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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
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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).

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