Background: Tumor necrosis factor (TNF) inhibitors (anti-TNF) are considered to be effective in inducing mucosal healing in patients with moderate-to-severe Ulcerative Colitis (UC). The role of IL-33 and its receptor, ST2, in intestinal inflammation is incompletely understood, with both pro-inflammatory and regulatory properties described. Recent evidence has shown that anti-TNF is able to modulate the IL-33/ST2 axis in inflammatory conditions. The aim of our study was to explore the potential role of the IL-33/ST2 axis in the mucosal healing process mediated by anti-TNF therapy in UC.
Methods: Endoscopic MAYO score was calculated before the first anti-TNF infusion (T0) and after 6 weeks (T2). 12 UC patients (MAYO score at T0 ≥2), grouped into 6 responders with mucosal healing (MAYO score ≤1) and 6 non-responders to anti-TNF at T2 (MAYO score ≥2) were enrolled. 10 healthy controls undergoing routine colonoscopy for tumor screening were also enrolled. At each time point, serum samples were collected and ELISA performed to assess IL-33/ST2 protein levels. Intestinal biopsies were also taken from the rectum and IHC was done to evaluate mucosal IL-33/ST2 expression and localization.
Results: IL-33 protein levels were significantly increased in responders vs. non-responders, both at T0 and T2. Among responders, IL-33 protein was slightly reduced at T2 vs. T0, while unchanged in non-responders. Interestingly, significantly higher levels of ST2 were found in responders vs. not responders at T0, while no differences between groups were found at T2. Among responders, ST2 levels were dramatically reduced at T2 vs. T0. No significant differences were found in non-responders at both time points. Healthy controls showed significantly lower levels of both IL-33 and ST2 compared with other groups. IHC confirmed these observations. In particular, IL-33 and ST2 staining was more intense within the inflamed and ulcerated mucosa of responders compared to non-responders at T0. After 6 weeks, ST2 staining was even more evident in responders, notably localized to the healed mucosa and in close proximity to areas of re-epithelialization. Little to no staining for both IL-33 and ST2 was present in healthy controls.
Conclusions: Our results suggest a possible role for IL-33/ST2 in predicting gut mucosal wound healing in patients with moderate-to-severe UC treated with anti-TNF. Further studies are underway to determine mechanisms of action that support these findings.