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* = Presenting author

P007 IL-36 α expression is elevated in ulcerative colitis and promotes colonic inflammation

S. E. Russell1, 2, R. M. Horan1, 2, A. M. Stefanska1, 2, A. Carey1, 2, 
G. Leon2, M. Aguilera3, D. Statovci3, T. Moran2, P. G. Fallon2, F. Shanahan3, E. K. Brint4, S. Melgar*3, S. Hussey2, 5, P. T. Walsh1, 2

1Trinity College Dublin, Dublin, Ireland, 2National Children’s Research Centre, Our Lady’s Children Hospital, Dublin, Ireland, 3University College Cork, APC Microbiome Institute, Cork, Ireland, 4University College Cork, Department of Pathology, Cork, Ireland, 5University College Dublin, Academic Centre for Paediatric Research, Dublin, Ireland

Background

A role for the IL-36 family of cytokines has been identified in the pathogenesis of psoriasis. Although significant mechanistic overlap can exist between psoriasis and inflammatory bowel diseases (IBD), to date, there have been no reports investigating the IL-36 family in gastrointestinal inflammation.

Methods

Gene and protein expression of IL-36 family members was investigated in the rectal mucosa of treatment-naïve IBD paediatric patients and in adult ulcerative colitis patients. IL-36 receptor deficient mice (Il36r-/-) were exposed to 7 days of dextran sodium sulphate (DSS) or infected with the enteropathogenic bacteria Citrobacter rodentium. Mice were monitored for clinical signs of disease, and colons were collected for cytokine analysis by ELISA and quantitative RT-polymerase chain reaction (PCR). Cells from the colonic lamina propria and mesenteric lymph nodes were isolated and immunophenotyped by flow cytometry. Faecal samples were collected at different time points for enumeration of viable C. rodentium counts and C. rodentium colonisation was detected by bioluminescent imaging.

Results

We demonstrate that expression levels of IL-36 α are specifically elevated in the colonic mucosa of ulcerative colitis patients. This elevated expression is mirrored in the inflamed colonic mucosa of mice, wherein IL-36 receptor deficiency confirmed this pathway as a mediator of mucosal inflammation. Il36r-/- mice exhibited reduced disease severity in an acute DSS-induced model of colitis in association with decreased innate inflammatory cell infiltration to the colon lamina propria. Consistent with these data, infection with C. rodentium resulted in reduced innate inflammatory cell recruitment and increased bacterial colonisation in the colons of Il36r-/- mice. Il36r-/- mice also exhibited altered T-helper (Th) cell responses in this model, with enhanced Th17 and reduced Th1 responses demonstrating that IL-36R signalling also regulates intestinal mucosal T-cell responses.

Conclusion

These data identify a novel role for IL-36 signalling in colonic inflammation and indicate that the IL-36R pathway may represent a novel target for therapeutic intervention in IBD.