mice forestomach Transcriptome or Gene expression. Mus musculus

Tyrosine kinase 2 (Tyk2) is part of cytokine signaling cascades, which regulate pro- and anti-inflammatory responses as well as epithelial barrier functions in the gut. Mutations in the human Tyk2 gene locus are associated with inflammatory bowel disease (IBD), but the specific role of Tyk2 in IBD onset and/or progression is unclear. Using dextran sodium sulfate (DSS) induced colitis in C57BL/6 mice we show that Tyk2 deficiency aggravates weight loss and IBD pathology scores and alters bacterial community composition. DSS-treated Tyk2-/- mice display less tyrosine phosphorylation of Stat3 (pY-Stat3) in colonic tissue and significant decreased proliferation of intestinal epithelial cells (IECs). IL-22 is a potent inducer of pY-Stat3 in IECs and has been described to protect from DSS-induced colitis. Colonic Tyk2-deficient IECs have reduced pY-Stat3 in response to IL-22 stimulation. Expression of the IL-22 response genes RegIII and RegIII is reduced in IECs derived from healthy and diseased Tyk2-/- mice. Tyk2 deficiency solely in IECs suffices to worsen DSS-induced colitis compared to wildtype littermates. The importance of Tyk2 in the prevention of acute colitis was recapitulated in Citrobacter rodentium induced disease. In summary, our data indicate that Tyk2 acts protective during acute colitis through amplification of homeostatic and inflammation-induced epithelial IL-22 signaling.