Lnc-IL7R alleviates PM2.5-mediated cellular senescence and apoptosis through EZH2 recruitment in chronic obstructive pulmonary disease.

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.

• Authors: Kang-Yun Lee, Shu-Chuan Ho, Wei-Lun Sun, Po-Hao Feng, Cheng-Wei Lin, Kuan-Yuan Chen, Hsiao-Chi Chuang, Chien-Hua Tseng, Tzu-Tao Chen, Sheng-Ming Wu
• Journal: Cell biology and toxicology (Cell Biol Toxicol) Vol. 38 Issue 6 Pg. 1097-1120 (12 2022) ISSN: 1573-6822 [Electronic] Netherlands
• PMID: 35303175 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature B.V.

Chemical References

• Cyclin-Dependent Kinase Inhibitor p16
• Cyclin-Dependent Kinase Inhibitor p21
• Enhancer of Zeste Homolog 2 Protein
• EZH2 protein, human
• IL7R protein, human
• Interleukin-7 Receptor alpha Subunit
• Particulate Matter
• RNA, Long Noncoding

Topics

• Humans
• Apoptosis (genetics)
• Cellular Senescence (genetics)
• Cyclin-Dependent Kinase Inhibitor p16 (genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Emphysema (genetics)
• Enhancer of Zeste Homolog 2 Protein (genetics, metabolism)
• Epigenesis, Genetic
• Interleukin-7 Receptor alpha Subunit (genetics, metabolism)
• Particulate Matter (toxicity)
• Pulmonary Disease, Chronic Obstructive (genetics)
• RNA, Long Noncoding (genetics)