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

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-g expression, in contrast to mature 8-week-old mice with a robust IFN-g response, consistent with the notion that deficient IFN-g production in immature mice permits RV-induced type 2 immune responses. We therefore examined the effects of intranasal IFN-g administration on RVinduced 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-g ex vivo. We found that, compared with untreated RV-infected immature mice, IFN-g treatment attenuated RV-induced IL-13 and Muc5ac mRNA expression and mucous metaplasia. IFN-g also reduced ILC2 expansion and the percentage of IL-13-secreting ILC2s. IFN-g had no effect on the mRNA or protein expression of IL-25, IL-33, or thymic stromal lymphoprotein. Finally, IFN-g treatment of sorted ILC2s reduced IL-5, IL-13, IL-17RB, ST2, and GATA-3 mRNA expression. We conclude that, in immature mice, IFN-g 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-g 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.

STAT1 Represses Cytokine-Producing Group 2 and Group 3 Innate Lymphoid Cells during Viral Infection

“…Prior reports suggest that ILC2 are intrinsically susceptible to inhibition to type I and II interferons, providing a likely explanation for the cell-intrinsic effect seen in our bone marrow chimeric mice (34, 43–46) . However, STAT1-dependent cell-extrinsic factors that regulate ILC frequencies have not been described.…”

“…Specifically, these studies have shown that type I and type II interferons directly repress ILC2 responses in vitro and in vivo in the context of viral infection or airway inflammation (34, 43–46). Data from our bone marrow chimeric mouse experiments suggest cell-intrinsic factors, such as the previously described direct inhibition of ILC2 by interferons (34, 44, 45), play a role in regulating ILC frequencies during viral infection.…”

The Innate Cytokines IL-25, IL-33, and TSLP Cooperate in the Induction of Type 2 Innate Lymphoid Cell Expansion and Mucous Metaplasia in Rhinovirus-Infected Immature Mice

“…Lung sections were stained with Periodic acid-Schiff (PAS) or AlexaFluor 488-conjugated anti-Muc5ac (Thermo Fisher Scientific, Rockford, IL) to visualize mucus (Sigma-Aldrich, St Louis, MO). Levels of Muc5ac staining in the airway epithelium were quantified by NIH ImageJ software (Bethesda, MD), as described (48). Muc5ac expression was represented as the fraction of Muc5ac + epithelium compared with the total basement membrane length.…”

All along the watchtower: group 2 innate lymphoid cells in allergic responses

“…Therefore, negative regulation of ILC2s is crucial to prevent pathologic type 2 inflammation. Cytokines associated with type 1 immunity, such as type I interferons (IFNs) [48], IFN-γ [49–52] and IL-27 [50] are dominant inhibitors of ILC2 activation. Androgen receptor (AR) signaling on ILC2s restricts their activation, and may account for the lower susceptibility to allergic airway inflammation in males [53,54].…”