METTL3/IGF2BP2-Mediated m6A RNA Methylation Drives Alveolar Macrophage-Dependent Neutrophil Recruitment in Cigarette Smoke-Induced COPD.

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.