Chronic obstructive pulmonary disease (COPD) is a highly prevalent respiratory disease characterized by airflow limitation and chronic inflammation. MiR-155 is described as an ancient regulator of the immune system. Our objective was to establish a role for miR-155 in cigarette smoke (CS)-induced inflammation and COPD. We demonstrate increased miR-155 expression by RT-qPCR in lung tissue of smokers without airflow limitation and patients with COPD compared to never smokers and in lung tissue and alveolar macrophages of CS-exposed mice compared to air-exposed mice. In addition, we exposed wild type and miR-155 deficient mice to CS and show an attenuated inflammatory profile in the latter. Alveolar macrophages were sorted by FACS from the different experimental groups and their gene expression profile was analyzed by RNA sequencing. This analysis revealed increased expression of miR-155 targets and an attenuation of the CS-induced increase in inflammation-related genes in miR-155 deficient mice. Moreover, intranasal instillation of a specific miR-155 inhibitor attenuated the CS-induced pulmonary inflammation in mice. Finally, elastase-induced emphysema and lung functional changes were significantly attenuated in miR-155 deficient mice. In conclusion, we highlight a role for miR-155 in CS-induced inflammation and the pathogenesis of COPD, implicating miR-155 as a new therapeutic target in COPD.
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Vogelmeier, C. F. et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary. Eur. Respir. J. 2017; 49, pii:1700214.
WHO. Burden of disease. http://www.who.int/topics/global_burden_of_disease/en/.
Murray, C. J. & Lopez, A. D. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 349, 1498–1504 (1997).
Hogg, J. C. & Timens, W. The pathology of chronic obstructive pulmonary disease. Annu. Rev. Pathol. 4, 435–459 (2009).
Abboud, R. T. & Vimalanathan, S. Pathogenesis of COPD. Part I. The role of protease-antiprotease imbalance in emphysema. Int. J. Tuberculosis Lung Dis. 12, 361–367 (2008).
Yang, S. R. et al. Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L46–L57 (2006).
Vigorito, E., Kohlhaas, S., Lu, D. & Leyland, R. miR-155: an ancient regulator of the immune system. Immunol. Rev. 253, 146–157 (2013).
Taganov, K. D., Boldin, M. P., Chang, K. J. & Baltimore, D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl Acad. Sci. USA 103, 12481–12486 (2006).
Thai, T. H. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007).
O'Connell, R. M., Taganov, K. D., Boldin, M. P., Cheng, G. & Baltimore, D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl Acad. Sci. USA 104, 1604–1609 (2007).
Haasch, D. et al. T cell activation induces a noncoding RNA transcript sensitive to inhibition by immunosuppressant drugs and encoded by the proto-oncogene, BIC. Cell Immunol. 217, 78–86 (2002).
Bluml, S. et al. Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice. Arthritis Rheum. 63, 1281–1288 (2011).
Singh, U. P. et al. miR-155 deficiency protects mice from experimental colitis by reducing T helper type 1/type 17 responses. Immunology 143, 478–489 (2014).
Zhang, J. et al. MicroRNA-155 modulates Th1 and Th17 cell differentiation and is associated with multiple sclerosis and experimental autoimmune encephalomyelitis. J. Neuroimmunol. 266, 56–63 (2014).
O'Connell, R. M. et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33, 607–619 (2010).
Murugaiyan, G., Beynon, V., Mittal, A., Joller, N. & Weiner, H. L. Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J. Immunol. 187, 2213–2221 (2011).
Johansson, K., Malmhall, C., Ramos-Ramirez, P. & Radinger, M. MicroRNA-155 is a critical regulator of type 2 innate lymphoid cells and IL-33 signaling in experimental models of allergic airway inflammation. J. Allergy Clin. Immunol. 139, 1007–1016, e9 (2016).
Malmhall, C. et al. MicroRNA-155 is essential for TH2-mediated allergen-induced eosinophilic inflammation in the lung. J. Allergy Clin. Immunol. 133, 1429–1438, e1427 (2014).
Zech, A. et al. MicroRNA-155 modulates P2R signaling and Th2 priming of dendritic cells during allergic airway inflammation in mice. Allergy 70, 1121–1129 (2015).
Wang, W. et al. Macrophage micro-RNA-155 promotes lipopolysaccharide-induced acute lung injury in mice and rats. Am. J. Physiol. Lung Cell Mol. Physiol. 311, L494–L506 (2016).
Xu, F. et al. Akt1-mediated regulation of macrophage polarization in a murine model of Staphylococcus aureus pulmonary infection. J. Infect. Dis. 208, 528–538 (2013).
Lu, Z. J. et al. MicroRNA-155 promotes the pathogenesis of experimental colitis by repressing SHIP-1 expression. World J. Gastroenterol. 23, 976–985 (2017).
Barnes, P. J. Alveolar macrophages as orchestrators of COPD. COPD 1, 59–70 (2004).
Culpitt, S. V. et al. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med 167, 24–31 (2003).
Finlay, G. A. et al. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am. J. respiratory Crit. Care Med. 156, 240–247 (1997).
Shapiro, S. D. The macrophage in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 160(5 Pt 2), S29–S32 (1999).
Conickx, G. et al. MicroRNA Profiling Reveals a Role for MicroRNA-218-5p in the Pathogenesis of Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 195, 43–56 (2017).
Conickx, G. et al. microRNA profiling in lung tissue and bronchoalveolar lavage of cigarette smoke-exposed mice and in COPD patients: a translational approach. Sci. Rep. 7, 12871 (2017).
The miRNA body-map. http://mellfire.ugent.be/public/body_map/index.php.
Allen, N. P. et al. RASSF6 is a novel member of the RASSF family of tumor suppressors. Oncogene 26, 6203–6211 (2007).
Elmesmari, A. et al. MicroRNA-155 regulates monocyte chemokine and chemokine receptor expression in Rheumatoid Arthritis. Rheumatology 55, 2056–2065 (2016).
Ma, L., Xue, H. B., Wang, F., Shu, C. M. & Zhang, J. H. MicroRNA-155 may be involved in the pathogenesis of atopic dermatitis by modulating the differentiation and function of T helper type 17 (Th17) cells. Clin. Exp. Immunol. 181, 142–149 (2015).
Kurowska-Stolarska, M. et al. The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis. J. Allergy Clin. Immunol. 139, 1946–1956 (2017).
Bruning, U. et al. MicroRNA-155 promotes resolution of hypoxia-inducible factor 1alpha activity during prolonged hypoxia. Mol. Cell Biol. 31, 4087–4096 (2011).
Nazari-Jahantigh, M. et al. MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages. J. Clin. Invest 122, 4190–4202 (2012).
O'Connell, R. M., Chaudhuri, A. A., Rao, D. S. & Baltimore, D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc. Natl Acad. Sci. USA 106, 7113–7118 (2009).
Androulidaki, A. et al. The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity 31, 220–231 (2009).
Bandyopadhyay, S., Long, M. E. & Allen, L. A. Differential expression of microRNAs in Francisella tularensis-infected human macrophages: miR-155-dependent downregulation of MyD88 inhibits the inflammatory response. PLoS ONE 9, e109525 (2014).
Li, Y., Ma, D., Wang, Z. & Yang, J. MicroRNA-155 deficiency in Kupffer cells Ameliorates liver ischemia-reperfusion injury in mice. Transplantation 101, 1600–1608 (2017).
Mann, M. et al. An NF-kappaB-microRNA regulatory network tunes macrophage inflammatory responses. Nat. Commun. 8, 851 (2017).
Bohlson, S. S., Fraser, D. A. & Tenner, A. J. Complement proteins C1q and MBL are pattern recognition molecules that signal immediate and long-term protective immune functions. Mol. Immunol. 44, 33–43 (2007).
Demoor, T. et al. The role of ChemR23 in the induction and resolution of cigarette smoke-induced inflammation. J. Immunol. 186, 5457–5467 (2011).
Hautamaki, R. D., Kobayashi, D. K., Senior, R. M. & Shapiro, S. D. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277, 2002–2004 (1997).
Churg, A. et al. Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-alpha release. Am. J. Respiratory Crit. Care Med. 167, 1083–1089 (2003).
Hancock, D. B. et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat. Genet. 42, 45–52 (2010).
Wang, L. et al. Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-kappaB-dependent manner. Cell Stem Cell 15, 51–65 (2014).
D'Hulst, A. I., Vermaelen, K. Y., Brusselle, G. G., Joos, G. F. & Pauwels, R. A. Time course of cigarette smoke-induced pulmonary inflammation in mice. Eur. Respir. J. 26, 204–213 (2005).
Seys, L. J. et al. Role of B cell-activating factor in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 192, 706–718 (2015).
Bracke, K. R. et al. Role of CXCL13 in cigarette smoke-induced lymphoid follicle formation and chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 188, 343–355 (2013).
Bracke, K. R. et al. Cigarette smoke-induced pulmonary inflammation and emphysema are attenuated in CCR6-deficient mice. J. Immunol. 177, 4350–4359 (2006).
Bracke, K. R. et al. Cigarette smoke-induced pulmonary inflammation, but not airway remodelling, is attenuated in chemokine receptor 5-deficient mice. Clin. Exp. Allergy 37, 1467–1479 (2007).
Lanckacker, E. A. et al. Short cigarette smoke exposure facilitates sensitisation and asthma development in mice. Eur. Respir. J. 41, 1189–1199 (2013).
Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).
The authors would like to thank Greet Barbier, Indra De Borle, Katleen De Saedeleer, Anouck Goethals, Marie-Rose Mouton and Ann Neesen (Department of Respiratory Medicine, Ghent University) for their excellent technical assistance. We would also like to thank Prof. Wim Janssens and Dr. Bart Vanaudenaerde (Department of Pneumology, Catholic University of Leuven) for providing us with explant lungs of patients with severe COPD, and Prof. Dirk Elewaut (Department of Rheumatology, Ghent University) for the use of the FACSAria. The research described in this article was supported by the Concerted Research Action of the Ghent University (BOF/GOA, 01G02714 and 01G00819) and by the Fund for Scientific Research in Flanders (FWO Vlaanderen, G052518N and EOS‐contract G0G2318N). F.M.V. and S.P. are post-doctoral researchers of the Fund for Scientific Research–Flanders and this work was further supported by a Special Research Fund (BOF) scholarship of Ghent University to Francisco Avila Cobos (BOF.DOC.2017.0026.01).
G.F.J. reports grants and personal fees from AstraZeneca, grants from Chiesi, personal fees from Eureca, grants and personal fees from GlaxoSmithKline, grants and personal fees from Novartis, personal fees from Teva, outside the submitted work. T.M. reports grants from Belspo, grants from Ghent University, during the conduct of the study; personal fees from GlaxoSmithKline, outside the submitted work; and is shareholder of Oryzon Genomics. All other authors have nothing to disclose.
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De Smet, E.G., Van Eeckhoutte, H.P., Avila Cobos, F. et al. The role of miR-155 in cigarette smoke-induced pulmonary inflammation and COPD. Mucosal Immunol 13, 423–436 (2020). https://doi.org/10.1038/s41385-019-0241-6
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