Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by cytokine driven inflammation that disrupts the mucosa and impedes intestinal structure and functions. Flightless I (Flii) is an immuno-modulatory protein is a member of the gelsolin family of actin-remodelling proteins that regulates cellular and inflammatory processes critical in tissue repair. Here we investigated its involvement in UC and show that Flii is significantly elevated in colonic tissues of patients with inflammatory bowel disease. Using an acute murine model of colitis, we characterised the contribution of Flii to UC using mice with low (Flii+/−), normal (Flii+/+) and high Flii (FliiTg/Tg). High levels of Flii resulted in significantly elevated disease severity index scores, increased rectal bleeding and degree of colon shortening whereas, low Flii expression decreased disease severity, reduced tissue inflammation and improved clinical indicators of UC. Mice with high levels of Flii had significantly increased histological disease severity and elevated mucosal damage with significantly increased inflammatory cell infiltrate and significantly higher levels of TNF-α, IFN-γ, IL-5 and IL-13 pro-inflammatory cytokines. Additionally, Flii overexpression resulted in decreased β-catenin levels, inhibited Wnt/β-catenin signalling and impaired regeneration of colonic crypts. These studies suggest that high levels of Flii, as is observed in patients with UC, may adversely affect mucosal healing via mechanisms involving Th1 and Th2 mediated tissue inflammation and Wnt/β-catenin signalling pathway.
Highlights
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) with incidences of 7.6 to 13.9 cases per 100,000 people in Westernised industrialized nations
UC is a chronic inflammatory disease that can lead to severe consequences including colectomy and significantly increased risk of colorectal cancer
Retrospective and prospective studies with UC patients have highlighted the importance of mucosal healing as the critical endpoint in disease management[27,28]
Summary
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) with incidences of 7.6 to 13.9 cases per 100,000 people in Westernised industrialized nations. Demonstrated that infliximab and adalimumab, TNF-α antibody therapies, are effective for patients with moderate to severe colitis significantly improving mucosal healing and rates of disease remission decreasing the need for colectomy[3,4]. Immuno-modulatory protein Flightless I (Flii) impairs skin barrier development, function and recovery post skin blistering and wounding[6,7] It negatively affects cellular processes including cellular adhesion, migration and proliferation as well as tight junction formation and macrophage and fibroblast cell secretion of TNF-α in the context of wound healing[7,8,9,10,11,12]. Our hypothesis was that Flii would alter tissue inflammation and promote colitis development
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