PTBP1-TRAF6 Axis Aggravates Chronic Obstructive Pulmonary Disease by Promoting M1 Macrophage Polarization and Impairing Clearance of Neutrophil Extracellular Traps

To elucidate the role of the polypyrimidine tract-binding protein 1 (PTBP1)-tumor necrosis factor receptor-associated factor 6 (TRAF6) pathway in chronic obstructive pulmonary disease (COPD), with a particular focus on its regulatory effects on macrophage polarization and clearance of neutrophil extracellular traps (NETs). A COPD-like mouse model was established via cigarette smoke (CS) exposure. Lung injury, macrophage polarization, and levels of NETs were assessed. The role of TRAF6 in macrophage polarization and NETs clearance was assessed through lentiviral modulation of TRAF6 expression. RNA immunoprecipitation-quantitative polymerase chain reaction (RIP-qPCR), RNA stability assays, and Western blotting were performed to investigate the regulatory mechanism of PTBP1 on TRAF6 expression. The COPD-like mouse model exhibited increased M1 and decreased M2 macrophage populations, along with elevated NETs formation. Both PTBP1 and TRAF6 were upregulated in lung tissues of the COPD-like mouse model and cigarette smoke extract (CSE)-treated macrophages. Mechanistically, PTBP1 bound to and stabilized TRAF6 mRNA, enhancing TRAF6 expression. Inhibition of the PTBP1-TRAF6 pathway alleviated lung injury, restored macrophage polarization balance, and promoted NETs clearance. PTBP1 enhances TRAF6 expression by stabilizing its mRNA, promoting M1 macrophage polarization and impairing NETs clearance, ultimately aggravating COPD.