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Endothelial sensing of AHR ligands regulates intestinal homeostasis

Endothelial cells line the blood and lymphatic vasculature, and act as an essential physical barrier, control nutrient transport, facilitate tissue immunosurveillance and coordinate angiogenesis and lymphangiogenesis(1,2). In the intestine, dietary and microbial cues are particularly important in th...

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Autores principales: Wiggins, Benjamin G., Wang, Yi-Fang, Burke, Alice, Grunberg, Nil, Vlachaki Walker, Julia M., Dore, Marian, Chahrour, Catherine, Pennycook, Betheney R., Sanchez-Garrido, Julia, Vernia, Santiago, Barr, Alexis R., Frankel, Gad, Birdsey, Graeme M., Randi, Anna M., Schiering, Chris
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10533400/
https://www.ncbi.nlm.nih.gov/pubmed/37586410
http://dx.doi.org/10.1038/s41586-023-06508-4
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author Wiggins, Benjamin G.
Wang, Yi-Fang
Burke, Alice
Grunberg, Nil
Vlachaki Walker, Julia M.
Dore, Marian
Chahrour, Catherine
Pennycook, Betheney R.
Sanchez-Garrido, Julia
Vernia, Santiago
Barr, Alexis R.
Frankel, Gad
Birdsey, Graeme M.
Randi, Anna M.
Schiering, Chris
author_facet Wiggins, Benjamin G.
Wang, Yi-Fang
Burke, Alice
Grunberg, Nil
Vlachaki Walker, Julia M.
Dore, Marian
Chahrour, Catherine
Pennycook, Betheney R.
Sanchez-Garrido, Julia
Vernia, Santiago
Barr, Alexis R.
Frankel, Gad
Birdsey, Graeme M.
Randi, Anna M.
Schiering, Chris
author_sort Wiggins, Benjamin G.
collection PubMed
description Endothelial cells line the blood and lymphatic vasculature, and act as an essential physical barrier, control nutrient transport, facilitate tissue immunosurveillance and coordinate angiogenesis and lymphangiogenesis(1,2). In the intestine, dietary and microbial cues are particularly important in the regulation of organ homeostasis. However, whether enteric endothelial cells actively sense and integrate such signals is currently unknown. Here we show that the aryl hydrocarbon receptor (AHR) acts as a critical node for endothelial cell sensing of dietary metabolites in adult mice and human primary endothelial cells. We first established a comprehensive single-cell endothelial atlas of the mouse small intestine, uncovering the cellular complexity and functional heterogeneity of blood and lymphatic endothelial cells. Analyses of AHR-mediated responses at single-cell resolution identified tissue-protective transcriptional signatures and regulatory networks promoting cellular quiescence and vascular normalcy at steady state. Endothelial AHR deficiency in adult mice resulted in dysregulated inflammatory responses and the initiation of proliferative pathways. Furthermore, endothelial sensing of dietary AHR ligands was required for optimal protection against enteric infection. In human endothelial cells, AHR signalling promoted quiescence and restrained activation by inflammatory mediators. Together, our data provide a comprehensive dissection of the effect of environmental sensing across the spectrum of enteric endothelia, demonstrating that endothelial AHR signalling integrates dietary cues to maintain tissue homeostasis by promoting endothelial cell quiescence and vascular normalcy.
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spelling pubmed-105334002023-09-29 Endothelial sensing of AHR ligands regulates intestinal homeostasis Wiggins, Benjamin G. Wang, Yi-Fang Burke, Alice Grunberg, Nil Vlachaki Walker, Julia M. Dore, Marian Chahrour, Catherine Pennycook, Betheney R. Sanchez-Garrido, Julia Vernia, Santiago Barr, Alexis R. Frankel, Gad Birdsey, Graeme M. Randi, Anna M. Schiering, Chris Nature Article Endothelial cells line the blood and lymphatic vasculature, and act as an essential physical barrier, control nutrient transport, facilitate tissue immunosurveillance and coordinate angiogenesis and lymphangiogenesis(1,2). In the intestine, dietary and microbial cues are particularly important in the regulation of organ homeostasis. However, whether enteric endothelial cells actively sense and integrate such signals is currently unknown. Here we show that the aryl hydrocarbon receptor (AHR) acts as a critical node for endothelial cell sensing of dietary metabolites in adult mice and human primary endothelial cells. We first established a comprehensive single-cell endothelial atlas of the mouse small intestine, uncovering the cellular complexity and functional heterogeneity of blood and lymphatic endothelial cells. Analyses of AHR-mediated responses at single-cell resolution identified tissue-protective transcriptional signatures and regulatory networks promoting cellular quiescence and vascular normalcy at steady state. Endothelial AHR deficiency in adult mice resulted in dysregulated inflammatory responses and the initiation of proliferative pathways. Furthermore, endothelial sensing of dietary AHR ligands was required for optimal protection against enteric infection. In human endothelial cells, AHR signalling promoted quiescence and restrained activation by inflammatory mediators. Together, our data provide a comprehensive dissection of the effect of environmental sensing across the spectrum of enteric endothelia, demonstrating that endothelial AHR signalling integrates dietary cues to maintain tissue homeostasis by promoting endothelial cell quiescence and vascular normalcy. Nature Publishing Group UK 2023-08-16 2023 /pmc/articles/PMC10533400/ /pubmed/37586410 http://dx.doi.org/10.1038/s41586-023-06508-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wiggins, Benjamin G.
Wang, Yi-Fang
Burke, Alice
Grunberg, Nil
Vlachaki Walker, Julia M.
Dore, Marian
Chahrour, Catherine
Pennycook, Betheney R.
Sanchez-Garrido, Julia
Vernia, Santiago
Barr, Alexis R.
Frankel, Gad
Birdsey, Graeme M.
Randi, Anna M.
Schiering, Chris
Endothelial sensing of AHR ligands regulates intestinal homeostasis
title Endothelial sensing of AHR ligands regulates intestinal homeostasis
title_full Endothelial sensing of AHR ligands regulates intestinal homeostasis
title_fullStr Endothelial sensing of AHR ligands regulates intestinal homeostasis
title_full_unstemmed Endothelial sensing of AHR ligands regulates intestinal homeostasis
title_short Endothelial sensing of AHR ligands regulates intestinal homeostasis
title_sort endothelial sensing of ahr ligands regulates intestinal homeostasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10533400/
https://www.ncbi.nlm.nih.gov/pubmed/37586410
http://dx.doi.org/10.1038/s41586-023-06508-4
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