC, Yu MY, Li ZR, Wang YH, Ding DJ, Zheng J et al (2020) Acetaminophen sensitizing erastin-induced ferroptosis via modulation of Nrf2/heme oxygenase‐1 signaling pathway in non‐small‐cell lung cancer. J Cell Physiol 235(4):3329–3339

    Article  CAS  PubMed  Google Scholar 

  • Gouda MM, Bhandary YP (2018) Curcumin down-regulates IL-17A mediated p53-fibrinolytic system in bleomycin induced acute lung injury in vivo. J Cell Biochem 119(9):7285–7299

    Article  CAS  PubMed  Google Scholar 

  • Hu ZX, Zhang H, Yang SK, Wu XQ, He D, Cao K et al (2019) Emerging Role of Ferroptosis in Acute Kidney Injury. Oxidative Medicine and Cellular Longevity 2019: 8010614

  • Ji QJ, Sun ZR, Yang ZR, Zhang W, Ren Y, Chen WJ et al (2018) Protective effect of ginsenoside Rg1 on LPS-induced apoptosis of lung epithelial cells. Mol Immunol 136:168–174

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Singh SK, Viswakarma N, Sondarva G, Nair RS, Sethupathi P et al (2020) Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8(+) T cells. J Immunother Cancer 8(2):e000494

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee HS, Hwang CY, Shin SY, Kwon KS, Cho KH (2014) MLK3 is part of a feedback mechanism that regulates different cellular responses to reactive oxygen species. Sci Signal 7(328):ra52

    Article  PubMed  CAS  Google Scholar 

  • Li X, Duan LJ, Yuan SJ, Zhuang XB, Qiao TK, He J (2019a) Ferroptosis inhibitor alleviates Radiation-induced lung fibrosis (RILF) via down-regulation of TGF-β1. J Inflamm 16:11

    Article  CAS  Google Scholar 

  • Li Y, Feng DC, Wang ZY, Zhao Y, Sun RM, Tian DH et al (2019b) Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ 26(11):2284–2299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li YL, Wang DT, Li X, Shao Y, He YY, Yu HS et al (2019c) MiR-199a-5p suppresses non-small cell lung cancer via targeting MAP3K11. J Cancer 10(11):2472–2479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N et al (2020a) Ferroptosis: past, present and future. Cell Death Dis 11(2):88

    Article  PubMed  PubMed Central  Google Scholar 

  • Li YC, Cao YM, Xiao J, Shang JW, Tan Q, Ping F et al (2020b) Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia/reperfusion-induced acute lung injury. Cell Death Differ 27(9):2635–2650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liebl MC, Hofmann TG (2019) Cell Fate Regulation upon DNA Damage: p53 Serine 46 Kinases Pave the Cell Death Road. BioEssays 41(12):e1900127

    Article  PubMed  Google Scholar 

  • Liu HZ, Wang BS, Zhang JJ, Zhang SZ, Wang YL, Zhang J et al (2017) A novel lnc-PCF promotes the proliferation of TGF-β1-activated epithelial cells by targeting miR-344a-5p to regulate map3k11 in pulmonary fibrosis. Cell Death Dis 8(10):e3137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Kuang FM, Kroemer G, Klionsky DJ, Kang R, Tang DL (2020a) Autophagy-Dependent Ferroptosis: Machinery and Regulation. Cell Chemical Biology 27(4):420–435

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu PF, Feng YT, Li HW, Chen X, Wang GS, Xu SY et al (2020b) Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis. Cell Mol Biol Lett 25:10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma LY, Cheng YC, Zeng JJ (2019) MLK3 silence induces cervical cancer cell apoptosis via the Notch-1/autophagy network. Clin Exp Pharmacol Physiol 46(9):854–860

    Article  CAS  PubMed  Google Scholar 

  • Ma SX, Sun LY, Wu WH, Wu JL, Sun ZN, Ren JJ (2020) USP22 protects against myocardial ischemia-reperfusion injury via the SIRT1-p53/SLC7A11-dependent inhibition of ferroptosis-induced cardiomyocyte death. Front Physiol 11:551318

    Article  PubMed  PubMed Central  Google Scholar 

  • Mao C, Wang X, Liu YT, Wang M, Yan B, Jiang YQ et al (2018) A G3BP1-interacting lncRNA promotes ferroptosis and apoptosis in cancer via nuclear sequestration of p53. Cancer Res 78(13):3484–3496

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mao HM, Zhao YH, Li HX, Lei L (2020) Ferroptosis as an emerging target in inflammatory diseases. Prog Biophys Mol Biol 155:20–28

    Article  CAS  PubMed  Google Scholar 

  • Mccullough RL, Saikia P, Pollard KA, Mcmullen MR, Nagy LE, Roychowdhury S (2016) Myeloid mixed lineage kinase 3 contributes to chronic ethanol-induced inflammation and hepatocyte injury in mice. Gene Expr 17(1):61–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Needham DM, Wozniak AW, Hough CL, Morris PE, Dinglas VD, Jackson JC et al (2014) Risk factors for physical impairment after acute lung injury in a national, multicenter study. American Journal of Respiratory & Critical Care Medicine 189(10):1214–1224

    Article  Google Scholar 

  • Neudecker V, Brodsky KS, Clambey ET, Schmidt EP, Packard TA, Davenport B et al (2017) Neutrophil transfer of miR-223 to lung epithelial cells dampens acute lung injury in mice. Sci Transl Med 9(408):eaah5360

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Qiang ZZ, Dong H, Xia YY, Chai DD, Hu R, Jiang H (2020) Nrf2 and STAT3 alleviates ferroptosis-mediated IIR-ALI by regulating SLC7A11. Oxidative medicine and cellular longevity 2020: 5146982

  • Qiu YB, Wan BB, Liu G, Wu YX, Chen D, Lu MD et al (2020) Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis. Respir Res 21(1):232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rattanasinchai C, Gallo KA (2016) MLK3 Signaling in Cancer Invasion. Cancers (Basel) 8(5):51

    Article  CAS  Google Scholar 

  • Ren R, Chen SD, Fan J, Zhang G, Li JB (2018) miRNA-138 regulates MLK3/JNK/MAPK pathway to protect BV-2 cells from H2O2-induced apoptosis. Bratisl Lek Listy 119(05):284–288

    CAS  PubMed  Google Scholar 

  • Schroyer AL, Stimes NW, Abi Saab WF, Chadee DN (2018) MLK3 phosphorylation by ERK1/2 is required for oxidative stress-induced invasion of colorectal cancer cells. Oncogene 37(8):1031–1040

    Article  CAS  PubMed  Google Scholar 

  • Song XH, Long DX (2020) Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases. Front NeuroSci 14:267

    Article  PubMed  PubMed Central  Google Scholar 

  • Sun QK, He QF, Xu JB, Liu QY, Lu YJ, Zhang ZC et al (2019) Guanine nucleotide-binding protein G(i)α2 aggravates hepatic ischemia-reperfusion injury in mice by regulating MLK3 signaling. FASEB Journal 33(6):7049–7060

    Article  CAS  PubMed  Google Scholar 

  • Tang DL, Chen X, Kang R, Kroemer G (2020) Ferroptosis: molecular mechanisms and health implications. Cell Res 31(2):107–125

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tomita K, Kohl R, MacLaurin BL, Hirsova P, Guo Q, Sanchez LHG et al (2017) Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis. JCI Insight 2(15):e94488

    Article  PubMed Central  Google Scholar 

  • Wang L, Zhang ZL, Li MM, Wang FX, Jia Y, Zhang F et al (2019a) P53-dependent induction of ferroptosis is required for artemether to alleviate carbon tetrachloride-induced liver fibrosis and hepatic stellate cell activation. IUBMB Life 71(1):45–56

    Article  CAS  PubMed  Google Scholar 

  • Wang YF, Zhang XR, Tian JM, Liu GZ, Li XF, Shen D (2019b) Sevoflurane alleviates LPS-induced acute lung injury via the microRNA27a3p/TLR4/MyD88/NFκB signaling pathway. Int J Mol Med 44(2):479–490

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang CB, Chen HY, Chen DY, Zhao MQ, Lin ZF, Guo M et al (2020a) The inhibition of H1N1 influenza virus-induced apoptosis by surface decoration of selenium nanoparticles with β-thujaplicin through reactive oxygen species-mediated AKT and p53 signaling pathways. ACS Omega 5(47):30633–30642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang JY, Deng B, Liu Q, Huang YS, Chen WT, Li J et al (2020b) Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload. Cell Death Dis 11(7):574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei SQ, Wang KW, Huang XM, Tang WN, Zhao ZX, Zhao ZW (2019) Knockdown of the lncRNA MALAT1 alleviates lipopolysaccharideinduced A549 cell injury by targeting the miR175p/FOXA1 axis. Mol Med Rep 20(2):2021–2029

    CAS  PubMed  Google Scholar 

  • Xing B, Li QJ, Li H, Chen SS, Cui ZY, Ma J et al (2018) miR-140-5p aggravates hypoxia-induced cell injury via regulating MLK3 in H9c2 cells. Biomedicine and Pharmacotherapy 103:1652–1657

    Article  CAS  PubMed  Google Scholar 

  • Yamaoka T, Arata S, Homma M, Homma T, Kusumoto S, Ando K et al (2019) Blockade of EGFR activation promotes TNF-induced lung epithelial cell apoptosis and pulmonary injury. Int J Mol Sci 20(16):4021

    Article  CAS  PubMed Central  Google Scholar 

  • Yang YN, Tai WL, Lu NH, Li T, Liu YJ, Wu WJ et al (2020) lncRNA ZFAS1 promotes lung fibroblast-to-myofibroblast transition and ferroptosis via functioning as a ceRNA through miR-150-5p/SLC38A1 axis. Aging 12(10):9085–9102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ye RS, Liu ZW (2019) ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by inhibiting the LPS-TLR4 pathway. Exp Mol Pathol 113:104350

    Article  PubMed  CAS  Google Scholar 

  • You LT, Dong X, Yin XB, Yang CJ, Leng X, Wang WP et al (2018) Rhein induces cell death in heparg cells through cell cycle arrest and apoptotic pathway. Int J Mol Sci 19(4):1060

    Article  PubMed Central  CAS  Google Scholar 

  • Yu HL, Song LL, Cao X, Li W, Zhao YY, Chen J et al (2020) Hederagenin attenuates cerebral ischaemia/reperfusion injury by regulating MLK3 signalling. Front Pharmacol 11:1173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Zhang X, Li X, Meng WB, Bai ZT, Rui SZ et al (2018) Effect of CCNB1 silencing on cell cycle, senescence, and apoptosis through the p53 signaling pathway in pancreatic cancer. J Cell Physiol 234(1):619–631

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Meng QS, Yin JL, Zhang ZY, Bao HG, Wang XL (2020) Anthocyanins attenuate neuroinflammation through the suppression of MLK3 activation in a mouse model of perioperative neurocognitive disorders. Brain Res 1726:146504

    Article  CAS  PubMed  Google Scholar 

  • Zhou H, Li F, Niu JY, Zhong WY, Tang MY, Lin D et al (2019) Ferroptosis was involved in the oleic acid-induced acute lung injury in mice. Sheng li xue bao 71(5):689–697

    PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

None.

Author information

Authors and Affiliations

  1. The 2nd department of Critical Care Medicine, Xi’an Chest Hospital, 710061, Xi’an, Shaanxi, China

    Xiangjun Chen, Gangqiang Qi, Fang Fang & Li Wang

  2. Department of Respiratory Medicine, Shaanxi Provincial People’s Hospital, Xi’an, China

    Yi Miao

  3. East section of Hangtian Avenue, Chang’an District, 710061, Xi’an, Shaanxi, China

    Li Wang

Authors
  1. Xiangjun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gangqiang Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fang Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Gangqiang Qi: Conceptualization, Software. Xiangjun Chen: Data curation, Methodology, Writing- Original draft preparation. Yi Miao:Data curation, Fang Fang: Investigation. Li Wang: Software, Validation.

Corresponding author

Correspondence to Li Wang.

Ethics declarations

CRediT authorship contribution statement

Li Wang: Conceptualization, Software. Xiangjun Chen: Data curation, Methodology, Writing- Original draft preparation. Gangqiang Qi and Yi Miao: Investigation. Fang Fang: Software, Validation.

Declaration of competing interest

The authors declare that there are no conflicts of Interests.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, X., Qi, G., Fang, F. et al. Silence of MLK3 alleviates lipopolysaccharide-induced lung epithelial cell injury via inhibiting p53-mediated ferroptosis. J Mol Histol 53, 503–510 (2022). https://doi.org/10.1007/s10735-022-10064-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10735-022-10064-y

Keywords

Search

Navigation