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

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

<h4>Background</h4>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 ent...

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Autores principales: Barbara Renga, Andrea Mencarelli, Sabrina Cipriani, Claudio D'Amore, Adriana Carino, Angela Bruno, Daniela Francisci, Angela Zampella, Eleonora Distrutti, Stefano Fiorucci
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Publicado: Public Library of Science (PLoS) 2013
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spelling oai:doaj.org-article:95ac7d0acba945eca1cf9d528946926d2021-11-18T07:59:51ZThe bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation.1932-620310.1371/journal.pone.0054472https://doaj.org/article/95ac7d0acba945eca1cf9d528946926d2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23372731/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Barbara RengaAndrea MencarelliSabrina CiprianiClaudio D'AmoreAdriana CarinoAngela BrunoDaniela FrancisciAngela ZampellaEleonora DistruttiStefano FiorucciPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 1, p e54472 (2013)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Barbara Renga
Andrea Mencarelli
Sabrina Cipriani
Claudio D'Amore
Adriana Carino
Angela Bruno
Daniela Francisci
Angela Zampella
Eleonora Distrutti
Stefano Fiorucci
The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation.
description <h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.
format article
author Barbara Renga
Andrea Mencarelli
Sabrina Cipriani
Claudio D'Amore
Adriana Carino
Angela Bruno
Daniela Francisci
Angela Zampella
Eleonora Distrutti
Stefano Fiorucci
author_facet Barbara Renga
Andrea Mencarelli
Sabrina Cipriani
Claudio D'Amore
Adriana Carino
Angela Bruno
Daniela Francisci
Angela Zampella
Eleonora Distrutti
Stefano Fiorucci
author_sort Barbara Renga
title The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation.
title_short The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation.
title_full The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation.
title_fullStr The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation.
title_full_unstemmed The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation.
title_sort bile acid sensor fxr is required for immune-regulatory activities of tlr-9 in intestinal inflammation.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/95ac7d0acba945eca1cf9d528946926d
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