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This Article Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Mingle, B. Articles by Nagler, C. PubMed Articles by Mingle, B. Articles by Nagler, C.

Exacerbation of spontaneous colitis in the absence of flora derived TLR4 signals

¹ DRAI/CIID, Mass.General Hospital, 149 13th Street, room 6114, Charlestown, MA, 02129, ² Nestle Research Center, P.O. Box 44, Lausanne, CH-1000, Switzerland, ³ Ehime University School of Medicine, 454 Shitsukawa, Shigenobu-cho, Onsen-gun, 791-0295, Japan

Abstract

Complex immunoregulatory mechanisms are required to maintain non-responsiveness to dietary antigens and the commensal flora. We have reported that mice that are unable to signal via TLR4, the receptor for bacterial LPS, are highly susceptible to an allergic response to food. When the composition of the commensal flora is reduced and altered by antibiotic treatment, TLR4 wild-type mice become as susceptible to the induction of allergy as their TLR4 mutant counterparts. More recently we have shown that the mesenteric lymph nodes of TLR4 mutant mice are deficient in the generation of IL-10 secreting regulatory T cells (Tregs) and lack a population of plasmacytoid DC that constitutively makes IL-10. To further examine the contributions of IL-10 secreting Tregs and DC to mucosal non-responsiveness, we prepared TLR4xIL-10 double knockout (DKO) mice. We have found that the Th1 biased colitis previously reported in IL-10 deficient mice is greatly exacerbated in TLR4xIL-10 DKO mice. Our observations stand in contrast to a recent report from Rakoff-Nahoum et al (Immunity 2006 25:319) that shows that MyD88xIL-10 DKO mice are protected from the development of colitis. TLR4 is unique among bacteria responsive TLRs in its ability to signal via both MyD88 dependent and MyD88 independent pathways. Taken together with our observation that food allergy is linked to an inability to signal via TLR4, the exacerbation of spontaneous colitis in TLR4xIL-10 DKO mice supports a unique role for TLR4 signaling in the generation of flora induced immunoregulatory cells that control pathological responses at both ends of the Th1/Th2 spectrum.

Supported by NIH grants DK 55678 and DK43351.

This Article Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Mingle, B. Articles by Nagler, C. PubMed Articles by Mingle, B. Articles by Nagler, C.