Toll-like receptor 9–induced type I IFN protects mice from experimental colitis

Abstract

Experimental colitis is mediated by inflammatory or dysregulated immune responses to microbial factors of the gastrointestinal tract. In this study we observed that administration of Toll-like receptor 9 (TLR9) agonists suppressed the severity of experimental colitis in RAG1 -/-but not in SCID mice. This differential responsiveness between phenotypically similar but genetically distinct animals was related to a partial blockade in TLR9 signaling and defective production of type I IFN (i.e., IFN-α/β) in SCID mice upon TLR9 stimulation. The addition of neutralization antibodies against type I IFN abolished the antiinflammatory effects induced by TLR9 agonists, whereas the administration of recombinant IFN-β mimicked the antiinflammatory effects induced by TLR9 agonists in this model. Furthermore, mice deficient in the IFN-α/β receptor exhibited more severe colitis than wild-type mice did upon induction of experimental colitis. These results indicate that TLR9-triggered type I IFN has antiinflammatory functions in colitis. They also underscore the important protective role of type I IFN in intestinal homeostasis and suggest that strategies to modulate innate immunity may be of therapeutic value for the treatment of intestinal inflammatory conditions.

Salmonella Typhimurium Co-Opts the Host Type I IFN System To Restrict Macrophage Innate Immune Transcriptional Responses Selectively

“…The role we have identified for IFN-β in suppressing aspects of the TLR/NLR-driven innate inflammatory response is congruent with a significant literature detailing a homeostatic as well as anti-inflammatory role for type I IFNs in a variety of inflammatory and autoimmune conditions (34-36), particularly in the intestine (37-39). Of distinct relevance for the present study is work showing that lactic acid bacteria, a common commensal bacterium, constitutively stimulate low level production of IFN-β, but not IFN-α, in the small intestine via double-stranded RNA ligation of TLR3.…”

Type I Interferons Control Proliferation and Function of the Intestinal Epithelium

“…Second, IFN can contribute to immune defenses against conditionally pathogenic microbiota and intestinal inflammation. Katakura and coauthors previously reported a greater sensitivity of Ifnar1-null mice to intestinal inflammation caused by dextran sodium sulfate (53). Those authors also mentioned a positive effect of IFN on the protection of barrier properties of the epithelial cell sheet in vitro.…”

Plasmacytoid Dendritic Cells Mediate Anti-inflammatory Responses to a Gut Commensal Molecule via Both Innate and Adaptive Mechanisms

“…However, TLR9 activation–mediated type 1 IFNs are protective in experimental colitis (Katakura et al, 2005). Thus PDCs may promote protection against colitis via type 1 IFN secretion.…”