IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

Cigarette Smoke Extract-Treated Mouse Airway Epithelial Cells-Derived Exosomal LncRNA MEG3 Promotes M1 Macrophage Polarization and Pyroptosis in Chronic Obstructive Pulmonary Disease by Upregulating TREM-1 via m6A Methylation

  • Lijing Wang (Department of Geriatrics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University) ;
  • Qiao Yu (Department of Geriatrics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University) ;
  • Jian Xiao (Department of Geriatrics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University) ;
  • Qiong Chen (Department of Geriatrics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University) ;
  • Min Fang (Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, the "Double-First Class" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), Changsha Medical University) ;
  • Hongjun Zhao (Department of Rheumatology and Immunology, Xiangya Hospital, Central South University)
  • Received : 2023.10.18
  • Accepted : 2024.01.02
  • Published : 2024.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Cigarette smoke extract (CSE)-treated mouse airway epithelial cells (MAECs)-derived exosomes accelerate the progression of chronic obstructive pulmonary disease (COPD) by upregulating triggering receptor expressed on myeloid cells 1 (TREM-1); however, the specific mechanism remains unclear. We aimed to explore the potential mechanisms of CSE-treated MAECs-derived exosomes on M1 macrophage polarization and pyroptosis in COPD. In vitro, exosomes were extracted from CSE-treated MAECs, followed by co-culture with macrophages. In vivo, mice exposed to cigarette smoke (CS) to induce COPD, followed by injection or/and intranasal instillation with oe-TREM-1 lentivirus. Lung function and pathological changes were evaluated. CD68+ cell number and the levels of iNOS, TNF-α, IL-1β (M1 macrophage marker), and pyroptosis-related proteins (NOD-like receptor family pyrin domain containing 3, apoptosis-associated speck-like protein containing a caspase-1 recruitment domain, caspase-1, cleaved-caspase-1, gasdermin D [GSDMD], and GSDMD-N) were examined. The expression of maternally expressed gene 3 (MEG3), spleen focus forming virus proviral integration oncogene (SPI1), methyltransferase 3 (METTL3), and TREM-1 was detected and the binding relationships among them were verified. MEG3 increased N6-methyladenosine methylation of TREM-1 by recruiting SPI1 to activate METTL3. Overexpression of TREM-1 or METTL3 negated the alleviative effects of MEG3 inhibition on M1 polarization and pyroptosis. In mice exposed to CS, EXO-CSE further aggravated lung injury, M1 polarization, and pyroptosis, which were reversed by MEG3 inhibition. TREM-1 overexpression negated the palliative effects of MEG3 inhibition on COPD mouse lung injury. Collectively, CSE-treated MAECs-derived exosomal long non-coding RNA MEG3 may expedite M1 macrophage polarization and pyroptosis in COPD via the SPI1/METTL3/TREM-1 axis.

Keywords

Acknowledgement

This work was supported by Hunan Provincial Natural Science Foundation of China (Grant No. 2023JJ30943).

References

  1. Guo P, Li R, Piao TH, Wang CL, Wu XL, Cai HY. Pathological mechanism and targeted drugs of COPD. Int J Chron Obstruct Pulmon Dis 2022;17:1565-1575. https://doi.org/10.2147/COPD.S366126
  2. Vogelmeier CF, Roman-Rodriguez M, Singh D, Han MK, Rodriguez-Roisin R, Ferguson GT. Goals of COPD treatment: focus on symptoms and exacerbations. Respir Med 2020;166:105938.
  3. Alter P, Baker JR, Dauletbaev N, Donnelly LE, Pistenmaa C, Schmeck B, Washko G, Vogelmeier CF. Update in chronic obstructive pulmonary disease 2019. Am J Respir Crit Care Med 2020;202:348-355. https://doi.org/10.1164/rccm.202002-0370UP
  4. Brandsma CA, Van den Berge M, Hackett TL, Brusselle G, Timens W. Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine. J Pathol 2020;250:624-635. https://doi.org/10.1002/path.5364
  5. Lee KH, Woo J, Kim JY, Lee CH, Yoo CG. Cigarette smoke extract-induced downregulation of p300 is responsible for the impaired inflammatory cytokine response of macrophages. Cell Signal 2021;85:110050.
  6. Le Y, Wang Y, Zhou L, Xiong J, Tian J, Yang X, Gai X, Sun Y. Cigarette smoke-induced HMGB1 translocation and release contribute to migration and NF-κB activation through inducing autophagy in lung macrophages. J Cell Mol Med 2020;24:1319-1331. https://doi.org/10.1111/jcmm.14789
  7. Wang Y, Smith W, Hao D, He B, Kong L. M1 and M2 macrophage polarization and potentially therapeutic naturally occurring compounds. Int Immunopharmacol 2019;70:459-466. https://doi.org/10.1016/j.intimp.2019.02.050
  8. Sun J, Li Y. Pyroptosis and respiratory diseases: a review of current knowledge. Front Immunol 2022;13:920464.
  9. Lee JW, Chun W, Lee HJ, Min JH, Kim SM, Seo JY, Ahn KS, Oh SR. The role of macrophages in the development of acute and chronic inflammatory lung diseases. Cells 2021;10:897.
  10. Zhang C, Kan X, Zhang B, Ni H, Shao J. The role of triggering receptor expressed on myeloid cells-1 (TREM-1) in central nervous system diseases. Mol Brain 2022;15:84.
  11. Wang L, Chen Q, Yu Q, Xiao J, Zhao H. TREM-1 aggravates chronic obstructive pulmonary disease development via activation NLRP3 inflammasome-mediated pyroptosis. Inflamm Res 2021;70:971-980. https://doi.org/10.1007/s00011-021-01490-x
  12. Wang L, Chen Q, Yu Q, Xiao J, Zhao H. Cigarette smoke extract-treated airway epithelial cells-derived exosomes promote M1 macrophage polarization in chronic obstructive pulmonary disease. Int Immunopharmacol 2021;96:107700.
  13. Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem 2019;88:487-514. https://doi.org/10.1146/annurev-biochem-013118-111902
  14. Zhu Z, Lian X, Su X, Wu W, Zeng Y, Chen X. Exosomes derived from adipose-derived stem cells alleviate cigarette smoke-induced lung inflammation and injury by inhibiting alveolar macrophages pyroptosis. Respir Res 2022;23:5.
  15. Liu C, Lu J, Yuan T, Xie L, Zhang L. EPC-exosomal miR-26a-5p improves airway remodeling in COPD by inhibiting ferroptosis of bronchial epithelial cells via PTGS2/PGE2 signaling pathway. Sci Rep 2023;13:6126.
  16. Ouyang C, Wang W, Wu D, Wang W, Ye X, Yang Q. Analysis of serum exosome microRNAs in the rat model of chronic obstructive pulmonary disease. Am J Transl Res 2023;15:138-150.
  17. Han H, Hao L. Revealing lncRNA biomarkers related to chronic obstructive pulmonary disease based on bioinformatics. Int J Chron Obstruct Pulmon Dis 2022;17:2487-2515. https://doi.org/10.2147/COPD.S354634
  18. Lei Z, Guo H, Zou S, Jiang J, Kui Y, Song J. Long non-coding RNA maternally expressed gene regulates cigarette smoke extract induced lung inflammation and human bronchial epithelial apoptosis via miR-149-3p. Exp Ther Med 2021;21:60.
  19. Fan S, Ren Y, Zhang W, Zhang H, Wang C. Long non-coding maternally expressed gene 3 regulates cigarette smoke extract-induced apoptosis, inflammation and cytotoxicity by sponging miR-181a-2-3p in 16HBE cells. Oncol Lett 2021;21:45.
  20. Huang X, Lv D, Yang X, Li M, Zhang H. m6A RNA methylation regulators could contribute to the occurrence of chronic obstructive pulmonary disease. J Cell Mol Med 2020;24:12706-12715. https://doi.org/10.1111/jcmm.15848
  21. Hu T, Xu L, Jiang M, Zhang F, Li Q, Li Z, Wu C, Ding J, Li F, Wang J. N6-methyladenosine-methylomic landscape of lung tissues of mice with chronic obstructive pulmonary disease. Front Immunol 2023;14:1137195.
  22. Zhang Y, Wang L, Liu Y, Yan F. Mettl3-mediated transcriptome-wide m6A methylation induced by cigarette smoking in human bronchial epithelial cells. Toxicol In Vitro 2023;89:105584.
  23. He S, Chen D, Hu M, Zhang L, Liu C, Traini D, Grau GE, Zeng Z, Lu J, Zhou G, et al. Bronchial epithelial cell extracellular vesicles ameliorate epithelial-mesenchymal transition in COPD pathogenesis by alleviating M2 macrophage polarization. Nanomedicine 2019;18:259-271. https://doi.org/10.1016/j.nano.2019.03.010
  24. Li N, Liu Y, Cai J. LncRNA MIR155HG regulates M1/M2 macrophage polarization in chronic obstructive pulmonary disease. Biomed Pharmacother 2019;117:109015.
  25. Cardoso AOP, Pecli E Silva C, Dos Anjos FF, Quesnot N, Valenca HDM, Cattani-Cavalieri I, Brito-Gitirana L, Valenca SS, Lanzetti M. Diallyl disulfide prevents cigarette smoke-induced emphysema in mice. Pulm Pharmacol Ther 2021;69:102053.
  26. Chen Z, Wu H, Fan W, Zhang J, Yao Y, Su W, Wang Y, Li P. Naringenin suppresses BEAS-2B-derived extracellular vesicular cargoes disorder caused by cigarette smoke extract thereby inhibiting M1 macrophage polarization. Front Immunol 2022;13:930476.
  27. Bi H, Wang G, Li Z, Zhou L, Zhang M, Ye J, Wang Z. Long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) participates in chronic obstructive pulmonary disease through regulating human pulmonary microvascular endothelial cell apoptosis. Med Sci Monit 2020;26:e920793.
  28. Tang W, Shen Z, Guo J, Sun S. Screening of long non-coding RNA and TUG1 inhibits proliferation with TGF-β induction in patients with COPD. Int J Chron Obstruct Pulmon Dis 2016;11:2951-2964. https://doi.org/10.2147/COPD.S109570
  29. Wu X, Chen D, Yu L. The value of circulating long non-coding RNA maternally expressed gene 3 as a predictor of higher acute respiratory distress syndrome risk and 28-day mortality in sepsis patients. J Clin Lab Anal 2020;34:e23488.
  30. Zou DM, Zhou SM, Li LH, Zhou JL, Tang ZM, Wang SH. Knockdown of long noncoding RNAs of maternally expressed 3 alleviates hyperoxia-induced lung injury via inhibiting thioredoxin-interacting protein-mediated pyroptosis by binding to miR-18a. Am J Pathol 2020;190:994-1005. https://doi.org/10.1016/j.ajpath.2019.12.013
  31. Wang L, Zhao H, Raman I, Yan M, Chen Q, Li QZ. Peripheral blood mononuclear cell gene expression in chronic obstructive pulmonary disease: miRNA and mRNA regulation. J Inflamm Res 2022;15:2167-2180. https://doi.org/10.2147/JIR.S337894
  32. Xu P, Zhang X, Liu Q, Xie Y, Shi X, Chen J, Li Y, Guo H, Sun R, Hong Y, et al. Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke. Cell Death Dis 2019;10:555.
  33. Zhong WJ, Zhang J, Duan JX, Zhang CY, Ma SC, Li YS, Yang NS, Yang HH, Xiong JB, Guan CX, et al. TREM-1 triggers necroptosis of macrophages through mTOR-dependent mitochondrial fission during acute lung injury. J Transl Med 2023;21:179.
  34. Cheng C, Wu Y, Xiao T, Xue J, Sun J, Xia H, Ma H, Lu L, Li J, Shi A, et al. METTL3-mediated m6A modification of ZBTB4 mRNA is involved in the smoking-induced EMT in cancer of the lung. Mol Ther Nucleic Acids 2020;23:487-500.  https://doi.org/10.1016/j.omtn.2020.12.001
  35. Liu Y, Liu Z, Tang H, Shen Y, Gong Z, Xie N, Zhang X, Wang W, Kong W, Zhou Y, et al. The N6-methyladenosine (m6A)-forming enzyme METTL3 facilitates M1 macrophage polarization through the methylation of STAT1 mRNA. Am J Physiol Cell Physiol 2019;317:C762-C775. https://doi.org/10.1152/ajpcell.00212.2019
  36. Guo M, Yan R, Ji Q, Yao H, Sun M, Duan L, Xue Z, Jia Y. IFN regulatory factor-1 induced macrophage pyroptosis by modulating m6A modification of circ_0029589 in patients with acute coronary syndrome. Int Immunopharmacol 2020;86:106800.
  37. Maghsoudloo M, Azimzadeh Jamalkandi S, Najafi A, Masoudi-Nejad A. Identification of biomarkers in common chronic lung diseases by co-expression networks and drug-target interactions analysis. Mol Med 2020;26:9.
  38. Tu X, Kim RY, Brown AC, de Jong E, Jones-Freeman B, Ali MK, Gomez HM, Budden KF, Starkey MR, Cameron GJM, et al. Airway and parenchymal transcriptomics in a novel model of asthma and COPD overlap. J Allergy Clin Immunol 2022;150:817-829.e6. https://doi.org/10.1016/j.jaci.2022.04.032