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Expression of the Atypical Chemokine Receptor ACKR4 Identifies a Novel

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Expression of the Atypical Chemokine Receptor ACKR4 Identifies a Novel Expression of the Atypical Chemokine Receptor ACKR4 Identifies a Novel Population of Intestinal Submucosal Fibroblasts That Preferentially Expresses This information is current as Endothelial Cell Regulators of September 26, 2021. Carolyn A. Thomson, Serge A. van de Pavert, Michelle Stakenborg, Evelien Labeeuw, Gianluca Matteoli, Allan McI Mowat and Robert J. B. Nibbs J Immunol published online 14 May 2018 Downloaded from http://www.jimmunol.org/content/early/2018/05/11/jimmun ol.1700967 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2018/05/11/jimmunol.170096 Material 7.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published May 14, 2018, doi:10.4049/jimmunol.1700967 The Journal of Immunology Expression of the Atypical Chemokine Receptor ACKR4 Identifies a Novel Population of Intestinal Submucosal Fibroblasts That Preferentially Expresses Endothelial Cell Regulators Carolyn A. Thomson,*,1 Serge A. van de Pavert,† Michelle Stakenborg,‡ Evelien Labeeuw,‡ Gianluca Matteoli,‡ Allan McI Mowat,*,2 and Robert J. B. Nibbs*,2 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 mi- Downloaded from gratory APCs in the skin-draining lymph nodes of Ackr4-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 Ackr4 deficiency does not affect dendritic cell abundance in the small intestine and mesenteric lymph nodes, at steady state or after R848-induced mobilization. Moreover, Ackr4 expression is largely restricted to mesenchymal cells in the intestine, where it identifies a previously uncharacterized population of fibroblasts residing exclusively in the submucosa. Com- 2 + pared with related Ackr4 mesenchymal cells, these Ackr4 fibroblasts have elevated expression of genes encoding endothelial cell http://www.jimmunol.org/ regulators and lie in close proximity to submucosal blood and lymphatic vessels. We also provide evidence that Ackr4+ 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 Ackr4 and have transcriptional and anatomical properties that strongly suggest roles in endothelial cell regulation. The Journal of Immunology, 2018, 201: 000–000. he intestine is a complex and dynamic organ requiring leukocytes can move and migrate (1–3). These processes are es- continuous interactions between many different haemo- sential for tissue development and repair, maintenance of ho- T poietic and nonhaemopoietic (stromal) cell types. These meostasis, adaptation to environmental challenges, and response by guest on September 26, 2021 include resident and migratory leukocytes, epithelial cells, blood to disease. vessel endothelial cells (BECs), lymphatic endothelial cells Leukocyte migration in the intestine and elsewhere is dependent (LECs), neurons, and various populations of mesenchymal cells, on chemokines, which engage conventional G-protein–coupled such as pericytes, smooth muscle cells, fibroblasts, and myofi- chemokine receptors on leukocytes (4). There are also four broblasts. Mesenchymal cells play many important roles in the atypical chemokine receptors (ACKRs) that regulate chemokine- physiological and immunological functions of the intestine (1–3). driven migration by transcytosing, sequestering, or scavenging In addition to providing the three-dimensional matrix of the tissue, chemokines (5). ACKRs are typically expressed by stromal cells they supply growth factors critical for epithelial cell renewal, in highly defined microanatomical niches, where they have been regulate endothelial cell function, contribute to innate and adaptive shown to be capable of regulating leukocyte trafficking into, immune responses, and provide surfaces upon which interstitial within, and out of tissues (5). ACKR4, previously known as *Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary by Research Foundation Flanders Grant G0D8317N and Ph.D. fellowship ZKD1563 and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom; (to M.S.). †Centre d’Immunologie de Marseille-Luminy, Aix Marseille Universite´, CNRS, The microarray data presented in this article have been submitted to the National INSERM, 13288 Marseille Cedex 9, France; and ‡Laboratory of Mucosal Immunol- Center for Biotechnology Information’s Gene Expression Omnibus database (https:// ogy, Department of Chronic Diseases, Metabolism and Ageing, Translational Re- www.ncbi.nlm.nih.gov/geo/) under accession number GSE113665. search Center for Gastrointestinal Disorders, Catholic University Leuven, BE-3000 Leuven, Belgium Address correspondence and reprint requests to Prof. Robert J.B. Nibbs, University of Glasgow, 120 University Place, Glasgow G12 8TA, U.K. E-mail address: robert. 1Current address: Department of Physiology and Pharmacology, Cumming School of [email protected] Medicine, University of Calgary, Calgary, AB, Canada. The online version of this article contains supplemental material. 2A.M.M. and R.J.B.N. contributed equally to this work. Abbreviations used in this article: ACKR, atypical chemokine receptor; AF, Alexa ORCIDs: 0000-0003-3906-7539 (C.A.T.); 0000-0002-7147-4380 (S.A.v.d.P.); 0000- Fluor; BEC, blood vessel endothelial cell; BMP, bone morphogenetic protein; CM, 0002-4086-0289 (M.S.); 0000-0002-2902-4976 (G.M.); 0000-0001-9389- circular muscle; DC, dendritic cell; DN, double negative; DSS, dextran sodium 3079 (A.M.M.); 0000-0002-8150-0044 (R.J.B.N.). sulfate; FDR, false discovery rate; FRC, fibroblastic reticular cell; IESC, intestinal Received for publication July 6, 2017. Accepted for publication April 10, 2018. epithelial stem cell; iMC, intestinal mesenchymal cell; LC, Langerhans cell; LEC, lymphatic endothelial cell; LM, longitudinal muscle; LN, lymph node; LP, lamina This work was supported by a project grant (MR/L000598) from the United Kingdom propria; ME, muscularis externa; MHCII, MHC class II; MLN, mesenteric LN; Medical Research Council (to C.A.T., A.M.M., and R.J.B.N.). S.A.v.d.P. was sup- QPCR, quantitative real-time PCR; SCS, subcapsular sinus; SI, small intestine; ported by A*MIDEX Chaire d’Excellence Grant ANR-11-IDEX-0001-002, Fonda- SLN, skin-draining LN; aSMA, a smooth muscle actin; WT, wild-type. tion pour la Recherche Me´dicale Jeunes Equipes Grant AJE20150633331, and France Bio Imaging Grant ANR-10-INBS-04-01, and G.M., E.L., and M.S. were supported Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700967 2 ACKR4 AND SUBMUCOSAL FIBROBLASTS IN THE INTESTINE CCRL1 or CCX–CKR, binds with high affinity to CCL19 and purchased from Biolegend: CD103–PE (2E7), CD11c–PE/Cy7 (N418), CCL21, which direct leukocyte migration through CCR7, and to CD146–PerCP/Cy5.5 and CD146–APC (ME-9F1), B220–PerCP/Cy5.5 ε CCL25, the sole ligand for CCR9 (6–9). By internalizing and (RA3–6B2), CD3 –PerCP/Cy5.5 (145-2C11), CD31–BV605 and CD31– PE (390), CD45–PerCP/Cy5.5, CD55–PE (RIKO-3), CD66a–APC (Mab- degrading its ligands, ACKR4 can regulate their abundance and CC1), CD105–APC (MJ7/18), CD106–PE (429), CD9–Alexa Fluor (AF) shape chemokine gradients (10–12). In vivo, this has been most 647 (MZ3), CD90.2–PE (30-H12), EPCAM–PerCP/Cy5.5 and EPCAM– studied in the skin, where, under steady-state and inflammatory APC/Cy7 (G8.8), F4/80–BV605 and F4/80–APC (BM8), GP38–PE/ conditions, the CCR7-dependent trafficking of Langerhans cells Cy7 (8.1.1), ICAM1–PE (YN1/1.7.4), Ly6G–PE (1A8), MHC class II (MHCII)–BV510 (M5/114.15.2), NK1.1–PerCP/Cy5.5 (PK136), PDGFRa– (LCs) and dendritic cells (DCs) to draining lymph nodes (LNs) is PE (APA5), and SCA1–APC (D7). The following anti-mouse Abs controlled by ACKR4 expression on keratinocytes, a subset of were purchased from eBioscience (San Diego, CA): CD11b–AF700 dermal LECs, and by LECs lining the ceiling of the LN subcap- and CD11b–eFluor 450 (M1/70), CD45–AF700 and CD45–eFluor 450 sular sinus (SCS) (11–15). CCR7 is also essential for the migra- (30-F11), CD166–PE (ALC48), Ly6C–eFluor 450 (HK1.4), and Ter119– tion of DCs from the small intestine (SI) to the mesenteric LNs eFluor 450 (TER-119). BD Biosciences (Franklin Lakes, NJ) supplied CD29–PE (HM b1-1), CD34–AF647 (RAM34), and Siglec F–PE (MLNs) (9), but the function of ACKR4 in this context has not (E50-2440). Dead cells were excluded using 7AAD (BioLegend) or Fix- been explored. Ackr4 transcripts are detectable in the SI and colon able Viability Dye eFluor 780 (eBioscience). Stained cells were analyzed of mice (7), and GFP+ cells are present in the SI of Ackr4gfp/+ or sorted using an LSR II (BD Biosciences) or a FACSAria I, IIu, or III . reporter mice (13), although the identity of these cells is not clear.
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