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

• Published in: PloS one 2013-01, Vol.8 (1), p.e54472
• Main Authors: Renga, Barbara, Mencarelli, Andrea, Cipriani, Sabrina, D'Amore, Claudio, Carino, Adriana, Bruno, Angela, Francisci, Daniela, Zampella, Angela, Distrutti, Eleonora, Fiorucci, Stefano
• Format: Article
• Language: English
• Subjects: Acids; Animal tissues; Animals; Bile; Biology; Cell activation; Cells, Cultured; Colitis; Colitis - chemically induced; Colitis - genetics; Colitis - immunology; CpG islands; Deoxycholic acid; Gastroenterology; Gene expression; Gene Expression Regulation - drug effects; Genes; Genetic research; Homeostasis; Humans; Immune response; Immune system; Immunity; Immunity, Innate - genetics; Inflammation; Inflammatory bowel disease; Innate immunity; Interferon; Interferon regulatory factor 7; Interferon Regulatory Factor-7 - genetics; Interferon Regulatory Factor-7 - immunology; Intestinal microflora; Intestine; Intestines - immunology; Ligands; Lipid metabolism; Lipids; Male; Medicine; Metabolism; Mice; Mice, Knockout; Microbiota; Microbiota (Symbiotic organisms); Microorganisms; Monocytes; Monocytes - cytology; Monocytes - metabolism; MyD88 protein; Myeloid Differentiation Factor 88 - deficiency; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; Oligodeoxyribonucleotides - pharmacology; Physiological aspects; Probiotics; Promoter Regions, Genetic; Proteins; Receptors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - immunology; Receptors, Cytoplasmic and Nuclear - metabolism; Rodents; Signal Transduction - drug effects; Signal Transduction - physiology; Signal Transduction - radiation effects; Signaling; TLR2 protein; TLR3 protein; TLR9 protein; Toll-Like Receptor 9 - deficiency; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - immunology; Toll-like receptors; Transcription factors; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha - immunology; Tumor necrosis factor-α
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0054472

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. 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. 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.