Interferon regulatory factor 7 alleviates the experimental colitis through enhancing IL-28A-mediated intestinal epithelial integrity.

Background: The incidence of inflammatory bowel disease (IBD) is on the rise in developing countries, and investigating the underlying mechanisms of IBD is essential for the development of targeted therapeutic interventions. Interferon regulatory factor 7 (IRF7) is known to exert pro-inflammatory effects in various autoimmune diseases, yet its precise role in the development of colitis remains unclear.
Methods: We analyzed the clinical significance of IRF7 in ulcerative colitis (UC) by searching RNA-Seq databases and collecting tissue samples from clinical UC patients. And, we performed dextran sodium sulfate (DSS)-induced colitis modeling using WT and Irf7 ^-/- mice to explore the mechanism of IRF7 action on colitis.
Results: In this study, we found that IRF7 expression is significantly reduced in patients with UC, and also demonstrated that Irf7 ^-/- mice display heightened susceptibility to DSS-induced colitis, accompanied by elevated levels of colonic and serum pro-inflammatory cytokines, suggesting that IRF7 is able to inhibit colitis. This increased susceptibility is linked to compromised intestinal barrier integrity and impaired expression of key molecules, including Muc2, E-cadherin, β-catenin, Occludin, and Interleukin-28A (IL-28A), a member of type III interferon (IFN-III), but independent of the deficiency of classic type I interferon (IFN-I) and type II interferon (IFN-II). The stimulation of intestinal epithelial cells by recombinant IL-28A augments the expression of Muc2, E-cadherin, β-catenin, and Occludin. The recombinant IL-28A protein in mice counteracts the heightened susceptibility of Irf7 ^-/- mice to colitis induced by DSS, while also elevating the expression of Muc2, E-cadherin, β-catenin, and Occludin, thereby promoting the integrity of the intestinal barrier.
Conclusion: These findings underscore the pivotal role of IRF7 in preserving intestinal homeostasis and forestalling the onset of colitis.
(© 2024. The Author(s).)