Pulmonary IL- 33 orchestrates innate immune cells to mediate respiratory syncytial virus- evoked airway hyperreactivity and eosinophilia

Abstract

BackgroundRespiratory 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.MethodsThe role of IL- 33/ILC2 axis in RSV- induced AHR inflammation and eosinophilia 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.ResultsWe found that IL- 33- activated ILC2s were crucial for the development of AHR and airway inflammation, during RSV infection. ILC2- derived IL- 13 was sufficient 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 inflammation, suggesting the importance of IL- 33 signaling in these cells. Local and peripheral eosinophilia is linked to both ILC2 and myeloid IL- 33 signaling.ConclusionsThis study highlights the importance of IL- 33- activated ILC2s in mediating RSV- triggered AHR and eosinophilia. In addition, IL- 33 signaling in myeloid cells is crucial for airway inflammation.Respiratory syncytial virus induces ILC2 to produce IL- 5 and IL- 13 through IL- 33, which is crucial for the development of airway hyperreactivity and airway inflammation. Myeloid cell- derived IL- 33 and suppression of tumorigenicity 2- positive myeloid cells contribute to cytokine production and cellular inflammation in airway. Both ILC2 and myeloid cell IL- 33 signaling contribute to local and peripheral eosinophilia.