Expression of the atypical chemokine receptor ACKR4 identifies a novel population of intestinal submucosal fibroblasts that preferentially expresses endothelial cell regulators

Thomson, C. A., van de Pavert, S. A., Stakenborg, M., Labeeuw, E., Matteoli, G., Mowat, A. M. and Nibbs, R. J.B. (2018) Expression of the atypical chemokine receptor ACKR4 identifies a novel population of intestinal submucosal fibroblasts that preferentially expresses endothelial cell regulators. Journal of Immunology, 201(1), pp. 215-229. (doi: 10.4049/jimmunol.1700967) (PMID:29760193) (PMCID:PMC6013047)

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Abstract

Atypical chemokine receptors (ACKRs) are expressed by discrete populations of stromal cells at specific anatomical locations where they control leukocyte migration by scavenging or transporting chemokines. ACKR4 is an atypical receptor for CCL19, CCL21, and CCL25. In skin, ACKR4 plays indispensable roles in regulating CCR7-dependent APC migration, and there is a paucity of migratory APCs in the skin-draining lymph nodes of -deficient mice under steady-state and inflammatory conditions. This is caused by loss of ACKR4-mediated CCL19/21 scavenging by keratinocytes and lymphatic endothelial cells. In contrast, we show in this study that deficiency does not affect dendritic cell abundance in the small intestine and mesenteric lymph nodes, at steady state or after R848-induced mobilization. Moreover, expression is largely restricted to mesenchymal cells in the intestine, where it identifies a previously uncharacterized population of fibroblasts residing exclusively in the submucosa. Compared with related mesenchymal cells, these fibroblasts have elevated expression of genes encoding endothelial cell regulators and lie in close proximity to submucosal blood and lymphatic vessels. We also provide evidence that fibroblasts form physical interactions with lymphatic endothelial cells, and engage in molecular interactions with these cells via the VEGFD/VEGFR3 and CCL21/ACKR4 pathways. Thus, intestinal submucosal fibroblasts in mice are a distinct population of intestinal mesenchymal cells that can be identified by their expression of and have transcriptional and anatomical properties that strongly suggest roles in endothelial cell regulation.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nibbs, Professor Rob and Mowat, Professor Allan and Thomson, Miss Carolyn
Authors: Thomson, C. A., van de Pavert, S. A., Stakenborg, M., Labeeuw, E., Matteoli, G., Mowat, A. M., and Nibbs, R. J.B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Immunology
Publisher:American Association of Immunologists
ISSN:0022-1767
ISSN (Online):1550-6606
Published Online:14 May 2018

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
628061Regulation of intestinal Immune responses by the atypical Chemokine receptor CCRL1Robert NibbsMedical Research Council (MRC)MR/L000598/1III -IMMUNOLOGY