International Journal of COPD (Oct 2020)

Mechanisms by Which the MBD2/miR-301a-5p/CXCL12/CXCR4 Pathway Regulates Acute Exacerbations of Chronic Obstructive Pulmonary Disease

  • Shen W,
  • Weng Z,
  • Fan M,
  • Wang S,
  • Wang R,
  • Zhang Y,
  • Tian H,
  • Wang X,
  • Wu X,
  • Yang X,
  • Wei W,
  • Yuan K

Journal volume & issue
Vol. Volume 15
pp. 2561 – 2572

Abstract

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Wen Shen,1,* Zhiyin Weng,2,* Minjuan Fan,1 Shukun Wang,1 Ruili Wang,1 Yang Zhang,1 Hong Tian,1 Xi Wang,1 Xin Wu,1 Xiaolei Yang,1 Wei Wei,1 Kaifen Yuan1 1Respiratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 2School of Pharmaceutical Science, Kunming Medical University, Kunming, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kaifen YuanRespiratory Department, The Second Affiliated Hospital of Kunming Medical University, No. 374 Dianmian Road, Kunming 650101, Yunnan Province, People’s Republic of ChinaTel +86-13888320577Email [email protected]: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible expiratory airflow obstruction, and its chronic course is worsened by recurrent acute exacerbations. Our previous microarray assay identified microRNA (miR)-301a-5p as being associated with progression of acute exacerbation of COPD (AE-COPD); however, the mechanism underlying COPD pathogenesis remains unknown.Methods: Samples of serum and peripheral blood mononuclear cells (PBMCs) were isolated from healthy control subjects and patients with stable COPD (R-COPD) or with an acute exacerbation of COPD (AE-COPD). Human HULEC-5a and human bronchial epithelial (HBE) cells were transfected with methyl-CpG-binding domain protein 2 (MBD2), sh-MBD2, miR-301a-5p mimics or an inhibitor, and then stimulated with cigarette smoke extract (CSE). Conditioned medium co-culture assays were performed by adding the supernatant of medium derived from HULEC-5a cells transfected with miR-301a-5p mimics or inhibitor into wells containing si-c-x-c motif chemokine receptor 4 (CXCR4)-transfected-lung fibroblasts or human leukemic THP-1 cell line macrophages. Transwell assays were performed to analyze cell migration.Results: Our analysis of clinical samples showed that decreased miR-301a-5p levels in patients with AE-COPD were positively correlated with levels of MBD2 expression, but negatively correlated with levels of chemokine ligand C-X-C motif chemokine ligand 12 (CXCL12) expression. MBD2 overexpression significantly promoted miR-301a-5p production, but suppressed CXCL12 production in HULEC-5a and HBE cells. CXCL12 was confirmed to be a direct target of miR-301a-5p. CXCR4 knockdown significantly enhanced the suppressive effect of miR-301a-5p mimics and attenuated the promotional effects of the miR-301a-5p inhibitor on the migration of circulating fibroblasts and macrophages, as well as the expression levels of phospho-mitogen-activated protein kinase (p-MEK) and phospho-protein kinase B (p-AKT).Conclusion: In summary, the MBD2/miR-301a-5p/CXCL12/CXCR4 pathway was shown to affect the migration of lung fibroblasts and monocyte-derived macrophages, which may play an important role during COPD exacerbations.Keywords: chronic obstructive pulmonary disease, microRNA-301a-5p, inflammatory chemokine, cell recruitment

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