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已发表论文
METTL3/IGF2BP2 介导的 m6A RNA 甲基化驱动香烟烟雾诱导的慢性阻塞性肺疾病中肺泡巨噬细胞依赖的中性粒细胞募集
Authors Lin A, Wang J, Wang L, Zhang Y
Received 30 April 2025
Accepted for publication 17 October 2025
Published 29 October 2025 Volume 2025:18 Pages 15033—15047
DOI https://doi.org/10.2147/JIR.S532958
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Cynthia Koziol-White
Andi Lin,1,* Jian Wang,2,* Lixing Wang,3 Yaping Zhang3,4
1The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian, 362000, People’s Republic of China; 2Department of Pathology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362000, People’s Republic of China; 3Clinical Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362000, People’s Republic of China; 4Fujian Key Laboratory of Lung Stem Cells, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362000, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Yaping Zhang, Email icesuri@126.com
Introduction: Chronic inflammatory infiltration caused by cigarette smoke is one of the primary characteristics that define chronic obstructive pulmonary disease (COPD), but the epigenetic mechanisms governing immune cell crosstalk remain poorly defined. This study aims to elucidate the critical role of m6A RNA methylation in modulating alveolar macrophage-neutrophil interactions during COPD progression.
Methods: A mouse COPD model was employed, combined with mechanistic studies that included pharmacological inhibition, RNA stability assay, RIP, m6A-qPCR, and cell chemotaxis assay in cells, to investigate the effect of cigarette smoke exposure on m6A regulatory molecules and immune cell interactions.
Results: Cigarette smoke exposure upregulated METTL3 and IGF2BP2 expression in alveolar macrophages. METTL3-mediated m6A modification promoted the stability of CXCL8 mRNA in an IGF2BP2-dependent manner, leading to enhanced CXCL8 secretion and neutrophil recruitment. Concurrently, METTL3-mediated m6A modification stabilized ICAM-1 mRNA in endothelial cells, facilitating neutrophil adhesion and transmigration. This dual-cell mechanism synergistically amplifies neutrophilic inflammation in COPD.
Discussion: Our results uncover a novel epitranscriptional pathway through which cigarette smoke promotes neutrophilic inflammation via m6A-dependent regulation of both CXCL8 in macrophages and ICAM-1 in endothelial cells. These findings position the METTL3/IGF2BP2/m6A axis as a central regulatory mechanism coordinating multicellular interactions in COPD pathogenesis and suggest its potential as a therapeutic target for modulating disease progression.
Keywords: cigarette, alveolar macrophages, METTL3, STM2457, COPD, CXCL8
1The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian, 362000, People’s Republic of China; 2Department of Pathology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362000, People’s Republic of China; 3Clinical Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362000, People’s Republic of China; 4Fujian Key Laboratory of Lung Stem Cells, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362000, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Yaping Zhang, Email icesuri@126.com
Introduction: Chronic inflammatory infiltration caused by cigarette smoke is one of the primary characteristics that define chronic obstructive pulmonary disease (COPD), but the epigenetic mechanisms governing immune cell crosstalk remain poorly defined. This study aims to elucidate the critical role of m6A RNA methylation in modulating alveolar macrophage-neutrophil interactions during COPD progression.
Methods: A mouse COPD model was employed, combined with mechanistic studies that included pharmacological inhibition, RNA stability assay, RIP, m6A-qPCR, and cell chemotaxis assay in cells, to investigate the effect of cigarette smoke exposure on m6A regulatory molecules and immune cell interactions.
Results: Cigarette smoke exposure upregulated METTL3 and IGF2BP2 expression in alveolar macrophages. METTL3-mediated m6A modification promoted the stability of CXCL8 mRNA in an IGF2BP2-dependent manner, leading to enhanced CXCL8 secretion and neutrophil recruitment. Concurrently, METTL3-mediated m6A modification stabilized ICAM-1 mRNA in endothelial cells, facilitating neutrophil adhesion and transmigration. This dual-cell mechanism synergistically amplifies neutrophilic inflammation in COPD.
Discussion: Our results uncover a novel epitranscriptional pathway through which cigarette smoke promotes neutrophilic inflammation via m6A-dependent regulation of both CXCL8 in macrophages and ICAM-1 in endothelial cells. These findings position the METTL3/IGF2BP2/m6A axis as a central regulatory mechanism coordinating multicellular interactions in COPD pathogenesis and suggest its potential as a therapeutic target for modulating disease progression.
Keywords: cigarette, alveolar macrophages, METTL3, STM2457, COPD, CXCL8