IL-33 drives eosinophil infiltration and pathogenic type 2 helper T-cell immune responses leading to chronic experimental ileitis

Carlo De Salvo, Xiao Ming Wang, Luca Pastorelli, Benedetta Mattioli, Sara Omenetti, Kristine A. Buela, Saleem Chowdhry, Rekha R. Garg, Wendy A. Goodman, Alex Rodriguez-Palacios, Dirk E. Smith, Derek W. Abbott, Fabio Cominelli, Giorgos Bamias, Wei Xin, James J. Lee, Maurizio Vecchi, Theresa T. Pizarro

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Although a clear association has been established between IL-33 and inflammatory bowel disease, mechanistic studies to date, primarily using acute murine models of colitis, have yielded contradicting results, demonstrating both pathogenic and protective roles. We used a well-characterized, spontaneous model of inflammatory bowel disease [ie, SAMP1/YitFc (SAMP) mice] to investigate the role of IL-33 during chronic intestinal inflammation. Our results showed marked eosinophil infiltration into the gut mucosa with increased levels of eotaxins and type 2 helper T-cell (Th2) cytokines as disease progressed and became more severe, which could be reversed upon either eosinophil depletion or blockade of IL-33 signaling. Exogenous IL-33 administration recapitulated these effects in ilea of uninflamed (parental) control AKR/J mice. Human data supported these findings, showing colocalization and up-regulation of IL-33 and eosinophils in the colonic mucosa of inflammatory bowel disease patients versus noninflamed controls. Finally, colonization of commensal flora by fecal material transplantation into germ-free SAMP and the presence of the gut microbiome induced IL-33, subsequent eosinophil infiltration, and mounting of Th2 immune responses, leading to exacerbation of chronic intestinal inflammation characteristic of SAMP mice. These data demonstrate a pathogenic role for IL-33-mediated eosinophilia and activation of Th2 immunity in chronic intestinal inflammation that is dependent on the gut microbiome. Targeting IL-33 may represent a novel therapeutic approach to treat patients with inflammatory bowel disease.

Original languageEnglish (US)
Pages (from-to)885-898
Number of pages14
JournalAmerican Journal of Pathology
Volume186
Issue number4
DOIs
StatePublished - Apr 1 2016

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    De Salvo, C., Wang, X. M., Pastorelli, L., Mattioli, B., Omenetti, S., Buela, K. A., Chowdhry, S., Garg, R. R., Goodman, W. A., Rodriguez-Palacios, A., Smith, D. E., Abbott, D. W., Cominelli, F., Bamias, G., Xin, W., Lee, J. J., Vecchi, M., & Pizarro, T. T. (2016). IL-33 drives eosinophil infiltration and pathogenic type 2 helper T-cell immune responses leading to chronic experimental ileitis. American Journal of Pathology, 186(4), 885-898. https://doi.org/10.1016/j.ajpath.2015.11.028