The interleukin-10/interleukin-10Rα axis in fibroblasts limits large intestinal pathology by suppressing Type I interferon signaling.

Recent studies identified that the dysregulation of fibroblast activity, in addition to impairment in epithelial integrity and uncontrolled immune response, is implicated in the pathogenesis of inflammatory bowel disease (IBD). The anti-inflammatory cytokine interleukin (IL)-10 and its receptors IL-10Rα and IL-10Rβ have IBD-associated single nucleotide polymorphisms. In the intestine, IL-10 signaling is essential for maintaining an anti-inflammatory state of myeloid cells and inducing regulatory T cells, thereby preventing intestinal inflammation linked to IBD development. However, its impact on the physiology and pathophysiology of intestinal fibroblasts is poorly understood. Here, we show that Il10ra deficiency leads to increased expression of a subset of genes in colonic fibroblasts, most of which are associated with the Type I interferon (IFN) and Type II IFN signaling pathways. In addition, Pdgfra-cre; Il10raf/f mice aged 16 weeks or older develop chronic spontaneous colitis and subsequent fibrosis accompanied by enhanced infiltration by myeloid cells and effector CD4+ T cells in the lamina propria of the colon. Moreover, Pdgfra-cre; Il10raf/f mice at 12 weeks of age exhibit more severe clinical symptoms than those of Il10raf/f mice during dextran sodium sulfate-induced colitis that can be suppressed by the administration of anti-IFNAR1 antibody but not anti-IFNGR1 antibody. Therefore, inhibition of the Type I IFN pathway via IL-10Rα signaling in fibroblasts is one of the IL-10-dependent mechanisms underlying the prevention of large intestinal pathology.