IFN-γ Blocks Development of an Asthma Phenotype in Rhinovirus-Infected Baby Mice by Inhibiting Type 2 Innate Lymphoid Cells.
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.
Departments of 1 Pediatrics and Communicable Diseases, and.
Mingyuan
M
Han
2 Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan.
Jun Young
JY
Hong
Departments of 1 Pediatrics and Communicable Diseases, and.
Suraj
S
Jaipalli
Departments of 1 Pediatrics and Communicable Diseases, and.
Charu
C
Rajput
Departments of 1 Pediatrics and Communicable Diseases, and.
Jing
J
Lei
Departments of 1 Pediatrics and Communicable Diseases, and.
Joanna L
JL
Hinde
Departments of 1 Pediatrics and Communicable Diseases, and.
Qiang
Q
Chen
Departments of 1 Pediatrics and Communicable Diseases, and.
Natalie M
NM
Hershenson
Departments of 1 Pediatrics and Communicable Diseases, and.
J Kelley
JK
Bentley
Departments of 1 Pediatrics and Communicable Diseases, and.|2 Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan.
Marc B
MB
Hershenson
D000818:Animals; D000831:Animals, Newborn; D001249:Asthma / Q000150:complications / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D019070:Cell Lineage / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology / Q000627:therapeutic use*; D018793:Interleukin-13 / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008679:Metaplasia; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000378:metabolism; D010641:Phenotype; D010850:Picornaviridae Infections / Q000150:complications / Q000276:immunology* / Q000821:virology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012229:Rhinovirus / Q000187:drug effects / Q000502:physiology*
D018793:Interleukin-13; D012333:RNA, Messenger; D007371:Interferon-gamma
IL-25; asthma; neonatal; rhinovirus; type 2 innate lymphoid cells
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