Abstract
BackgroundToll 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 FindingsIn 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/SignificanceIntestinal 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.
Highlights
Innate immunity is central to host defense against invading pathogens, providing recognition of microorganisms and rapid deployment and activation of effector cells [1]
Farnesoid X Receptor (FXR) is differentially regulated by Toll like receptors (TLRs) in monocytes We have first investigated whether expression of FXR gene is regulated by TLRs agonists
While exposure of monocytes to TLR3 agonist had no effect on FXR expression, exposure of PMBC-derived monocytes to TLR7/8 and TLR9 ligands resulted in,3 fold induction of FXR mRNA (Figure 1 A; n = 3; p,0.05)
Summary
Innate immunity is central to host defense against invading pathogens, providing recognition of microorganisms and rapid deployment and activation of effector cells [1]. The ability to recognize microorganisms depends in part on a family of receptors known as the Toll-like receptors (TLRs) [1,2]. There are 13 known mammalian TLRs. Ligand engagement of TLR leads to activation of two pathways. TLR1, 2, 4, 5, 6, 7, 8, and 9 signal via the MyD88 adaptor, whereas TLR3 activates an alternative ‘‘MyD88-independent’’ pathway [1,2]. TLR4 is the only receptor known to activate both MyD88 dependent and independent pathways [1,2]. Toll like receptors (TLRs) sense the intestinal microbiota and regulate the innate immune response. FXR regulates lipid metabolism and innate immunity
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