STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing

By G. Pickert, C. Neufert, M. Leppkes, Yan Zheng, Nadine Wittkopf, Moritz Warntjen, H. Lehr, Sebastian Hirth, B. Weigmann, S. Wirtz and 3 more. Journal of Experimental Medicine, 2009

1,046 citations recorded by the source corpus.

Signal transducer and activator of transcription (STAT) 3 is a pleiotropic transcription factor with important functions in cytokine signaling in a variety of tissues. However, the role of STAT3 in the intestinal epithelium is not well understood. We demonstrate that development of colonic inflammation is associated with the induction of STAT3 activity in intestinal epithelial cells (IECs). Studies in genetically engineered mice showed that epithelial STAT3 activation in dextran sodium sulfate colitis is dependent on interleukin (IL)-22 rather than IL-6. IL-22 was secreted by colonic CD11c+ cells in response to Toll-like receptor stimulation. Conditional knockout mice with an IEC-specific deletion of STAT3 activity were highly susceptible to experimental colitis, indicating that epithelial STAT3 regulates gut homeostasis. STAT3IEC-KO mice, upon induction of colitis, showed a striking defect of epithelial restitution. Gene chip analysis indicated that STAT3 regulates the cellular stress response, apoptosis, and pathways associated with wound healing in IECs. Consistently, both IL-22 and epithelial STAT3 were found to be important in wound-healing experiments in vivo. In summary, our data suggest that intestinal epithelial STAT3 activation regulates immune homeostasis in the gut by promoting IL-22–dependent mucosal wound healing.

Subfields: Immunology, Pathology and Forensic Medicine, Surgery

View Paper: https://www.semanticscholar.org/paper/9ee39f0673647bd8cdd658cee9d8bdd52c7b7b3e

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Citations in the corpus

Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. (2019, background): “Consequently, IEC-specific STAT3 deletion augments dextran-sodium sulfate (DSS)-induced epithelial erosions and impaired proliferation (Pickert et al., 2009).”
Genetics and pathogenesis of inflammatory bowel disease (2011, background): “STAT3, the gene encoding which lies within an IBD-implicated locus, is activated in epithelial cells from patients with IBD, and IEC-specific Stat3 deletion affects epithelial repai”
Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22 (2011, background): “Additionally, in the intestine, IL-22 deficiency exacerbates tissue destruction in dextran sodium sulfate–mediated colitis or a T cell–transfer model of coliti”
Mucosal healing in inflammatory bowel diseases: a systematic review (2012, background): “Mucosal healing in IBD is therefore a tightly controlled process associated with suppression of inflammation and improvement of intestinal barrier function.(30) It is also dependent on the balance of migration, proliferation and functional differentiation of IECs adjacent to the injured area.”
IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine (2012, neutral): “IL-22 has an important function in the promotion of antimicrobial immunity via induction of antimicrobial peptides, and in tissue repair via induction of epithelial cell proliferation and survival 5, 8, 9 .”
Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer (2009, background): “These genes include STAT3 targets such as RegIIIβ and RegIIIγ, Tff3 and inducible form of Hsp70 (Hsp72) (36,47,77,78).”
NF‐κB and the link between inflammation and cancer (2012, background): “The candidate cytokines include IL-22, IL-11, and epidermal growth factor (EGF) family members (117, 118).”
Interleukin-22 Promotes Intestinal Stem Cell-Mediated Epithelial Regeneration (2015, neutral): “To evaluate if Stat3 was important for ISCs during tissue damage in vivo, we performed a gene set enrichment analysis (GSEA), assessing expression of a published Lgr5 + ISC gene signature (GEO dataset GSE33948) 16 in another dataset of WT (Stat3 fl/fl ) vs. epithelial Stat3-deficient (Stat3 fl/fl ;V”