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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

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Abstract

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.

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Acknowledgements

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.

Funding

This study was supported by the National Natural Science Foundation of China (grant number 81470220, 81470219), Science and Technology Planning Project of Guangdong Province, China (grant number 2016A020215220), Science and Technology Program of Guangzhou, China (grant number 201707010076), and Natural Science Foundation of Guangdong Province, China (grant number S2013010015990). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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    1. Department of Respiratory Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-Sen University, Guangzhou, People’s Republic of China

      Hong-tao Li, Yu-sen Lin, Hui Liu, Xiao-ling Zou, Yan-hong Wang, Hai-ling Yang & Tian-tuo Zhang

    2. Department of Pediatrics, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China

      Zhuang-gui Chen

    3. Department of Otolaryngology, Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China

      Jin Ye

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    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 ([2014]2-11).

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    Hong-tao Li and Zhuang-gui Chen contributed equally to this work.

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    Supplementary Fig. 1

    CpG-ODNs and BUD synergistically alleviate nose and lung inflammation as well as other nasal symptoms. OVA-sensitized and challenged mice received intranasal treatment with CpG-ODNs and BUD 1 h after each OVA challenge, and histological examination of the nose and lung was performed 48 h after final OVA exposure. (A) Eosinophils in the BALF were counted under a light microscope. (B) Lung inflammation scores were obtained as described in the main text. Sneezing (C) and nasal rubbing (D) events after the last nasal challenge were counted. Representative photomicrographs of lung sections stained with H&E for cell infiltrate assessment (E). Original magnification, ×200. Representative micrographs for pathological and morphological changes in nasal tissues, as obtained by H&E (F) and PAS (G) staining. Original magnification, ×400; scale bars, 50 μm. (DOC 14710 kb)

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    Li, Ht., Chen, Zg., Lin, Ys. et al. 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. Inflammation 41, 1304–1320 (2018). https://doi.org/10.1007/s10753-018-0779-6

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