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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 2/2005

Open Access 01-12-2004 | Research article

Chemokine receptors in the rheumatoid synovium: upregulation of CXCR5

Authors: Caroline Schmutz, Alison Hulme, Angela Burman, Mike Salmon, Brian Ashton, Christopher Buckley, Jim Middleton

Published in: Arthritis Research & Therapy | Issue 2/2005

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Abstract

In patients with rheumatoid arthritis (RA), chemokine and chemokine receptor interactions play a central role in the recruitment of leukocytes into inflamed joints. This study was undertaken to characterize the expression of chemokine receptors in the synovial tissue of RA and non-RA patients. RA synovia (n = 8) were obtained from knee joint replacement operations and control non-RA synovia (n = 9) were obtained from arthroscopic knee biopsies sampled from patients with recent meniscal or articular cartilage damage or degeneration. The mRNA expression of chemokine receptors and their ligands was determined using gene microarrays and PCR. The protein expression of these genes was demonstrated by single-label and double-label immunohistochemistry. Microarray analysis showed the mRNA for CXCR5 to be more abundant in RA than non-RA synovial tissue, and of the chemokine receptors studied CXCR5 showed the greatest upregulation. PCR experiments confirmed the differential expression of CXCR5. By immunohistochemistry we were able to detect CXCR5 in all RA and non-RA samples. In the RA samples the presence of CXCR5 was observed on B cells and T cells in the infiltrates but also on macrophages and endothelial cells. In the non-RA samples the presence of CXCR5 was limited to macrophages and endothelial cells. CXCR5 expression in synovial fluid macrophages and peripheral blood monocytes from RA patients was confirmed by PCR. The present study shows that CXCR5 is upregulated in RA synovial tissue and is expressed in a variety of cell types. This receptor may be involved in the recruitment and positioning of B cells, T cells and monocytes/macrophages in the RA synovium. More importantly, the increased level of CXCR5, a homeostatic chemokine receptor, in the RA synovium suggests that non-inflammatory receptor–ligand pairs might play an important role in the pathogenesis of RA.
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Literature
1.
Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, O'Fallon WM, Goronzy JJ, Weyand CM: Lymphoid neogenesis in rheumatoid synovitis. J Immunol. 2001, 167: 1072-1080.CrossRefPubMed
2.
Szekanecz Z, Strieter RM, Kunkel SL, Koch AE: Chemokines in rheumatoid arthritis. Springer Semin Immunopathol. 1998, 20: 115-132. 10.1007/BF00832002.CrossRefPubMed
3.
Feldmann M, Brennan FM, Maini RN: Rheumatoid arthritis. Cell. 1996, 85: 307-310. 10.1016/S0092-8674(00)81109-5.CrossRefPubMed
4.
Luster AD: Chemokines – chemotactic cytokines that mediate inflammation. N Engl J Med. 1998, 338: 436-445. 10.1056/NEJM199802123380706.CrossRefPubMed
5.
Haringman JJ, Kraan MC, Smeets TJM, Zwinderman KH, Tak PP: Chemokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis. Ann Rheum Dis. 2003, 62: 715-721. 10.1136/ard.62.8.715.PubMedCentralCrossRefPubMed
6.
Podolin PL, Bolognese BJ, Foley JJ, Schmidt DB, Buckley PT, Widdowson KL, Jin Q, White JR, Lee JM, Goodman RB, et al: A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit. J Immunol. 2002, 169: 6435-6444.CrossRefPubMed
7.
D'Ambrosio D, Panina-Bordignon P, Sinigaglia F: Chemokine receptors in inflammation: an overview. J Immunol Methods. 2003, 273: 3-13. 10.1016/S0022-1759(02)00414-3.CrossRefPubMed
8.
Murdoch C, Finn A: Chemokine receptors and their role in inflammation and infectious diseases. Blood. 2000, 95: 3032-3043.PubMed
9.
Buckley CD, Amft N, Bradfield PF, Pilling D, Ross E, Arenzana-Seisdedos F, Amara A, Curnow SJ, Lord JM, Scheel-Toellner D, Salmon M: Persistent induction of the chemokine receptor CXCR4 by TGF-β1 on synovial T cells contributes to their accumulation within the rheumatoid synovium. J Immunol. 2000, 165: 3423-3429.CrossRefPubMed
10.
Nanki T, Lipsky PE: Cytokine, activation marker, and chemokine receptor expression by individual CD4+ memory T cells in rheumatoid arthritis synovium. Arthritis Res. 2000, 2: 415-423. 10.1186/ar120.PubMedCentralCrossRefPubMed
11.
Shadidi KR, Thompson KM, Henriksen JE, Natvig JB, Aavak T: Association of antigen specificity and migratory capacity of memory T cells in rheumatoid arthritis. Scand J Immunol. 2002, 55: 274-283. 10.1046/j.0300-9475.2002.01036.x.CrossRefPubMed
12.
Ruth JH, Rottman JB, Katschke KJ, Qin S, Wu L, LaRosa G, Ponath P, Pope RM, Koch AE: Selective lymphocyte chemokine receptor expression in the rheumatoid joint. Arthritis Rheum. 2001, 44: 2750-2760. 10.1002/1529-0131(200112)44:12<2750::AID-ART462>3.0.CO;2-C.CrossRefPubMed
13.
Ruth JH, Shahrara S, Park CC, Morel JC, Kumar P, Qin S, Koch AE: Role of macrophage inflammatory protein-3α and its ligand CCR6 in rheumatoid arthritis. Lab Invest. 2003, 83: 579-588.CrossRefPubMed
14.
Katschke KJ, Rottman JB, Ruth JH, Qin S, Wu L, LaRosa G, Ponath P, Park CC, Pope RM, Koch AE: Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. Arthritis Rheum. 2001, 44: 1022-1032. 10.1002/1529-0131(200105)44:5<1022::AID-ANR181>3.0.CO;2-N.CrossRefPubMed
15.
Brühl H, Wagner K, Kellner H, Schattenkirchner M, Schlöndorff D, Mack M: Surface expression of CC- and CXC-chemokine receptors on leucocytes subsets in inflammatory joint diseases. Clin Exp Immunol. 2001, 126: 551-559. 10.1046/j.1365-2249.2001.01679.x.PubMedCentralCrossRefPubMed
16.
Blades MC, Ingegnoli F, Wheller SK, Manzo A, Wahid S, Panayi GS, Perretti M, Pitzalis C: Stromal cell-derived factor 1 (CXCL12) induces monocyte migration into human synovium transplanted onto SCID mice. Arthritis Rheum. 2002, 46: 824-836. 10.1002/art.10102.CrossRefPubMed
17.
Page G, Lebecque S, Miossec P: Anatomic localization of immature and mature dendritic cells in an ectopic lymphoid organ: correlation with selective chemokine expression in rheumatoid synovium. J Immunol. 2002, 168: 5333-5341.CrossRefPubMed
18.
Shadidi KR: New drug targets in rheumatoid arthritis: focus on chemokines. BioDrugs. 2004, 18: 181-187.CrossRefPubMed
19.
Szekanecz Z, Kim J, Koch AE: Chemokines and chemokine receptors in rheumatoid arthritis. Semin Immunol. 2003, 15: 15-21. 10.1016/S1044-5323(02)00124-0.CrossRefPubMed
20.
Förster R, Emrich T, Kremmer E, Lipp M: Expression of the G-protein-coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells. Blood. 1994, 84: 830-840.PubMed
21.
Barella L, Loetscher M, Tobler A, Baggiolini M, Moser B: Sequence variation of a novel heptahelical leucocyte receptor through alternative transcript formation. Biochem J. 1995, 309: 773-779.PubMedCentralCrossRefPubMed
22.
Amft N, Curnow SJ, Scheel-Toellner D, Devadas A, Oates J, Crocker J, Hamburger J, Ainsworth J, Mathews J, Salmon M, Bowman SJ, Buckley CD: Ectopic expression of the B cell-attracting chemokine BCA-1 (CXCL13) on endothelial cells and within lymphoid follicles contributes to the establishment of germinal center-like structure in Sjögren's syndrome. Arthritis Rheum. 2001, 44: 2633-2641. 10.1002/1529-0131(200111)44:11<2633::AID-ART443>3.0.CO;2-9.CrossRefPubMed
23.
Salomonsson S, Larsson P, Tengnér P, Mellquist E, Hjelmström P, Wahren-Herlenius M: Expression of the B cell-attracting chemokine CXCL13 in the target organ and autoantibody production in ectopic lymphoid tissue in the chronic inflammatory disease Sjögren's syndrome. Scand J Immunol. 2002, 55: 336-342. 10.1046/j.1365-3083.2002.01058.x.CrossRefPubMed
24.
Müller G, Höpken UE, Stein H, Lipp M: Systemic immunoregulatory and pathogenic functions of homeostatic chemokine receptors. J Leukoc Biol. 2002, 72: 1-8.PubMed
25.
Shi K, Hayashida K, Kaneko M, Hashimoto J, Tomita T, Lipsky PE, Yoshikawa H, Ochi T: Lymphoid chemokine B-cell-attracting chemokine-1 (CXCL13) is expressed in germinal center of ectopic lymphoid follicles within the synovium of chronic arthritis patients. J Immunol. 2001, 166: 650-655.CrossRefPubMed
26.
Hjelmström P: Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines. J Leukoc Biol. 2001, 69: 331-339.PubMed
27.
Förster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M: A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell. 1996, 87: 1037-1047. 10.1016/S0092-8674(00)81798-5.CrossRefPubMed
28.
Ansel KM, Ngo VN, Hyman PL, Luther SA, Förster R, Sedgwick JD, Browning JL, Lipp M, Cyster JG: A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature. 2000, 406: 309-314. 10.1038/35018581.CrossRefPubMed
29.
Kirkham B, Portek I, Lee CS, Stavros B, Lenarczyk A, Lassere M, Edmonds J: Intraarticular variability of synovial membrane histology, immunohistology, and cytokine mRNA expression in patients with rheumatoid arthritis. J Rheumatol. 1999, 26: 777-784.PubMed
30.
Lawrance IC, Fiocchi C, Chakravarti S: Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes. Hum Mol Genet. 2001, 10: 445-456. 10.1093/hmg/10.5.445.CrossRefPubMed
31.
Ruschpler P, Lorenz P, Eichler W, Koczan D, Hänel C, Scholz R, Melzer C, Thiesen H-J, Stiehl P: High CXCR3 expression in synovial mast cells associated with CXCL9 and CXCL10 expression in inflammatory synovial tissues of patients with rheumatoid arthritis. Arthritis Res Ther. 2003, 5: R241-R252. 10.1186/ar783.PubMedCentralCrossRefPubMed
32.
Gu J, Märker-Hermann E, Baeten D, Tsai WC, Gladman D, Xiong M, Deister H, Kuipers JG, Huang F, Song YW, et al: A 588-gene micorarray analysis of the peripheral blood mononuclear cells of spondyloarthropathy patients. Rheumatology. 2002, 41: 759-766. 10.1093/rheumatology/41.7.759.CrossRefPubMed
33.
Weyand CM, Goronzy JJ, Takemura S, Kurtin PJ: Cell–cell interactions in synovitis. Interactions between T cells and B cells in rheumatoid arthritis. Arthritis Res Ther. 2000, 2: 457-463. 10.1186/ar128.CrossRef
34.
Goronzy JJ, Weyand CM: B cells as a therapeutic target in autoimmune disease. Arthritis Res. 2003, 5: 131-135.CrossRef
35.
Campbell DJ, Kim CH, Butcher EC: Chemokines in the systemic organization of immunity. Immunol Rev. 2003, 195: 58-71. 10.1034/j.1600-065X.2003.00067.x.CrossRefPubMed
36.
Müller G, Lipp M: Shaping up adaptive immunity: the impact of CCR7 and CXCR5 on lymphocyte trafficking. Microcirculation. 2003, 10: 325-334. 10.1038/sj.mn.7800197.CrossRefPubMed
37.
Okada T, Ngo VN, Ekland EH, Förster R, Lipp M, Littman DR, Cyster JG: Chemokine requirements for B cell entry to lymph nodes and Peyer's patches. J Exp Med. 2002, 196: 65-75. 10.1084/jem.20020201.PubMedCentralCrossRefPubMed
38.
Ebisuno Y, Tanaka T, Kanemitsu N, Kanda H, Yamaguchi K, Kaisho T, Akira S, Miyasaka M: Cutting edge: the B cell chemokine CXC chemokine ligand 13/B lymphocyte chemoattractant is expressed in the high endothelial venules of lymph nodes and Peyer's patches and affects B cell trafficking across high endothelial venules. J Immunol. 2003, 171: 1642-1646.CrossRefPubMed
39.
Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B: CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med. 2000, 192: 1553-1562. 10.1084/jem.192.11.1553.PubMedCentralCrossRefPubMed
40.
Breitfeld D, Ohl Lars, Kremmer E, Ellwart J, Sallusto F, Lipp M, Förster R: Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med. 2000, 192: 1545-1552. 10.1084/jem.192.11.1545.PubMedCentralCrossRefPubMed
41.
Kim CH, Rott LS, Clark-Lewis I, Campbell DJ, Wu L, Butcher EC: Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J Exp Med. 2001, 193: 1373-1381. 10.1084/jem.193.12.1373.PubMedCentralCrossRefPubMed
42.
Dupuy d'Angeac A, Monier S, Jorgensen C, Gao Q, Travaglio-Encinoza A, Bologna C, Combe B, Sany J, Reme T: Increased percentage of CD3+, CD57+ lymphocytes in patients with rheumatoid arthritis. Correlation with duration of disease. Arthritis Rheum. 1993, 36: 608-612.CrossRefPubMed
43.
Arai K, Yamamura S, Seki S, Hanyu T, Takahashi HE, Abo T: Increase of CD57+ T cells in knee joints and adjacent bone marrow of rheumatoid arthritis (RA) patients: implication for an anti-inflammatory role. Clin Exp Immunol. 1998, 111: 345-352. 10.1046/j.1365-2249.1998.00511.x.PubMedCentralCrossRefPubMed
44.
Maeda T, Yamada H, Nagamine R, Shuto T, Nakashima Y, Hirata G, Iwamoto Y: Involvement of CD4+, CD57+ T cells in the disease activity of rheumatoid arthritis. Arthritis Rheum. 2002, 46: 379-384. 10.1002/art.10133.CrossRefPubMed
45.
Edwards JCW: The synovium. Rheumatology. Edited by: Klippel JH, Dieppe PA. 1998, London: Mosby, 6.1-6.8.
46.
Patterson AM, Schmutz C, Davis S, Gardner L, Ashton BA, Middleton J: Differential binding of chemokines to macrophages and neutrophils in the human inflamed synovium. Arthritis Res. 2002, 4: 209-214. 10.1186/ar408.PubMedCentralCrossRefPubMed
47.
Pablos JL, Santiago B, Galindo M, Torres C, Brehmer MT, Blanco FJ, García-Lázaro FJ: Synoviocyte-derived CXCL12 is displayed on endothelium and induces angiogenesis in rheumatoid arthritis. J Immunol. 2003, 170: 2147-2152.CrossRefPubMed
48.
García-López MA, Sánchez-Madrid F, Rodríguez-Frade JM, Mellado M, Acevedo A, García MI: CXCR3 chemokine receptor distribution in normal and inflamed tissues: expression on activated lymphocytes, endothelial cells, and dendritic cells. Lab Invest. 2001, 81: 409-418.CrossRefPubMed
49.
Patterson AM, Siddall H, Chamberlain G, Gardner L, Middleton J: Expression of the duffy antigen/receptor for chemokine (DARC) by the inflamed synovial endothelium. J Pathol. 2002, 197: 108-116. 10.1002/path.1100.CrossRefPubMed
50.
Walsh DA, Wade M, Mapp PI, Blake DR: Focally regulated endothelial proliferation and cell death in human synovium. Am J Pathol. 1998, 152: 691-702.PubMedCentralPubMed
51.
52.
Addison CL, Daniel TO, Burdick MD, Liu H, Ehlert JE, Xue YY, Buechi L, Walz A, Richmond A, Strieter RM: The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity. J Immunol. 2000, 165: 5269-5277.CrossRefPubMed
53.
Bernardini G, Spinetti G, Ribatti D, Camarda G, Morbidelli L, Ziche M, Santoni A, Capogrossi MC, Napolitano M: I-309 binds to and activates endothelial cell function and acts as an angiogenic molecule in vivo. Blood. 2000, 96: 4039-4045.PubMed
54.
Salcedo R, Ponce ML, Young HA, Wasserman K, Ward JM, Kleinman HK, Oppenheim JJ, Murphy WJ: Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression. Blood. 2000, 96: 34-40.PubMed
55.
Koch AE, Volin MV, Woods JM, Kunkel SL, Connors MA, Harlow LA, Woodruff DC, Burdick MD, Strieter RM: Regulation of angiogenesis by C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide 78 in the rheumatoid joint. Arthritis Rheum. 2001, 44: 31-40. 10.1002/1529-0131(200101)44:1<31::AID-ANR5>3.0.CO;2-4.CrossRefPubMed
56.
Romagnani P, Annunziato F, Lasagni L, Lazzeri E, Beltrame C, Francalanci M, Uguccioni M, Galli G, Cosmi L, Maurenzig L, et al: Cell cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity. J Clin Invest. 2001, 107: 53-63.PubMedCentralCrossRefPubMed
57.
Salcedo R, Zhang X, Young HA, Michael N, Wasserman K, Ma W-H, Martins-Green M, Murphy WJ, Oppenheim J: Angiogenic effects of prostaglandin E2 are mediated by up-regulation of CXCR4 on human microvascular endothelial cells. Blood. 2003, 102: 1966-1977. 10.1182/blood-2002-11-3400.CrossRefPubMed
58.
Spinetti G, Camarda G, Bernardini G, Romano Di Peppe S, Capogrossi MC, Napolitano M: The chemokine CXCL13 (BCA-1) inhibits FGF-2 effects on endothelial cells. Biochem Biophys Res Commun. 2001, 289: 19-24. 10.1006/bbrc.2001.5924.CrossRefPubMed
59.
Hillyer P, Mordelet E, Flynn G, Male D: Chemokines, chemokine receptors and adhesion molecules on different human endothelia: discriminating the tissue-specific functions that affect leucocyte migration. Clin Exp Immunol. 2003, 134: 431-441. 10.1111/j.1365-2249.2003.02323.x.PubMedCentralCrossRefPubMed
60.
Jenh C-H, Cox MA, Hipkin W, Lu T, Pugliese-Sivo C, Gonsiorek W, Chou C-C, Narula SK, Zavodny PJ: Human B cell-attracting chemokine 1 (BCA-1; CXCL13) is an agonist for the human CXCR3 receptor. Cytokine. 2001, 15: 113-121. 10.1006/cyto.2001.0923.CrossRefPubMed
Metadata
Title
Chemokine receptors in the rheumatoid synovium: upregulation of CXCR5
Authors
Caroline Schmutz
Alison Hulme
Angela Burman
Mike Salmon
Brian Ashton
Christopher Buckley
Jim Middleton
Publication date
01-12-2004
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 2/2005
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar1475

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