Introduction:
Inflammatory bowel diseases (IBD) are chronic, relapsing and aggravating disorders in which the homeostasis in the gastrointestinal tract has been altered by aberrant immune responses towards environmental and microbial assaults in genetically predisposed individuals. The contribution of type I interferon signaling (i.e. STAT1:STAT2:IRF9) in the pathogenesis of IBD is controversial since conflicting results indicating either a protective or a supporting role during inflammation exist. We investigated the role of STAT2 in models of IBD and intestinal mucosal healing.
Methods:
Experimental colitis was induced in Stat2 knockout mice and wild type controls. High-resolution mini-endoscopy and in vivo imaging were used to assess disease development. Three-dimensional intestinal epithelial organoid cultures coupled with Nanostring®, RNA-Seq and gene ontology analysis were used to investigate the effects of STAT2-dependent signals specifically in intestinal epithelial cells. A colonic wound healing mouse model was employed to address the role of STAT2 during intestinal epithelial recovery. Human fresh biopsies and isolated primary epithelial cells were used to validate mouse data in IBD patients.
Results:
Compared to wild type controls Stat2 knockout mice were more resistant to experimental colitis as reflected by lower levels of intestinal inflammation on endoscopy and histology as well as accelerated mucosal restitution. Altered STAT2 activity was observed in samples from IBD patients. This effect could be ascribed to interferon since it induced a time- and dose-dependent phosphorylation of STAT2. Stat2 knockout organoids grew faster and were more resistant to cytokine-mediated cell death compared to wild type organoids. On the molecular level, STAT2 controlled sets of genes implicated in immune responses, cell death and would healing. Interestingly, IL-20 overexpression protected mice during colitis. We found that IL-20 lowered STAT2 activity while inducing anti-microbial genes in epithelial cells.
Conclusions:
STAT2 is an important regulator of intestinal homeostasis by controlling the turnover of the gut epithelium and mediating cell death during experimental colitis. These data emphasize a possible therapeutic value of STAT2 modulators in IBD.
