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Interplay of IL-33 and IL-35 Modulates Th2/Th17 Responses in Cigarette Smoke Exposure HDM-Induced Asthma

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Abstract

Cigarette smoke (CS) facilitates adverse effects on the airway inflammation and treatment of asthma. Here, we investigated the mechanisms by which CS exacerbates asthma. The roles of IL-33 and IL-35 in asthma development were examined by treatment with IL-33 knockout (IL-33 KO) or transfection of adenovirus encoding IL-35 (Ad-IL-35) in a murine model of cigarette smoke-exposure asthma. Furthermore, the involvement of IL-33 and IL-35 in regulating DCs and Th2/Th17 cells was examined in a coculture system of DCs with CD4+ T cells. Additionally, we observed the effect of CpG-ODNs on the balance of IL-33 and IL-35. We show that CS and house dust mite (HDM) exposure induced IL-33 and suppressed IL-35 levels in cigarette smoke-exposure asthma in vivo and in vitro. Treatment with IL-33 KO or Ad-IL-35 significantly attenuated airway hyperreactivity, goblet hyperplasia, airway remodelling, and eosinophil and neutrophil infiltration in the lung tissues from asthmatic mice. Furthermore, we demonstrated reciprocal regulation between CS and HDM-modulated IL-33 and IL-35. Mechanistically, IL-33 KO (or anti-ST2) and Ad-IL-35 attenuated Th2- and Th17-associated inflammation by downregulating TSLP-DC signalling. Finally, administration of CpG-ODNs suppressed the expression of IL-33/ST2 and elevated the levels of IL-35, which is mainly derived from CD4+Foxp+ Tregs, to alleviate Th2- and Th17-associated inflammation by inhibiting the activation of BMDCs. Taken together, the IL-33/ST2 pathway drives the DC-Th2 and Th17 responses of cigarette smoke-exposure asthma, while IL-35 has the opposite effect. CpG-ODNs represent a potential therapeutic strategy for modulating the balance of IL-33 and IL-35 to suppress allergic airway inflammation.

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The data used to support the findings of this study are included within the article and the supplementary information file.

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Acknowledgements

The authors express their gratitude to J Liu (Guangzhou Laide Liankang Biotechnology Co., Ltd.) for her assistance in establishing the mouse model. We sincerely thank Prof. Kefang Lai and Dr. Chuqin Huang (State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China) for invasive lung function assessment in mice. The current manuscript was revised by a native English speaking editor at American Journal Experts (AJE).

Funding

This study was funded by grants from National Natural Science Foundation of China (No. 81973984 and 81970017), and Basic and Applied Basic Research Foundation of Guangdong Province (No.2019A1515010918).

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  1. Department of Pulmonary and Critical Care 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

    **g Liu, Beiting Su, Peizhi Tao, Li Zheng, Yusen Lin, **aoling Zou, Hailing Yang, Wenbin Wu, Tiantuo Zhang & Hongtao Li

  2. Department of Pulmonary and Critical Care Medicine, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, People’s Republic of China

    Xuena Yang

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Contributions

J Liu, BT Su, and PZ Tao drafted the article. J Liu, BT Su, PZ Tao, XN Yang, L Zheng, YS Lin, XL Zou, HL Yang, and WB Wu performed the experiments and contributed to acquisition of data. J Liu, BT Su, PZ Tao, XN Yang, L Zheng, TT Zhang, and HT Li analysed the data. HT Li and TT Zhang designed the study and revised the article. All authors read and approved the final manuscript.

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Correspondence to Tiantuo Zhang or Hongtao Li.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University.

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Liu, J., Su, B., Tao, P. et al. Interplay of IL-33 and IL-35 Modulates Th2/Th17 Responses in Cigarette Smoke Exposure HDM-Induced Asthma. Inflammation 47, 173–190 (2024). https://doi.org/10.1007/s10753-023-01902-6

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