CpG-ODNs and Budesonide Act Synergistically to Improve Allergic Responses in Combined Allergic Rhinitis and Asthma Syndrome Induced by Chronic Exposure to Ovalbumin by Modulating the TSLP-DC-OX40L Axis
The experimental model of combined allergic rhinitis and asthma syndrome (CARAS) has shown that CpG oligodeoxynucleotides (CpG-ODNs) are potential inhibitors of type 2 helper cell-driven inflammatory responses. Currently available CpG-ODNs modestly inhibit allergic responses in CARAS, while a combination strategy for upper airway treatment by co-administration of CpG-ODNs and glucocorticoids may show good efficacy. This study aimed to assess the therapeutic effects of CpG-ODNs combined with budesonide (BUD) on upper and lower-airway inflammation and remodeling in mice with CARAS induced by chronic exposure to ovalbumin (OVA), exploring the possible underlying molecular mechanisms. A BALB/c mouse model of chronic CARAS was established by systemic sensitization and repeated challenge with OVA. Treatment with CpG-ODNs or BUD by intranasal administration was started 1 h after OVA challenge. Then, nasal mucosa and lung tissues were fixed and stained for pathologic analysis. The resulting immunologic variables and TSLP-DC-OX40L axis parameters were evaluated. Both CpG-ODNs and BUD intranasal administration are effective on reducing Th2-type airway inflammation and tissue remodeling. Co-administration of CpG-ODNs and BUD was more effective than each monotherapy in attenuating upper and lower-airway inflammation as well as airway remodeling in chronic CARAS. Notably, combination of CpG-ODNs with BUD modulated the TSLP-DC-OX40L axis, as demonstrated by decreased TSLP production in the nose and lung, alongside decreased TSLPR and OX40L in DC. Intranasal co-administration of CpG-ODNs and BUD synergistically alleviates airway inflammation and tissue remodeling in experimental chronic CARAS, through shared cellular pathways, as a potent antagonist of the TSLP-DC-OX40L axis.
KEY WORDSBronchial asthma Allergic rhinitis CpG oligodeoxynucleotides Dendritic cells Thymic stromal lymphopoietin
We gratefully thank Qing Liu for helping us to establish the animal model. We also thank Rong Yao for administrative assistance. This manuscript was edited for English language by MedSci.
Compliance with Ethical Standards
All the animal experiments conformed to the principles for the care and use of animals in biomedical research. The study protocol was approved by the ethics committee of animal experiments of the Vaccine Research Institute of Sun Yat-Sen University vivarium (2-11).
The authors declare that they have no competing interests.
- 5.Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2016. Available from: http://www.ginasthma.org.
- 8.Chung, K.F., S.E. Wenzel, J.L. Brozek, A. Bush, M. Castro, P.J. Sterk, I.M. Adcock, E.D. Bateman, E.H. Bel, E.R. Bleecker, L.P. Boulet, C. Brightling, P. Chanez, S.E. Dahlen, R. Djukanovic, U. Frey, M. Gaga, P. Gibson, Q. Hamid, N.N. Jajour, T. Mauad, R.L. Sorkness, and W.G. Teague. 2014. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. The European Respiratory Journal 43 (2): 343–373.CrossRefPubMedGoogle Scholar
- 11.Zhao, S., Y. Jiang, X. Yang, D. Guo, Y. Wang, J. Wang, R. Wang, and C. Wang. 2017. Lipopolysaccharides promote a shift from Th2-derived airway eosinophilic inflammation to Th17-derived neutrophilic inflammation in an ovalbumin-sensitized murine asthma model. The Journal of Asthma 54 (5): 447–455.CrossRefPubMedGoogle Scholar
- 12.RS, Irwin, and N.D. Richardson. 2006. Side effects with inhaled corticosteroids: the physician’s perception. Chest 130 (S1): 41S–53S.Google Scholar
- 13.Zöllner, E.W., C. Lombard, U. Galal, S. Hough, E. Irusen, and E. Weinberg. 2011. Hypothalamicpituitary-adrenal axis suppression in asthmatic children on inhaled and nasal corticosteroids-more common than expected? Journal of Pediatric Endocrinology & Metabolism 24 (7–8): 529–534.Google Scholar
- 18.Marshall, J.D., K. Fearon, C. Abbate, S. Subramanian, P. Yee, J. Gregorio, R.L. Coffman, and G. Van Nest. 2003. Identification of a novel CpG DNA class and motif that optimally stimulate B cell and plasmacytoid dendritic cell functions. Journal of Leukocyte Biology 73: 781–792.CrossRefPubMedGoogle Scholar
- 19.Li, H.T., T.T. Zhang, Z.G. Chen, J. Ye, H. Liu, X.L. Zou, Y.H. Wang, and H.L. Yang. 2015. Intranasal administration of CpG oligodeoxynucleotides reduces lower airway inflammation in a murine model of combined allergic rhinitis and asthma syndrome. International Immunopharmacology 28 (1): 390–398.CrossRefPubMedGoogle Scholar
- 20.Li, H.T., Z.G. Chen, H. Liu, J. Ye, X.L. Zou, Y.H. Wang, H.L. Yang, P. Meng, and T.T. Zhang. 2016. Treatment of allergic rhinitis with CpG oligodeoxynucleotides alleviates the lower airway outcomes of combined allergic rhinitis and asthma syndrome via a mechanism that possibly involves in TSLP. Experimental Lung Research 42 (6): 322–333.CrossRefPubMedGoogle Scholar
- 22.Chen, Z.G., P. Meng, H.T. Li, M. Li, L.F. Yang, Y. Yan, Y.T. Li, X.L. Zou, D.Y. Wang, and T.T. Zhang. 2017. Thymic stromal lymphopoietin contribution to the recruitment of circulating fibrocytes to the lung in a mouse model of chronic allergic asthma. The Journal of Asthma 3: 1–9. https://doi.org/10.1080/02770903.2017.1386213.CrossRefGoogle Scholar
- 37.Leigh, R., R. Ellis, J.N. Wattie, J.A. Hirota, K.I. Matthaei, P.S. Foster, P.M. O'Byrne, and M.D. Inman. 2004. Type 2 cytokines in the pathogenesis of sustained airway dysfunction and airway remodeling in mice. American Journal of Respiratory and Critical Care Medicine 169 (7): 860–867.CrossRefPubMedGoogle Scholar
- 47.Xanthou, G., T. Alissafi, M. Semitekolou, D.C. Simoes, E. Economidou, M. Gaga, B.N. Lambrecht, C.M. Lloyd, and V. Panoutsakopoulou. 2007. Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets. Nature Medicine 13 (5): 570–578.CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Idzko, M., H. Hammad, M. van Nimwegen, M. Kool, M.A. Willart, F. Muskens, H.C. Hoogsteden, W. Luttmann, D. Ferrari, F. Di Virgilio, J.C. Virchow Jr., and B.N. Lambrecht. 2007. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nature Medicine 13 (8): 913–919.CrossRefPubMedGoogle Scholar
- 53.Ahrens, B., T. Freund, R.D. Rha, A.M. Dittrich, D. Quarcoo, A. Hutloff, and E. Hamelmann. 2009. Lipopolysaccharide stimulation of dendritic cells induces interleukin-10 producing allergen-specific T cells in vitro but fails to prevent allergic airway disease. Experimental Lung Research 35 (4): 307–323.CrossRefPubMedGoogle Scholar