Type I interferon (T1IFN) production has been implicated in maintaining intestinal homeostasis and T1IFN receptor (IFNAR) signalling has protective effects in experimental colitis. T1IFN, namely IFNα and IFNβ have been trialled in IBD patients, with conflicting results. This suggests an incomplete understanding of T1IFN signalling in the intestine. We previously showed IFNε is highly expressed by epithelial cells of the female reproductive tract, where it is involved in protection against pathogens. IFNε expression has recently also been shown in epithelial cells of jejunum and rectum in rhesus macaques.
Here we show IFNε is expressed in human and mouse intestinal epithelium and expression is decreased in inflamed conditions. Furthermore, our results show IFNε limits inflammation in the DSS colitis model, as IFNε-/- mice had more severe disease when compared to wildtype (WT) mice. Regulatory T cells (Treg) are crucial for maintaining intestinal homeostasis, and we observed FoxP3+ Treg frequencies were decreased in DSS-treated IFNε-/- mice, suggesting a role for IFNε in maintaining the intestinal Treg compartment.
Our data indicates that, as shown previously for IFNβ, IFNε can bind to IFNAR1 in the absence of IFNAR2 resulting in a distinct non-canonical gene signature. This non-canonical IFNAR signalling is relevant in experimental colitis, as IFNAR2-/- mice showed more severe clinical symptoms than both WT and IFNAR1-/- mice after DSS treatment. Interestingly, neutralisation of IFNε in IFNAR2-/- mice resulted in ameliorated colitis severity. This indicates that while conventional IFNε signalling is protective, non-canonical signalling by IFNε at this site is pathogenic.
These findings show the importance of IFNε in mucosal immunity and IBD, where non-canonical signalling may be pathologically relevant. As IFNε is expressed constitutively in mucosal epithelium, this makes it an appealing target for therapy in IBD.