Abstract
Blocking interferon-function by therapeutic intervention of the JAK-STAT-axis is a novel promising treatment option for inflammatory bowel disease (IBD). Although JAK inhibitors have proven efficacy in patients with active ulcerative colitis (UC), they failed to induce clinical remission in patients with Crohn's disease (CD). This finding strongly implicates a differential contribution of JAK signaling in both entities. Here, we dissected the contribution of different STAT members downstream of JAK to inflammation and barrier dysfunction in a mouse model of Crohn's disease like ileitis and colitis (Casp8ΔIEC mice). Deletion of STAT1 in Casp8ΔIEC mice was associated with reduced cell death and a partial rescue of Paneth cell function in the small intestine. Likewise, organoids derived from the small intestine of these mice were less sensitive to cell death triggered by IBD-key cytokines such as TNFα or IFNs. Further functional in vitro and in vivo analyses revealed the impairment of MLKL-mediated necrosis as a result of deficient STAT1 function, which was in turn associated with improved cell survival. However, a decrease in inflammatory cell death was still associated with mild inflammation in the small intestine. The impact of STAT1 signaling on gastrointestinal inflammation dependent on the localization of inflammation, as STAT1 is essential for intestinal epithelial cell death regulation in the small intestine, whereas it is not the key factor for intestinal epithelial cell death in the context of colitis. Of note, additional deletion of STAT2 was not sufficient to restore Paneth cell function but strongly ameliorated ileitis. In summary, we provide here compelling molecular evidence that STAT1 and STAT2, both contribute to intestinal homeostasis, but have non-redundant functions. Our results further demonstrate that STATs individually affect the distinct pathophysiology of inflammation in the ileum and colon, respectively, which might explain the diverse outcome of JAK inhibitors on inflammatory bowel diseases.
Highlights
Based on similarity in their structure and function as well as sharing of downstream signaling pathways, interferons (IFNs) are grouped into three families: Type I with IFNα, IFNβ, and several minor subtypes; Type II with IFNγ and Type III with IFNλs
We have demonstrated that Paneth cell depletion in a Caspase8 proficient context is associated with IFN-induced cell death and STAT1 mediated transcriptional control of Mlkl gene expression [13]
Clinical research and studies in experimental disease models have delineated the ambivalent role of IFNs and STAT1 in orchestrating epithelial cell homeostasis including induction of death as a key aspect of chronic inflammation as well as conducting mucosal healing during colonic inflammation [13, 14]
Summary
Based on similarity in their structure and function as well as sharing of downstream signaling pathways, interferons (IFNs) are grouped into three families: Type I with IFNα, IFNβ, and several minor subtypes; Type II with IFNγ and Type III with IFNλs. The main differences of these both forms is the localization of inflammation: While ulcerative colitis only affects the colon, Crohn’s disease can cause inflammatory lesions along the whole gastrointestinal tract predominantly in the terminal ileum. In this context, it has just recently been shown that IFNλ is a key factor for small intestinal inflammation that can trigger mucosal inflammation by influencing host cell death pathways in the context of IBD [13]. IFNλ promotes tissue regeneration and mucosal healing in the colonic tissue, highlighting a specific regulation of downstream signaling mechanisms depending on the cellular and spatial context [14]
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