Toll-like receptor 9–induced type I IFN protects mice from experimental colitis
Kyoko Katakura, … , Lars Eckmann, Eyal Raz
Kyoko Katakura, … , Lars Eckmann, Eyal Raz
Published March 1, 2005
Citation Information: J Clin Invest. 2005;115(3):695-702. https://doi.org/10.1172/JCI22996.
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Article Immunology

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.

Authors

Kyoko Katakura, Jongdae Lee, Daniel Rachmilewitz, Gloria Li, Lars Eckmann, Eyal Raz

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Figure 1

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Histological evaluation. (A–F) WT mice (A and B), RAG1–/– mice (C and D)...
Histological evaluation. (A–F) WT mice (A and B), RAG1–/– mice (C and D), and SCID mice (E and F) were treated with ISS-ODN (DSS + ISS; A, C, and E) or were injected with saline (DSS; B, D, and F) and 2 hours later were given 1.5% DSS in the drinking water. After 7 days, paraffin sections of the colon were prepared and stained with H&E. In WT and RAG1–/– mice, ISS treatment markedly attenuated colitis, as shown by the absence of mucosal ulceration and inflammatory cell infiltration in the same strain not treated with ISS (A and C). In contrast, SCID mice exhibited extensive mucosal ulceration and inflammatory cell infiltration into mucosa, submucosa, and muscle regardless of ISS treatment (E and F).