818 | wileyonlinelibrary.com/journal/all Allergy. 2020;75:818–830. © 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. Received: 24 January 2019 | Revised: 17 September 2019 | Accepted: 2 October 2019 DOI: 10.1111/all.14091 ORIGINAL ARTICLE Asthma and Lower Airway Disease Pulmonary IL-33 orchestrates innate immune cells to mediate respiratory syncytial virus-evoked airway hyperreactivity and eosinophilia Yi-Hsiu Wu 1,2 | Alan Chuan-Ying Lai 2 | Po-Yu Chi 2 | Christina Li-Ping Thio 2 | Wei-Yu Chen 3 | Ching-Hui Tsai 4 | Yungling Leo Lee 2,4 | Nicholas W. Lukacs 5 | Ya-Jen Chang 1,2 Abbreviations: AHR, airway hyperreactivity; BALF, bronchoalveolar lavage fluid; DC, dendritic cell; ILC, innate lymphoid cell; ILC2, group 2 innate lymphoid cell; PFU, plaque‐forming unit; RSV, respiratory syncytial virus; WT, wild type. 1 Taiwan International Graduate Program in Molecular Medicine, National Yang‐Ming University and Academia Sinica, Taipei, Taiwan 2 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 3 Institute for Translational Research in Biomedicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan 4 Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan 5 Department of Pathology, University of Michigan, Ann Arbor, MI, USA Correspondence Ya‐Jen Chang, Institute of Biomedical Sciences, Academia Sinica, No. 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan. Email: yajchang@ibms.sinica.edu.tw Funding information This work was supported in part by the Ministry of Science and Technology [105‐2628‐B‐001‐009‐MY3 to YJC] and by the Academia Sinica Career Development Award [104‐CDA‐L05 to YJC] in Taiwan. Abstract Background: Respiratory syncytial virus (RSV) infection is epidemiologically linked to asthma. During RSV infection, IL‐33 is elevated and promotes immune cell activation, leading to the development of asthma. However, which immune cells are responsible for triggering airway hyperreactivity (AHR), inflammation and eosinophilia remained to be clarified. We aimed to elucidate the individual roles of IL‐33‐activated innate immune cells, including ILC2s and ST2 + myeloid cells, in RSV infection‐triggered pathophysiology. Methods: The role of IL‐33/ILC2 axis in RSV‐induced AHR inflammation and eosino‐ philia were evaluated in the IL‐33‐deficient and YetCre‐13 Rosa‐DTA mice. Myeloid‐ specific, IL‐33‐deficient or ST2‐deficient mice were employed to examine the role of IL‐33 and ST2 signaling in myeloid cells. Results: We found that IL‐33‐activated ILC2s were crucial for the development of AHR and airway inflammation, during RSV infection. ILC2‐derived IL‐13 was suffi‐ cient for RSV‐driven AHR, since reconstitution of wild‐type ILC2 rescued RSV‐driven AHR in IL‐13‐deficient mice. Meanwhile, myeloid cell‐derived IL‐33 was required for airway inflammation, ST2 + myeloid cells contributed to exacerbation of airway in‐ flammation, suggesting the importance of IL‐33 signaling in these cells. Local and peripheral eosinophilia is linked to both ILC2 and myeloid IL‐33 signaling. Conclusions: This study highlights the importance of IL‐33‐activated ILC2s in mediat‐ ing RSV‐triggered AHR and eosinophilia. In addition, IL‐33 signaling in myeloid cells is crucial for airway inflammation. KEYWORDS asthma, eosinophilia, IL‐33, ILC2, respiratory syncytial virus