Lung · 2026
NOP2 Exacerbates Pulmonary Inflammation in a Murine Model of Chronic Obstructive Pulmonary Disease by Inducing Neutrophil Extracellular Traps Mediating M1 Macrophage Polarization.
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Guo Chunyan, Chen Sai, Shao Zhuxiang, Zhai Shengping
Аннотация
BACKGROUND: This study aims to explore the molecular mechanism of NOP2 in inducing neutrophil extracellular traps (NETs) and M1 macrophage polarization in a murine model of COPD.
METHODS: A murine model of COPD was established using cigarette smoke exposure combined with LPS stimulation. Lung pathological changes and fibrosis were evaluated by H&E and Masson staining. The inflammatory cytokines in bronchoalveolar lavage fluid and NETs-related biomarkers in serum were detected by ELISA. Immunofluorescence was applied to observe the colocalization of Cit-H3 with CD86/CD206 in lung tissues. In vitro, RAW264.7 macrophages were treated with cigarette smoke extract. NETs were induced by PMA and co-cultured with RAW264.7 cells. Cell viability, macrophage polarization, and the expression of NOP2, TUG1, TRIM27, EZH2, iNOS and Arg-1 were determined by CCK-8, flow cytometry, qRT-PCR or Western blot. MeRIP, actinomycin D assay, RNA pull-down, RIP and Co-IP were performed to detect m5C modification, TUG1 stability, molecular binding and EZH2 ubiquitination.
RESULTS: NOP2, TUG1 and TRIM27 were highly expressed in our murine model of COPD. NOP2 inhibition alleviated lung injury, suppressed NETs, M1 polarization and pulmonary inflammation. Mechanistically, NOP2 stabilized and elevated TUG1 expression via m5C modification. TUG1 acted as a molecular scaffold to recruit TRIM27 and EZH2, facilitating TRIM27-mediated EZH2 ubiquitination. TUG1 overexpression or EZH2 inhibition partially reversed the protective effects of NOP2 silencing.
CONCLUSIONS: NOP2 aggravates pulmonary inflammation in a murine model of COPD by promoting NETs and M1 polarization via the TUG1/TRIM27/EZH2 axis.
METHODS: A murine model of COPD was established using cigarette smoke exposure combined with LPS stimulation. Lung pathological changes and fibrosis were evaluated by H&E and Masson staining. The inflammatory cytokines in bronchoalveolar lavage fluid and NETs-related biomarkers in serum were detected by ELISA. Immunofluorescence was applied to observe the colocalization of Cit-H3 with CD86/CD206 in lung tissues. In vitro, RAW264.7 macrophages were treated with cigarette smoke extract. NETs were induced by PMA and co-cultured with RAW264.7 cells. Cell viability, macrophage polarization, and the expression of NOP2, TUG1, TRIM27, EZH2, iNOS and Arg-1 were determined by CCK-8, flow cytometry, qRT-PCR or Western blot. MeRIP, actinomycin D assay, RNA pull-down, RIP and Co-IP were performed to detect m5C modification, TUG1 stability, molecular binding and EZH2 ubiquitination.
RESULTS: NOP2, TUG1 and TRIM27 were highly expressed in our murine model of COPD. NOP2 inhibition alleviated lung injury, suppressed NETs, M1 polarization and pulmonary inflammation. Mechanistically, NOP2 stabilized and elevated TUG1 expression via m5C modification. TUG1 acted as a molecular scaffold to recruit TRIM27 and EZH2, facilitating TRIM27-mediated EZH2 ubiquitination. TUG1 overexpression or EZH2 inhibition partially reversed the protective effects of NOP2 silencing.
CONCLUSIONS: NOP2 aggravates pulmonary inflammation in a murine model of COPD by promoting NETs and M1 polarization via the TUG1/TRIM27/EZH2 axis.