Type I interferon (IFN) signalling has been implicated in maintaining intestinal homeostasis and administration of IFNβ ameliorates intestinal inflammation in dextran sulphate sodium (DSS) colitis, a murine model for intestinal inflammation. Furthermore, Ifnar1-/- mice show increased susceptibility to DSS colitis and to T cell mediated colitis.
We previously showed that IFNε is highly expressed by epithelial cells of the female reproductive tract, where it is involved against protection against sexually transmitted pathogens. While the expression of IFNε is most abundant in the FRT in mice, expression has also been shown in epithelial cells of other tissues as demonstrated in rhesus macaques, where IFNε protein expression was detected in the epithelium of the jejunum and rectum, indicating that IFNε will likely play a role in local immune responses in the intestine.
We have previously shown that while both IFNα and IFNβ can bind to IFNAR2, IFNβ can form a stable complex with IFNAR1 resulting in a distinct IFNβ-IFNAR1 pro-inflammatory gene signature. We also demonstrated that Ifnar1-/- mice were protected from LPS toxicity, whereas Ifnar2-/- mice were as susceptible as C57BL/6 wildtype (WT) mice suggesting that IFNAR1–IFN-β signalling is pathologically relevant. Unpublished data indicates IFNε can stably bind to IFNAR1 in the absence of IFNAR2 as well, suggesting a role in non-canonical IFNAR signalling.
We studied the role of IFNε in modulating intestinal inflammation in the dextran sulphate sodium (DSS) colitis model and show IFNε prevents intestinal inflammation in this model as IFNε-/- mice showed exacerbated intestinal inflammation compared to both WT and Ifnar1-/- mice and resemble Ifnar2-/- mice in disease susceptibility.
Our data suggests IFNε plays a broader role in mucosal immunity than protection of the reproductive tract from infection only.