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

Am J Respir Cell Mol Biol. 2017 Feb;56(2):242-251. doi: 10.1165/rcmb.2016-0056OC.

Abstract

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.

Keywords: IL-25; asthma; neonatal; rhinovirus; type 2 innate lymphoid cells.

MeSH terms

  • Animals
  • Animals, Newborn
  • Asthma / complications
  • Asthma / drug therapy*
  • Asthma / immunology*
  • Asthma / virology
  • Cell Lineage / drug effects
  • 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
  • Phenotype
  • Picornaviridae Infections / complications
  • Picornaviridae Infections / immunology*
  • Picornaviridae Infections / virology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rhinovirus / drug effects
  • Rhinovirus / physiology*

Substances

  • Interleukin-13
  • RNA, Messenger
  • Interferon-gamma