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


RESULTS
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
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.
Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, Perugia, Italy.
Barbara
B
Renga
Andrea
A
Mencarelli
Sabrina
S
Cipriani
Claudio
C
D'Amore
Adriana
A
Carino
Angela
A
Bruno
Daniela
D
Francisci
Angela
A
Zampella
Eleonora
E
Distrutti
Stefano
S
Fiorucci
D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology; D007422:Intestines / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D000099150:Receptor, Farnesoid X-Activated
D050839:Interferon Regulatory Factor-7; D053594:Myeloid Differentiation Factor 88; D009838:Oligodeoxyribonucleotides; D018160:Receptors, Cytoplasmic and Nuclear; D051217:Toll-Like Receptor 9; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha; D000099150:Receptor, Farnesoid X-Activated; C494235:Irf7 protein, mouse; C507780:Myd88 protein, mouse; C099713:nuclear receptor subfamily 0, group B, member 2