Type I and type III interferons (IFNs) are recognized for their non-redundant importance in limiting viral infection; however their roles as homeostatic and inflammatory mediators are less well characterized. Ulcerative colitis (UC), involves perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. To characterize the contributions of type I and type III IFNs to the formation, progression, and resolution of UC, we used mice deficient in type I IFN, type III IFN, and type I/III IFN signaling and a murine model of acute UC, which follows exposure of mice to dextran sulfate sodium (DSS)-containing water.
We observed that IFN signaling contributes to the acute inflammatory response and mucosal wound healing, consistent with increased IFN-induced Mx2 promoter-driven luciferase expression when Mx2-Luciferase reporter mice were exposed to DSS. Experiments demonstrated enhanced susceptibility of mice deficient in type I/III IFN signaling as measured by diffuse destruction of the colonic epithelium, and decreased proliferative capacity resulting in increased mortality. Adoptive transfer of WT bone marrow rescued type I/III IFN-deficient mice, and restored the proliferative capacity of the epithelium. Interestingly, WT mice that were reconstituted with bone marrow from mice deficient in type I/III IFN signaling also survived, suggesting that IFN signaling in either the epithelial or the hematopoietic compartment is sufficient for protection against DSS-induced colitis.
Therefore, complete loss of IFN signaling results in impaired mucosal wound healing during DSS-induced colitis. Ongoing experiments have revealed that compartmentalized and coordinated action of type I and III IFNs contributes to maintaining intestinal tissue homeostasis and balancing tissue repair and inflammatory responses following acute intestinal injury.