IL-20-mediated suppression of pro-inflammatory epithelial STAT2 signaling in mucosal healing and inflammatory bowel disease
Final Report Abstract
Inflammatory bowel disease (IBD) affects approximately 2.5 to 3 million people in Europe, constituting 0.4% of the population and incurring over 5 billion EUR annually in direct healthcare costs - comparable to chronic diseases like diabetes and cancer. Germany ranks among the countries with the highest global prevalence of IBD, with 322 cases per 100,000 for Crohn's disease and 412 per 100,000 for ulcerative colitis, impacting more than 500,000 individuals. IBD affects individuals across all demographics and requires lifelong care, often involving invasive procedures, hospitalizations, surgeries, and advanced treatments such as biologics. The disease arises from a dysregulated immune response to environmental and microbial factors in genetically predisposed individuals, frequently leading to severe complications such as fibrosis and colorectal cancer. Microbiota-driven immune responses result in the release of pro-inflammatory cytokines, including type I interferon (IFN), which activate STAT2 and trigger epithelial cell death. This compromises the intestinal barrier, allowing microbial translocation into the lamina propria that exacerbates inflammation. Anti-inflammatory cytokines from the IL-10 superfamily are critical for resolving inflammation and supporting tissue repair, yet the role of IL-20, a member of this cytokine family, was previously unknown in IBD. In the first funding period, we found that Stat2-/- mice exhibited greater resistance to inflammation and faster recovery compared to wild-type controls, whereas Il20-/- and Il20rb-/- mice were more susceptible. In IBD patients, STAT2 and IL-20 levels correlated with disease activity, supporting our hypothesis that IL-20 antagonizes the IFN/STAT2 pathway and acts as a compensatory mechanism to restore gut homeostasis. To explore this, we focused in the second funding period on investigated the molecular interactions driving type I IFN/STAT2- mediated inflammation and examined the cell-specific mechanisms by which IL-20 disrupts this axis to resolve inflammation and restore barrier function. Using cell-specific conditional knock-out strains, organoid cultures of mouse and human intestines, advanced imaging, RNA sequencing, and pharmacological modulation of cell-death pathways, we demonstrated that type I IFN induces necroptosis in intestinal epithelial cells. IL-20 partially blocked these effects, with a lesser impact from IL-10. Notably, IL-20 levels were elevated during remission and significantly higher in patients responding to anti-TNF therapy compared to nonresponders. While IL-10 plays a primary role in maintaining gut mucosal homeostasis, our findings suggest that IL-20 takes a central role during the resolution phase of inflammation, aiding in the restoration of homeostasis. IL-20RA and IL-20RB were expressed on intestinal epithelial cells in IBD patients, where IL-20 activated STAT3 and suppressed IFN/STAT2 signaling. In experimental models of dextran sulfate sodium-induced colitis and during mucosal healing, epithelial cells were the primary source of IL-20. Mice deficient in IL-20 signaling components exhibited increased susceptibility to colitis compared to wild-type controls, which was linked to elevated IFN/STAT2 activity. Furthermore, epithelial cell-specific STAT2- deficient mice displayed reduced colitis susceptibility compared to wild-type animals, and IL- 20 overexpression suppressed colitis activity in mice. In summary, we demonstrated that IL-20 mitigates colitis and promotes mucosal healing by counteracting type I IFN/STAT2 death signaling in intestinal epithelial cells. These findings provide new insights into the resolution phase of gut inflammation and lay a foundation for developing novel therapies for IBD by targeting IL-20-regulated STAT2 signaling pathways.
Publications
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Activation of Epithelial Signal Transducer and Activator of Transcription 1 by Interleukin 28 Controls Mucosal Healing in Mice With Colitis and Is Increased in Mucosa of Patients With Inflammatory Bowel Disease. Gastroenterology, 153(1), 123-138.e8.
Chiriac, Mircea T.; Buchen, Barbara; Wandersee, Alexandra; Hundorfean, Gheorghe; Günther, Claudia; Bourjau, Yvonne; Doyle, Sean E.; Frey, Benjamin; Ekici, Arif B.; Büttner, Christian; Weigmann, Benno; Atreya, Raja; Wirtz, Stefan; Becker, Christoph; Siebler, Jürgen & Neurath, Markus F.
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The Microbiome in Visceral Medicine: Inflammatory Bowel Disease, Obesity and Beyond. Visceral Medicine, 33(2), 153-162.
Chiriac, Mircea T.; Mahapatro, Mousumi; Neurath, Markus F. & Becker, Christoph
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Interferon Lambda Promotes Paneth Cell Death Via STAT1 Signaling in Mice and Is Increased in Inflamed Ileal Tissues of Patients With Crohn’s Disease. Gastroenterology, 157(5), 1310-1322.e13.
Günther, Claudia; Ruder, Barbara; Stolzer, Iris; Dorner, Heidrun; He, Gui-Wei; Chiriac, Mircea Teodor; Aden, Konrad; Strigli, Anne; Bittel, Miriam; Zeissig, Sebastian; Rosenstiel, Philip; Atreya, Raja; Neurath, Markus F.; Wirtz, Stefan & Becker, Christoph
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Targeting Immune Cell Wiring in Ulcerative Colitis. Immunity, 51(5), 791-793.
Neurath, Markus F. & Chiriac, Mircea T.
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IL-20 controls resolution of experimental colitis by regulating epithelial IFN/STAT2 signalling. Gut, 73(2), 282-297.
Chiriac, Mircea Teodor; Hracsko, Zsuzsanna; Günther, Claudia; Gonzalez-Acera, Miguel; Atreya, Raja; Stolzer, Iris; Wittner, Leonie; Dressel, Anja; Schickedanz, Laura; Gamez-Belmonte, Reyes; Erkert, Lena; Hundorfean, Gheorghe; Zundler, Sebastian; Rath, Timo; Vetrano, Stefania; Danese, Silvio; Sturm, Gregor; Trajanoski, Zlatko; Kühl, Anja A. ... & Neurath, Markus F.
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STAT2 Controls Colorectal Tumorigenesis and Resistance to Anti-Cancer Drugs. Cancers, 15(22), 5423.
Chiriac, Mircea T.; Hracsko, Zsuzsanna; Becker, Christoph & Neurath, Markus F.
