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 (, ), immune-related GTPase family M protein 1 (, ) or VD3 receptor (, ) 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 .

RESULTS

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

CONCLUSIONS

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