Endothelial sensing of AHR ligands regulates intestinal homeostasis

Benjamin G. Wiggins (), Yi-Fang Wang, Alice Burke, Nil Grunberg, Julia M. Vlachaki Walker, Marian Dore, Catherine Chahrour, Betheney R. Pennycook, Julia Sanchez-Garrido, Santiago Vernia, Alexis R. Barr, Gad Frankel, Graeme M. Birdsey, Anna M. Randi and Chris Schiering ()
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Benjamin G. Wiggins: Imperial College London
Yi-Fang Wang: MRC London Institute of Medical Sciences
Alice Burke: Imperial College London
Nil Grunberg: Imperial College London
Julia M. Vlachaki Walker: Imperial College London
Marian Dore: MRC London Institute of Medical Sciences
Catherine Chahrour: MRC London Institute of Medical Sciences
Betheney R. Pennycook: Imperial College London
Julia Sanchez-Garrido: Imperial College London
Santiago Vernia: Imperial College London
Alexis R. Barr: Imperial College London
Gad Frankel: Imperial College London
Graeme M. Birdsey: Imperial College London
Anna M. Randi: Imperial College London
Chris Schiering: Imperial College London

Nature, 2023, vol. 621, issue 7980, 821-829

Abstract: Abstract 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 lymphangiogenesis1,2. 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.

Date: 2023
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DOI: 10.1038/s41586-023-06508-4

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