Intestinal epithelial cell tyrosine kinase 2 transduces IL-22 signals to protect from acute colitis

Eva Hainzl, Silvia Stockinger, Isabella Rauch, Susanne Heider, David Berry, Caroline Lassnig, Clarissa Schwab, Felix Rosebrock, Gabriel Milinovich, Michaela Schlederer, Michael Wagner, Christa Schleper, Alexander Loy, Tim Urich, Lukas Kenner, Xiaonan Han, Thomas Decker, Birgit Strobl, Mathias Müller

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2-/- mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22-STAT3 target genes is reduced in IECs from healthy and colitic Tyk2-/- mice. Experiments with conditional Tyk2-/- mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22-Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22-dependent colitis was confirmed in Citrobacter rodentium-induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3.

Original languageEnglish (US)
Pages (from-to)5011-5024
Number of pages14
JournalJournal of Immunology
Volume195
Issue number10
DOIs
StatePublished - Nov 15 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Hainzl, E., Stockinger, S., Rauch, I., Heider, S., Berry, D., Lassnig, C., Schwab, C., Rosebrock, F., Milinovich, G., Schlederer, M., Wagner, M., Schleper, C., Loy, A., Urich, T., Kenner, L., Han, X., Decker, T., Strobl, B., & Müller, M. (2015). Intestinal epithelial cell tyrosine kinase 2 transduces IL-22 signals to protect from acute colitis. Journal of Immunology, 195(10), 5011-5024. https://doi.org/10.4049/jimmunol.1402565