IFN-γ Blocks Development of an Asthma Phenotype in Rhinovirus-Infected Baby Mice by Inhibiting Type 2 Innate Lymphoid Cells

• Published in: American journal of respiratory cell and molecular biology Vol. 56; no. 2; pp. 242 - 251
• Main Authors: Han, Mingyuan, Hong, Jun Young, Jaipalli, Suraj, Rajput, Charu, Lei, Jing, Hinde, Joanna L, Chen, Qiang, Hershenson, Natalie M, Bentley, J Kelley, Hershenson, Marc B
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.02.2017
• Subjects: Animals; Animals, Newborn; Asthma - complications; Asthma - drug therapy; Asthma - immunology; Asthma - virology; Cell Lineage - drug effects; Enterovirus; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Gene Expression Regulation - drug effects; HeLa Cells; Humans; Immunity, Innate - drug effects; Interferon-gamma - pharmacology; Interferon-gamma - therapeutic use; Interleukin-13 - metabolism; Lymphocytes - drug effects; Lymphocytes - immunology; Metaplasia; Mice; Mice, Inbred BALB C; Mucus - metabolism; Original Research; Phenotype; Picornaviridae; Picornaviridae Infections - complications; Picornaviridae Infections - immunology; Picornaviridae Infections - virology; Rhinovirus - drug effects; Rhinovirus - physiology; RNA, Messenger - genetics; RNA, Messenger - metabolism; neonatal; IL-25; asthma; type 2 innate lymphoid cells; rhinovirus
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2016-0056OC

Early-life wheezing-associated infections with rhinovirus (RV) have been associated with asthma development in children. We have shown that RV infection of 6-day-old mice induces mucous metaplasia and airways hyperresponsiveness, which is dependent on IL-13, IL-25, and type 2 innate lymphoid cells (ILC2s). Infection of immature mice fails to induce lung IFN-γ expression, in contrast to mature 8-week-old mice with a robust IFN-γ response, consistent with the notion that deficient IFN-γ production in immature mice permits RV-induced type 2 immune responses. We therefore examined the effects of intranasal IFN-γ administration on RV-induced ILC2 expansion and IL-13 expression in 6-day-old BALB/c and IL-13 reporter mice. Airway responses were assessed by histology, immunofluorescence microscopy, quantitative polymerase chain reaction, ELISA, and flow cytometry. Lung ILC2s were also treated with IFN-γ ex vivo. We found that, compared with untreated RV-infected immature mice, IFN-γ treatment attenuated RV-induced IL-13 and Muc5ac mRNA expression and mucous metaplasia. IFN-γ also reduced ILC2 expansion and the percentage of IL-13-secreting ILC2s. IFN-γ had no effect on the mRNA or protein expression of IL-25, IL-33, or thymic stromal lymphoprotein. Finally, IFN-γ treatment of sorted ILC2s reduced IL-5, IL-13, IL-17RB, ST2, and GATA-3 mRNA expression. We conclude that, in immature mice, IFN-γ inhibits ILC2 expansion and IL-13 expression in vivo and ex vivo, thereby attenuating RV-induced mucous metaplasia. These findings demonstrate the antagonistic function of IFN-γ on ILC2 expansion and gene expression, the absence of which may contribute to the development of an asthma-like phenotype after early-life RV infection.