Oral Presentation Lorne Infection and Immunity 2021

Interferon ε as a novel regulator of intestinal homeostasis (#55)

Eveline D de Geus 1 2 , Jennifer S Volaric 1 2 , Gemma L D'Adamo 1 2 , Vanessa R Marcelino 1 2 , Linden J Gearing 1 2 , Jodee A Gould 1 2 , Nicole A de Weerd 1 2 , Niamh E Mangan 1 2 , Samuel C Forster 1 2 , Edward M Giles 1 2 3 , Paul J Hertzog 1 2
  1. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Monash University, Clayton, VIC, Australia
  3. Department of Paediatrics, Monash University, Clayton, Victoria

Disruption of intestinal immune balance can lead to inflammatory bowel diseases (IBD). 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 another T1IFN ligand is important for maintaining intestinal homeostasis. 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 lost in inflamed conditions. Furthermore, our results show IFNε limits intestinal 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. To rule out the involvement of IFNβ in experimental inflammation, we compared susceptibility to DSS colitis in WT and IFNβ-/- mice and found no significant differences in disease severity, nor in intestinal Treg frequencies. Finally, 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. The importance of T1IFN signalling in maintaining intestinal homeostasis was confirmed in a cohort of paediatric IBD samples (n=150), where we found a dysregulated T1IFN response when compared to non-IBD control samples. Furthermore, this T1IFN response correlated with specific bacterial strains present in these samples.

These findings show IFNε is a new factor involved in the pathogenesis of IBD, and non-canonical IFNAR signalling may be a mechanism for its protective effect. This makes the IFNε-IFNAR pathway a promising therapeutic target for the treatment of IBD.