Abstract
Aberrant interferon gamma (IFNγ) expression is associated with the pathogenesis of numerous autoimmune- and inflammatory disorders, including inflammatory bowel diseases (IBD). However, the requirement of IFNγ for the pathogenesis of chronic intestinal inflammation remains controversial. The aim of this study was thus to investigate the role of IFNγ in experimental mouse models of innate and adaptive immune cell-mediated intestinal inflammation using genetically and microbiota-stabilized hosts. While we find that IFNγ drives acute intestinal inflammation in the anti-CD40 colitis model in an innate lymphoid cell (ILC)-dependent manner, IFNγ secreted by both transferred CD4 T cells and/or cells of the lymphopenic Rag1−/− recipient mice was dispensable for CD4 T cell-mediated colitis. In the absence of IFNγ, intestinal inflammation in CD4 T cell recipient mice was associated with enhanced IL17 responses; consequently, targeting IL17 signaling in IFNγ-deficient mice reduced T cell-mediated colitis. Intriguingly, in contrast to the anti-CD40 model of colitis, depletion of ILC in the Rag1−/− recipients of colitogenic CD4 T cells did not prevent induction of colonic inflammation. Together, our findings demonstrate that IFNγ represents an essential, or a redundant, pro-inflammatory cytokine for the induction of intestinal inflammation, depending on the experimental mouse model used and on the nature of the critical disease inducing immune cell populations involved.
Highlights
Inflammatory bowel diseases (IBD) comprise two distinct entities, ulcerative colitis (UC) and Crohn’s disease (CD), that are characterized by chronic relapsing intestinal inflammation in genetically susceptible individuals [1]
This suggests that ILC3 intrinsic IFNγ-production was sufficient for induction of acute intestinal inflammation in the anti-CD40 innate colitis model
When either colitogenic Ifng−/− CD4 T cells were transferred into Ifng+/+ Rag1−/− recipients, or upon transfer of colitogenic Ifng+/+ CD4 T cells into Ifng-/Rag1−/− recipients comparable kinetics of weight loss and extent of histopathological alterations to those shown in Figures 1D–F were seen
Summary
Inflammatory bowel diseases (IBD) comprise two distinct entities, ulcerative colitis (UC) and Crohn’s disease (CD), that are characterized by chronic relapsing intestinal inflammation in genetically susceptible individuals [1]. Recent genome wide association studies in IBD patients have elucidated distinct genetic defects, which contribute to uncontrolled inflammatory responses and changes in the gut microbiome. The use of animal models has been indispensable in deciphering the complex pathophysiology underlying IBD and in the design of several approved compounds for the treatment of IBD. The therapeutic armamentarium for IBD is constantly growing with anti-TNF agents being at present the treatment of choice, in patients with steroid-resistant IBD. Around 10–30% of IBD patients do not respond to TNF targeting strategies or lose responsiveness with progression of disease. A better understanding of the complex immune pathways
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