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PLoS One. 2013;8(1):e54472. doi: 10.1371/journal.pone.0054472. Epub 2013 Jan 25.

The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation.

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1
Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, Perugia, Italy.

Abstract

BACKGROUND:

Toll like receptors (TLRs) sense the intestinal microbiota and regulate the innate immune response. A dysregulation of TLRs function participates into intestinal inflammation. Farnesoid X Receptor (FXR) is a nuclear receptor and bile acid sensor highly expressed in entero-hepatic tissues. FXR regulates lipid metabolism and innate immunity.

METHODOLOGY/PRINCIPAL FINDINGS:

In this study we have investigated whether FXR gene expression/function in the intestine is modulated by TLRs. We found that in human monocytes activation of membrane TLRs (i.e. TLR2, 4, 5 and 6) downregulates, while activation of intracellular TLRs (i.e. TLR3, 7, 8 and 9) upregulates the expression of FXR and its target gene SHP, small heterodimer partner. This effect was TLR9-dependent and TNFα independent. Intestinal inflammation induced in mice by TNBS downregulates the intestinal expression of FXR in a TLR9-dependent manner. Protection against TNBS colitis by CpG, a TLR-9 ligand, was lost in FXR(-/-) mice. In contrast, activation of FXR rescued TLR9(-/-) and MyD88(-/-) mice from colitis. A putative IRF7 response element was detected in the FXR promoter and its functional characterization revealed that IRF7 is recruited on the FXR promoter under TLR9 stimulation.

CONCLUSIONS/SIGNIFICANCE:

Intestinal expression of FXR is selectively modulated by TLR9. In addition to its role in regulating type-I interferons and innate antiviral immunity, IRF-7 a TLR9-dependent factor, regulates the expression of FXR, linking microbiota-sensing receptors to host's immune and metabolic signaling.

PMID:
23372731
PMCID:
PMC3555871
DOI:
10.1371/journal.pone.0054472
[Indexed for MEDLINE]
Free PMC Article
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