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TLR4 Signaling Selectively and Directly Promotes CGRP Release from Vagal Afferents in the Mouse

There has been a long-standing debate regarding the role of peripheral afferents in mediating rapid-onset anorexia among other responses elicited by peripheral inflammatory insults. Thus, the current study assessed the sufficiency of peripheral afferents expressing toll-like receptor 4 (TLR4) to the...

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Autores principales: Jia, Lin, Lee, Syann, Tierney, Jessica A., Elmquist, Joel K., Burton, Michael D., Gautron, Laurent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877464/
https://www.ncbi.nlm.nih.gov/pubmed/33318075
http://dx.doi.org/10.1523/ENEURO.0254-20.2020
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author Jia, Lin
Lee, Syann
Tierney, Jessica A.
Elmquist, Joel K.
Burton, Michael D.
Gautron, Laurent
author_facet Jia, Lin
Lee, Syann
Tierney, Jessica A.
Elmquist, Joel K.
Burton, Michael D.
Gautron, Laurent
author_sort Jia, Lin
collection PubMed
description There has been a long-standing debate regarding the role of peripheral afferents in mediating rapid-onset anorexia among other responses elicited by peripheral inflammatory insults. Thus, the current study assessed the sufficiency of peripheral afferents expressing toll-like receptor 4 (TLR4) to the initiation of the anorexia caused by peripheral bacterial lipopolysaccharide (LPS). We generated a Tlr4 null (Tlr4(LoxTB)) mouse in which Tlr4 expression is globally disrupted by a loxP-flanked transcription blocking (TB) cassette. This novel mouse model allowed us to restore the endogenous TLR4 expression in specific cell types. Using Zp3-Cre and Na(v)1.8-Cre mice, we produced mice that express TLR4 in all cells (Tlr4(LoxTB) X Zp3-Cre) and in peripheral afferents (Tlr4(LoxTB) X Na(v)1.8-Cre), respectively. We validated the Tlr4(LoxTB) mice, which were phenotypically identical to previously reported global TLR4 knock-out mice. Contrary to our expectations, the administration of LPS did not cause rapid-onset anorexia in mice with Na(v)1.8-restricted TLR4. The later result prompted us to identify Tlr4-expressing vagal afferents using in situ hybridization (ISH). In vivo, we found that Tlr4 mRNA was primarily enriched in vagal Na(v)1.8 afferents located in the jugular ganglion that co-expressed calcitonin gene-related peptide (CGRP). In vitro, the application of LPS to cultured Na(v)1.8-restricted TLR4 afferents was sufficient to stimulate the release of CGRP. In summary, we demonstrated using a new mouse model that vagally-expressed TLR4 is selectively involved in stimulating the release of CGRP but not in causing anorexia.
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spelling pubmed-78774642021-02-12 TLR4 Signaling Selectively and Directly Promotes CGRP Release from Vagal Afferents in the Mouse Jia, Lin Lee, Syann Tierney, Jessica A. Elmquist, Joel K. Burton, Michael D. Gautron, Laurent eNeuro Research Article: New Research There has been a long-standing debate regarding the role of peripheral afferents in mediating rapid-onset anorexia among other responses elicited by peripheral inflammatory insults. Thus, the current study assessed the sufficiency of peripheral afferents expressing toll-like receptor 4 (TLR4) to the initiation of the anorexia caused by peripheral bacterial lipopolysaccharide (LPS). We generated a Tlr4 null (Tlr4(LoxTB)) mouse in which Tlr4 expression is globally disrupted by a loxP-flanked transcription blocking (TB) cassette. This novel mouse model allowed us to restore the endogenous TLR4 expression in specific cell types. Using Zp3-Cre and Na(v)1.8-Cre mice, we produced mice that express TLR4 in all cells (Tlr4(LoxTB) X Zp3-Cre) and in peripheral afferents (Tlr4(LoxTB) X Na(v)1.8-Cre), respectively. We validated the Tlr4(LoxTB) mice, which were phenotypically identical to previously reported global TLR4 knock-out mice. Contrary to our expectations, the administration of LPS did not cause rapid-onset anorexia in mice with Na(v)1.8-restricted TLR4. The later result prompted us to identify Tlr4-expressing vagal afferents using in situ hybridization (ISH). In vivo, we found that Tlr4 mRNA was primarily enriched in vagal Na(v)1.8 afferents located in the jugular ganglion that co-expressed calcitonin gene-related peptide (CGRP). In vitro, the application of LPS to cultured Na(v)1.8-restricted TLR4 afferents was sufficient to stimulate the release of CGRP. In summary, we demonstrated using a new mouse model that vagally-expressed TLR4 is selectively involved in stimulating the release of CGRP but not in causing anorexia. Society for Neuroscience 2021-01-15 /pmc/articles/PMC7877464/ /pubmed/33318075 http://dx.doi.org/10.1523/ENEURO.0254-20.2020 Text en Copyright © 2021 Jia et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article: New Research
Jia, Lin
Lee, Syann
Tierney, Jessica A.
Elmquist, Joel K.
Burton, Michael D.
Gautron, Laurent
TLR4 Signaling Selectively and Directly Promotes CGRP Release from Vagal Afferents in the Mouse
title TLR4 Signaling Selectively and Directly Promotes CGRP Release from Vagal Afferents in the Mouse
title_full TLR4 Signaling Selectively and Directly Promotes CGRP Release from Vagal Afferents in the Mouse
title_fullStr TLR4 Signaling Selectively and Directly Promotes CGRP Release from Vagal Afferents in the Mouse
title_full_unstemmed TLR4 Signaling Selectively and Directly Promotes CGRP Release from Vagal Afferents in the Mouse
title_short TLR4 Signaling Selectively and Directly Promotes CGRP Release from Vagal Afferents in the Mouse
title_sort tlr4 signaling selectively and directly promotes cgrp release from vagal afferents in the mouse
topic Research Article: New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877464/
https://www.ncbi.nlm.nih.gov/pubmed/33318075
http://dx.doi.org/10.1523/ENEURO.0254-20.2020
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