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

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 eosinophilia were evaluated in the IL-33-deficient and YetCre-13 Rosa-DTA mice. Myeloidspecific, 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 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. Conclusions:This 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. K E Y W O R D S asthma, eosinophilia, IL-33, ILC2, respiratory syncytial virus | 819 WU et al.

Role of IL‐25, IL‐33, and TSLP in triggering united airway diseases toward type 2 inflammation

“…In addition, the recruitment of ILC2s induced by vascular cell adhesion molecule 1 (VCAM‐1) in the endothelial cells of the lung depends on the receptor for advanced glycation end products (RAGE) 54‐56 . Stimulations of mice with recombinant IL‐33 resulted in blood eosinophilia, and increased serum levels of IgE, IgA, IL‐5, IL‐13, and splenomegaly, while anti–IL‐33 treatment significantly reduced nose‐scratching events, ameliorated nasal cavity eosinophilia, and downregulated serum IgE levels in the murine model of AR 57 …”

The Role of Dendritic Cells During Infections Caused by Highly Prevalent Viruses

“…The disease caused by hRSV is characterized mainly by the infiltration of eosinophils and neutrophils into the airways. An increase infiltration of neutrophils can contribute to lung damage (210)(211)(212). Even though CD8 + T cells are key in the clearance of the virus, it has been reported that the depletion of the CD4 + and CD8 + T cells in mice decreased the severity of the illness (213)(214)(215).…”

Regulatory B Lymphocytes Colonize the Respiratory Tract of Neonatal Mice and Modulate Immune Responses of Alveolar Macrophages to RSV Infection in IL-10-Dependant Manner

“…Finally, IFN-I is not the only modulator of CD5 + nBreg function. IL-33, an alarmin that belongs to the IL-1 family, is rapidly secreted following RSV exposure in neonates and contributes to the promotion of type-2 responses by promoting IL-13 and IL-5 production by ILC2 [13,45]. Recently, the importance of ILC2 in shaping the immune response early during RSV infection has been revealed in infants [46].…”

“…Recently, the importance of ILC2 in shaping the immune response early during RSV infection has been revealed in infants [46]. AMs are one of the source of IL-33 upon RSV infection [45,47,48], and it was shown that deletion of IL-33 production by myeloid cells strongly affects IL-5 secretion and eosinophil recruitment upon RSV infection [45]. Furthermore, IL-33 treatment promotes IL-10 production by B-cells in adult mice, thus protecting these mice from induction of inflammatory bowel disease [49].…”