Original Article

Serum Exosome-Derived MiR-7 Exacerbates Chronic Obstructive Pulmonary Disease by Regulating Macrophage Differentiation

Abstract

Background: Polarization of macrophages and miR-7 have been reported to greatly influence the progress of chronic obstructive pulmonary disease (COPD). However, the interaction is unclear. We aimed to investigate the role of miR-7 in the serum exosome of COPD, thus further revealing the underlying mechanism of COPD.

Methods: The study was conducted in 2022 in The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, China. COPD mouse model was established. Macrophages were sorted by flow cytometry assay. ELISA kits were used to detect the levels of TNF-α and IL-6. Exosomes were identified by confocal microscopy and PKH67 staining. RT-qPCR and western blot assay were performed to determine the mRNA and protein expressions. H&E staining assay was used to assess the tissue injury. CCK-8 assay was applied to evaluate cell viability. Luciferase reporter assay was used to confirm the binding between PIM1 and miR-7. 

Results: The exosomes derived from the COPD mice serum exerted high level of miR-7, which induced M1 differentiation of macrophages and increased the secretion of proinflammatory factors in vivo and in vitro. The effects of exosomes from COPD mice could be inhibited by miR-7 inhibitor. Bioinformatic prediction, luciferase reporter assay, and western blot assay showed an interaction between miR-7 and PIM1. Further examination showed that miR-7 regulated macrophage activation and differentiation to M1 via PIM1 in vitro.

Conclusions: miR-7 from serum exosomes might exacerbate COPD by stimulating macrophage differentiation to M1, supplying a potential therapeutic target for COPD treatment.

 

1. López-Campos JL, Tan W, Soriano JB (2016). Global burden of COPD. Respirology, 21(1):14-23.
2. Pauwels RA, Rabe KF (2004). Burden and clinical features of chronic obstructive pulmonary disease (COPD). Lancet, 364(9434):613-20.
3. Zuo L, He F, Sergakis GG, et al (2014). Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments. Am J Physiol Lung Cell Mol Physiol, 307(3):L205-18.
4. Agustí A, Edwards LD, Rennard SI, et al (2012). Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One, 7(5):e37483.
5. Barnes PJ (2004). Alveolar macrophages in chronic obstructive pulmonary disease (COPD). Cell Mol Biol (Noisy-le-grand), 50 Online Pub:OL627-37.
6. Karadag F, Karul AB, Cildag O, Yilmaz M, Ozcan H (2008). Biomarkers of systemic inflammation in stable and exacerbation phases of COPD. Lung, 186(6):403-9.
7. Eapen MS, Hansbro PM, McAlinden K, et al (2017). Abnormal M1/M2 macrophage phenotype profiles in the small airway wall and lumen in smokers and chronic obstructive pulmonary disease (COPD). Sci Rep, 7(1):13392.
8. Saetta M, Baraldo S, Corbino L, et al (1999). CD8+ve cells in the lungs of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 160(2):711-7.
9. Hogg JC, Chu F, Utokaparch S, et al (2004). The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med, 350(26):2645-53.
10. Szymczak I, Wieczfinska J, Pawliczak R (2016). Molecular Background of miRNA Role in Asthma and COPD: An Updated Insight. Biomed Res Int, 2016:7802521.
11. Correa-Medina M, Bravo-Egana V, Rosero S, et al (2009). MicroRNA miR-7 is preferentially expressed in endocrine cells of the developing and adult human pancreas. Gene Expr Patterns, 9(4):193-9.
12. Titze-de-Almeida R, Titze-de-Almeida SS (2018). miR-7 Replacement Therapy in Parkinson's Disease. Curr Gene Ther, 18(3):143-153.
13. Akbas F, Coskunpinar E, Aynaci E, Oltulu YM, Yildiz P (2012). Analysis of serum micro-RNAs as potential biomarker in chronic obstructive pulmonary disease. Exp Lung Res, 38(6):286-94.
14. Vlahos R, Bozinovski S, Gualano RC, Ernst M, Anderson GP (2006). Modelling COPD in mice. Pulm Pharmacol Ther, 19(1):12-7.
15. McGrath JC, Drummond GB, McLachlan EM, Kilkenny C, Wainwright CL (2010). Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br J Pharmacol, 160(7):1573-6.
16. Diaz EA, Chung Y, Lamoureux DP, et al (2013). Effects of fresh and aged traffic-related particles on breathing pattern, cellular responses, and oxidative stress. Air Quality, Atmosphere and Health, 6(2):431-444.
17. Canan CH, Gokhale NS, Carruthers B, et al (2014). Characterization of lung inflammation and its impact on macrophage function in aging. J Leukoc Biol, 96(3):473-80.
18. Livak KJ, Schmittgen TD (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods, 25(4):402-408.
19. Tanaka Y, Kamohara H, Kinoshita K, et al (2013). Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer, 119(6):1159-67.
20. Wu Y, Liu Y, Huang H, et al (2013). Dexmedetomidine inhibits inflammatory reaction in lung tissues of septic rats by suppressing TLR4/NF-κB pathway. Mediators Inflamm, 2013:562154.
21. Feng F, Jin Y, Duan L, et al (2016). Regulation of ozone-induced lung inflammation by the epidermal growth factor receptor in mice. Environ Toxicol, 31(12):2016-2027.
22. Santangelo A, Imbrucè P, Gardenghi B, et al (2018). A microRNA signature from serum exosomes of patients with glioma as complementary diagnostic biomarker. J Neurooncol, 136(1):51-62.
23. Madhavan B, Yue S, Galli U, et al (2015). Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. Int J Cancer, 136(11):2616-27.
24. Velasco-Torres Y, Ruiz-López V, Pérez-Bautista O, et al (2019). miR-34a in serum is involved in mild-to-moderate COPD in women exposed to biomass smoke. BMC Pulm Med, 19(1):227.
25. Xu H, Ling M, Xue J, et al (2018). Exosomal microRNA-21 derived from bronchial epithelial cells is involved in aberrant epithelium-fibroblast cross-talk in COPD induced by cigarette smoking. Theranostics, 8(19):5419-5433.
26. Rosas-Alonso R, Galera R, Sánchez-Pascuala JJ, et al (2020). Hypermethylation of Anti-oncogenic MicroRNA 7 is Increased in Emphysema Patients. Arch Bronconeumol (Engl Ed), 56(8):506-513.
27. Santio NM, Koskinen PJ (2017). PIM kinases: From survival factors to regulators of cell motility. Int J Biochem Cell Biol, 93:74-85.
28. Wang J, Cao Y, Liu Y, Zhang X, Ji F, Li J, Zou Y (2019). PIM1 inhibitor SMI-4a attenuated lipopolysaccharide-induced acute lung injury through suppressing macrophage inflammatory responses via modulating p65 phosphorylation. Int Immunopharmacol, 73:568-574.
29. de Vries M, Heijink IH, Gras R, et al (2014). Pim1 kinase protects airway epithelial cells from cigarette smoke-induced damage and airway inflammation. Am J Physiol Lung Cell Mol Physiol, 307(3):L240-51.
Files
IssueVol 52 No 3 (2023) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijph.v52i3.12139
Keywords
Chronic obstructive pulmonary disease Macrophage cells M1 cells

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Jiang Y, Wang J, Zhang H, Min Y, Gu T. Serum Exosome-Derived MiR-7 Exacerbates Chronic Obstructive Pulmonary Disease by Regulating Macrophage Differentiation. Iran J Public Health. 2023;52(3):563-574.