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Neutralizing responsiveness to Interleukin-33 abrogat1es experimental colitis through enhanced mucosal wound healing.

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Sedhom, M.A. | Pichery, M. | Ortega, N. | Foligné, B. | Grandjean, T. | Normand, S. | Brault, L. | Lefrancais, E. | Fallon, P.G. | Le Bert, Marc | Quesniaux, Valérie | Chamaillard, M. | Girard, J.-P. | Bernhard, R.

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International audience. Introduction:Novel therapeutic principles are urgently needed to cure inflammatory bowel diseases (IBD) that have been intrinsically linked to a deregulated inflammatory cytokine network. Here we identify the interleukin (IL)-1-like cytokine IL-33 and its receptor ST2 as novel negative regulators of wound healing in the colon of mice.Methods:Study in BL6 and IL-33R/ST2 deficient mice using dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis analyzing classical parameters of inflammation.Results:Genetic ablation of ST2 protected the colon from chemical insults by dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) that coincided with reduced acute pro-inflammatory response together with sustained expression of cytoprotective factors, including connexin-43. Likewise, administration of an anti-ST2 blocking antibody to mice treated by dextran sodium sulfate improved signs of morbidity, whereas recombinant IL-33 increased the risk for colitis. Consistently, the colonic mucosa of ST2-deficient mice was characterized by an enhanced wound healing response in a model of acute in vivo injury in the colon.Conclusion:In conclusion, we report here that the IL-33/ST2 axis plays a critical role in inflammation resolution by regulating self-renewal of the colonic epithelia, indicating neutralization of ST2 may represent a novel therapeutic target for effective treatment in IBD.

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