TIFA renders epithelial cells responsive to microbial ADP-heptose and drives colonic inflammation in mice

Introduction

TIFA was first identified more than 20 years ago as a binding protein for TRAF2/6, playing a role in pro-inflammatory signalling pathways.  More recently, it has been shown to be essential for signalling by the bacterial sensor ALPK1, which recognises bacterial cell wall metabolites; in particular, ADP-Heptose, in studies of H pylori interaction with the gastric epithelium. Now, Erkert and co-workers have demonstrated that TIFA is upregulated in mouse models of colitis and infection, and in IBD patients. TIFA was shown to be up-regulated by IL-22 and, via canonical/non-canonical NF-kB signalling, drive the expression of a range of chemokines and promote inflammasome activation.

Main Points

• Tifa (TRAF-Interacting protein with Forkhead-Associated domain protein) was a top 10 up-regulated gene common to colon tissue from mice with DSS-induced colitis and three mouse intestinal infection models.
• Tifa mRNA was localised to the intestinal crypts in mice, particularly the stem and transit amplifying cells. In the inflammatory models, expression was expanded up the crypt and on to the villi (ileum) and into the table region (colon).
• TIFA transcript levels were increased in biopsies from patients with UC or Crohn’s relative to those from healthy patients; expression levels correlated with histopathology score and the expression of NOS2 (known to be associated with more severe disease).
• Tifa expression was reduced in germ-free mice and in organoid cultures of mouse small intestinal epithelial cells (IEC), suggesting a role for the microbiome in maintaining Tifa
• Medium from Th17 T cell cultures, but not other T cell types, increased Tifa expression in SI organoids. IL-22 was the cytokine primarily responsible for Tifa up-regulation.
• In vivo, over-expression of IL-22 resulted increased Tifa expression along the crypt-villus axis, mimicking the effect of inflammation. In contrast, deletion of Il22 (systemic) or Il22ra (IEC-specific) reduced Tifa IL-22 signalling in the epithelium was dependent on STAT3.
• Gene expression profiles of SI organoids challenged with both IL-22 and ADP-Heptose showed a significant positive correlation with that of colon tissue from DSS-treated mice, including up-regulation of Tifa and genes coding for components/targets of the NF-kB signalling pathway and chemokines. Inflammasome activation was evidenced by an increase in cleaved gasdermin.  IL-22/ADP-Heptose challenge resulted in aggregation of TIFA into TIFAsomes, unlike challenge with IL-22 alone.
• The effect of IL-22/ADP-Heptose challenge in organoids was blocked by the deletion of Tifa. Tifa -/- mice showed reduced severity of DSS-induced colitis.
• Tifa -/- mice showed reduced severity of DSS-induced colitis.

Conclusion

The authors confirmed previous findings for the role of TIFA in microbial metobolite sensing, demonstrating its relevance to inflammation in the ileum/colon.  It can be seen that the ALPK1/TIFA signalling pathway is an important communication link between the intestinal microbiome and the mucosal immune system and could present new opportunities for therapeutic intervention in IBD.

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