Twist1 contributes to developing and sustaining corticosteroid resistance in ulcerative colitis

Area of Science:

• Gastroenterology
• Immunology
• Molecular Biology

Background:

• Corticosteroid resistance (CR) poses a significant challenge in ulcerative colitis (UC) treatment.
• The precise mechanisms underlying CR in UC remain largely unknown.
• Twist1 protein (TW1), an apoptosis inhibitor with immune regulatory roles, is implicated.

Purpose of the Study:

• To investigate the role of Twist1 protein (TW1) in the development and persistence of corticosteroid resistance (CR) in ulcerative colitis (UC).

Main Methods:

• Neutrophils were isolated from colon tissues of UC patients and a CR colitis mouse model.
• RNA sequencing was used to analyze inflammation-related gene activity.
• A CR colitis mouse model was established using dextran sulfate sodium and hypoxia.

Main Results:

• Elevated TW1 expression was observed in neutrophils from CR UC patients and CR mouse models.
• TW1 physically bound to glucocorticoid receptor-alpha (GRα), hindering steroid binding and abrogating steroid effects.
• STAT3 and Ras protein activator like 1 interaction sustained high TW1 expression in CR neutrophils.

Conclusions:

• High TW1 expression in neutrophils is a hallmark of corticosteroid resistance in UC.
• TW1 interferes with steroid-mediated regulation of neutrophil activity.
• TW1 inhibition successfully restored corticosteroid sensitivity in a CR murine model.