Type 1 interferon signalling orchestrated by gut microbiota suppresses IgE-mediated anaphylaxis associated with vitamin D3 signalling

Objective

IgE/antigen (Ag)-mediated systemic anaphylaxis (SA) involves alterations in type 1 interferon (IFN1), vitamin D3(VD3) and the gut microbiota. However, their interactions remain largely unknown. This study aimed to investigate the interactions between IFN1 and VD3 signalling at steady-state and their relationships with the gut microbiota underlying SA.

Methods

Female adult C57BL/6 mice lacking IFN1 alpha receptor subunit 1 (Ifnar1, Ifnar1^−/−), immune-related GTPase family M protein 1 (Irgm1, Irgm1^−/−) or VD3 receptor (Vdr, Vdr^−/−) were intravenously (IV) administered with IgE/Ag to induce passive SA (PSA) or intraperitoneally (IP) administered ovalbumin (OVA) on days 1, 15, and 29, followed by IV OVA on day 43 to induce active SA (ASA). IFNα (5000 U, 2 doses) and IFNα (3500 U, 12 doses) were IP administered in PSA and ASA models, respectively. Supplementation of VD3 (VD3-rich diet for 3 weeks) or bacteria (oral administration daily for 6 weeks) was performed. The effects of IFN1 and VD3 signalling on the activation of murine bone marrow-derived mast cells (mBMMCs) were tested in vitro.

Results

Compared to wild-type (Wt) mice, both PSA and ASA were more severe in Ifnar1^−/− or Vdr^−/− mice (with greater severity in Ifnar1^−/− than in Vdr^−/− mice), but were significantly attenuated in Irgm1^−/− mice. The inhibitory effects of exogenous IFNα on PSA and OVA-IgE production were partially impaired in Vdr^−/− mice, while the inhibitory effects of exogenous VD3 remained intact in Ifnar1^−/− mice. At steady state, the serum VD3 levels decreased in Ifnar1^−/− and increased in Irgm1^−/− mice, whereas the serum IFN1 levels remained unchanged in Vdr^−/− mice. During IgE production, endogenous IFN1 and VD3 expressions, along with faecal Alistipes and Bacteroides, decreased. Oral supplementation with Bacteroides significantly inhibited IgE production via the IFN1/VD3 axis, whereas Alistipes moderately reduced IgE production by slightly upregulating VD3 expression independent of IFN1 modulation. Both spontaneous- and induced-degranulation were more prominent in Vdr^−/− than in Ifnar1^−/− mBMMCs. IgE/Ag stimulation led to a greater reduction in membrane IFNAR1 in Vdr^−/− than in Wt mBMMCs. Inhibition of P38 and PKD2 kinase significantly and partially rescued membrane IFNAR1 expression in Vdr^−/− mBMMCs, respectively. Exogenous VD3 could reverse the IFNAR1 reduction and thereby enhance IFNα-mediated anti-degranulation in Wt mBMMCs, an effect that was lost in Vdr^−/− mBMMCs.

Conclusions

These findings demonstrate that IFN1 homeostasis is more relevant for limiting SA, partially through maintaining VD3 expression. A reduction in gut Bacteroides promotes IgE production by disrupting the IFN1/VD3 axis in vivo. VD3 appears more potent than IFNα in exerting anti-degranulation effects, as it antagonises the downregulation of membrane IFNAR1 on mBMMCs in vitro.