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P489 Defective anti-microbial peptides expression in Crohn’s disease mucosa can be reversed by strengthening IL-22 signalling

A. Fantou*1,2, J. Martin1,2, A. Jarry3, A. Bourreille4,5, R. Josien1,2

1Centre de Recherche en Transplantation et Immunologie UMR 1064, Inserm, Université de Nantes, CHU Nantes, 44000, Nantes, France, 2Laboratoire d'Immunologie, CHU Nantes, 44000, Nantes, France, 3CRCINA, INSERM, Université d'Angers, Université de Nantes, 44000, Nantes, France, 4Institut des Maladies de l’Appareil Digestif (IMAD), CHU Nantes, 44000, Nantes, France, 5UMR 1235, Neuropathies entériques et pathologies digestives, Université de Nantes,, 44000, Nantes, France

Background

The intestinal epithelium can be easily disrupted during gut inflammation as seen in inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) or Crohn’s disease (CD). Aetiology of IBD is still not fully understood, but recent evidences suggest that the intestinal epithelium might play a major role in the development and perpetuation of IBD. In fact, disturbances in mechanisms that control the homeostasis, protection and repair of intestinal epithelial cells can lead to increased intestinal permeability causing deregulated immune response to the commensal gut microbiota and ultimately chronic intestinal inflammation. The cytokines IL-22 and IL-17 are highly produced in the inflammatory mucosa of IBD patients. In rodent models of colitis, these two cytokines showed synergistic and protective roles during gut inflammation, by reinforcing epithelial barrier function. We have shown that IL-22 binding protein (IL-22BP), the soluble and specific inhibitor of IL-22, is also increased during IBD and could therefore hamper the protective actions of IL-22.

Methods

To further explore this hypothesis, we set up ex vivo cultures of colonic biopsies from patients with active CD and UC and analysed the expression and regulation of IL-22-dependent genes that may be controlled by IL-22BP.

Results

We first observed that, as previously described by others, the antimicrobial peptides (AMPs) BD2, BD3 and LNC2, known targets of IL-22, were induced at a lower level in the inflammatory mucosa of CD than of UC patients. We then demonstrated that this defect in AMPs expression in CD was reversed by ex vivo stimulation with IL-22 and IL-17, and identified IL-22 vs. IL-17-dependent as well as IL-22+IL-17 synergistic responses. Furthermore, we showed that the addition of IL-22BP to the culture medium blocked the induction of IL-22-dependent genes.

Conclusion

Our data strongly suggest that the defective AMPs production observed in CD might be related to lack of IL-22 and IL-17 actions on epithelial cells. We propose that the selective and transient blockade of IL-22BP could represent an interesting therapeutic strategy to unleash the protective effects of locally-produced IL-22 during flares in CD.