Abstract
Background
Long-term exposure to PM2.5 (particulate matter with an aerodynamic diameter of ≤ 2.5 μm) is associated with pulmonary injury and emphysema in patients with chronic obstructive pulmonary disease (COPD). We investigated mechanisms through which the long noncoding RNA lnc-IL7R contributes to cellular damage by inducing oxidative stress in COPD patients exposed to PM2.5.
Methods
Associations of serum lnc-IL7R levels with lung function, emphysema, and previous PM2.5 exposure in COPD patients were analyzed. Reactive oxygen species and lnc-IL7R levels were measured in PM2.5-treated cells. The levels of lnc-IL7R and cellular senescence–associated genes, namely p16INK4a and p21CIP1/WAF1, were determined through lung tissue section staining. The effects of p16INK4a or p21CIP1/WAF1 regulation were examined by performing lnc-IL7R overexpression and knockdown assays. The functions of lnc-IL7R-mediated cell proliferation, cell cycle, senescence, colony formation, and apoptosis were examined in cells treated with PM2.5. Chromatin immunoprecipitation assays were conducted to investigate the epigenetic regulation of p21CIP1/WAF1.
Results
Lnc-IL7R levels decreased in COPD patients and were negatively correlated with emphysema or PM2.5 exposure. Lnc-IL7R levels were upregulated in normal lung epithelial cells but not in COPD cells exposed to PM2.5. Lower lnc-IL7R expression in PM2.5-treated cells induced p16INK4a and p21CIP1/WAF1 expression by increasing oxidative stress. Higher lnc-IL7R expression protected against cellular senescence and apoptosis, whereas lower lnc-IL7R expression augmented injury in PM2.5-treated cells. Lnc-IL7R and the enhancer of zeste homolog 2 (EZH2) synergistically suppressed p21CIP1/WAF1 expression through epigenetic modulation.
Conclusion
Lnc-IL7R attenuates PM2.5-mediated p21CIP1/WAF1 expression through EZH2 recruitment, and its dysfunction may augment cellular injury in COPD.
Graphical abstract
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Availability of data and material
The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Code availability
Differential genes were analyzed in published microarray data sets.
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This manuscript was edited by Wallace Academic Editing.
Funding
This study was funded by the Ministry of Science and Technology of Taiwan (MOST: 108–2314-B-038–111-MY3 and 108–2314-B-038–063-MY3), Ministry of Education of the Republic of China (DP2-110–21121-01-T-01–01), and Taipei Medical University and Shuang Ho Hospital (110TMU-SHH-19).
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K. Y. L., S. C. H., and S. M. W conceptualized the study and reviewed the entire project and manuscript. W. L. S. and P. H. F. performed most of the experiments and wrote the manuscript. P. H. F. and C. W. L. designed the research and conducted the experiments. K. Y. C. and H. C. C. contributed to the exposure assessment. C. H. T. provided expertise on statistical and figure analyses. P. H. F., T. T. C., and K. Y. C. conducted patient information analyses and reviewed the manuscript. S. M. W. assumes responsibility for the content of the manuscript, including the data and analysis. All authors contributed to the critical revision of the manuscript for important intellectual content. All authors have read and approved the final manuscript.
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Highlights
• Low lnc-IL7R expression is associated with emphysema or PM2.5 exposure in COPD.
• Lnc-IL7R expression was upregulated in normal but not COPD lung epithelial cells exposed to PM2.5.
• Lnc-IL7R is a negative regulator of PM2.5-mediated p21CIP1/WAF1 and p16INK4a expression.
• Blockade of lnc-IL7R expression and EZH2 recruitment increases p21CIP1/WAF1 gene expression in cells exposed to PM2.5, which may aggravate cellular injury in COPD.
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Lee, KY., Ho, SC., Sun, WL. et al. Lnc-IL7R alleviates PM2.5-mediated cellular senescence and apoptosis through EZH2 recruitment in chronic obstructive pulmonary disease. Cell Biol Toxicol 38, 1097–1120 (2022). https://doi.org/10.1007/s10565-022-09709-1
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DOI: https://doi.org/10.1007/s10565-022-09709-1