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  • Review Article
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Leukocyte trafficking between stromal compartments: lessons from rheumatoid arthritis

Nature Reviews Rheumatology volume 14, pages 476–487 (2018)Cite this article

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Abstract

The trafficking of leukocytes from their site of production in the bone marrow through the circulation and into peripheral tissues is a highly coordinated and tightly regulated process in healthy individuals. Lymphocytes are long-lived cells that visit many lymphoid and peripheral tissues over their lifetime and can even recirculate back to the bone marrow, whereas granulocytes and monocytes are not thought to recirculate so widely. Using rheumatoid arthritis (RA) as an example, this Review explores the migratory journey of leukocytes during the establishment and resolution of disease — from the blood, through the lymphoid tissues and into peripheral sites such as the lungs and the gut before their entry into the synovium. This Review explores our current understanding of differences in the molecular processes that regulate leukocyte trafficking at different phases of disease and in different stromal compartments, which could help to explain the disease heterogeneity seen in patients with RA. Expanding our knowledge of these processes will open new avenues in the clinical management of RA, paving the way for personalized medicine that is founded on the pathological molecular signature of each patient, which varies according to their phase of disease or disease subtype.

Key points

  • Patients with rheumatoid arthritis (RA) have defects in at least one, if not multiple, checkpoints that regulate leukocyte entry into and exit from lymphoid and peripheral tissues, including the joints.

  • Even at the earliest phases of disease, patients with RA have impaired thymic output and naive T cells that have an immunosenescent phenotype.

  • Individuals at risk of RA show signs of alterations in the phenotype of lymphocytes trafficking through the draining lymph nodes of the joints.

  • Genetic predisposition and metabolic alterations in T cells can render them ‘sticky’ and hypermotile, contributing to aberrant lymphocyte trafficking throughout the body.

  • Interactions between fibroblasts and endothelial cells in the synovium evolve with disease, changing the shape and nature of the inflammatory infiltrate at each phase of RA.

  • Lymphatic vessels change during experimental inflammatory arthritis and represent a potential novel therapeutic target.

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Fig. 1: Migration of lymphocytes from the bone marrow to lymphoid organs and peripheral tissues.
Fig. 2: Leukocyte trafficking through peripheral tissues in pre-arthritis and early rheumatoid arthritis.
Fig. 3: Heterogeneity in leukocyte trafficking patterns in rheumatoid arthritis.
Fig. 4: Tissue-specific address codes regulate trafficking in the synovium.

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References

  1. Doita, M., Maeda, S., Kawai, K., Hirohata, K. & Sugiyama, T. Analysis of lymphocyte subsets of bone marrow in patients with rheumatoid arthritis by two colour immunofluorescence and flow cytometry. Ann. Rheum. Dis. 49, 168–171 (1990).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Hirohata, S. et al. Accelerated generation of CD14+ monocyte-lineage cells from the bone marrow of rheumatoid arthritis patients. Arthritis Rheum. 5, 836–843 (1996).

    Article  Google Scholar 

  3. Bugatti, S. et al. Ultrasonographic and MRI characterisation of the palindromic phase of rheumatoid arthritis. Ann. Rheum. Dis. 71, 625–626 (2012).

    Article  PubMed  Google Scholar 

  4. Jimenez-Boj, E. et al. Interaction between synovial inflammatory tissue and bone marrow in rheumatoid arthritis. J. Immunol. 175, 2579–2588 (2005).

    Article  PubMed  CAS  Google Scholar 

  5. Cosway, E., Anderson, G., Garside, P. & Prendergast, C. The thymus and rheumatology: should we care? Curr. Opin. Rheumatol. 28, 189–195 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Wagner, U., Schatz, A., Baerwald, C. & Rossol, M. Brief report: Deficient thymic output in rheumatoid arthritis despite abundance of prethymic progenitors. Arthritis Rheum. 65, 2567–2572 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  7. McGovern, J. L. et al. Th17 cells are restrained by Treg cells via the inhibition of interleukin-6 in patients with rheumatoid arthritis responding to anti-tumor necrosis factor antibody therapy. Arthritis Rheum. 64, 3129–3138 (2012).

    Article  PubMed  CAS  Google Scholar 

  8. Nadkarni, S., Mauri, C. & Ehrenstein, M. R. Anti-TNF-α therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-β. J. Exp. Med. 204, 33–39 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Byng-Maddick, R. & Ehrenstein, M. R. The impact of biological therapy on regulatory T cells in rheumatoid arthritis. Rheumatology 54, 768–775 (2015).

    Article  PubMed  CAS  Google Scholar 

  10. Ponchel, F. et al. Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis. Blood 100, 4550–4556 (2002).

    Article  PubMed  CAS  Google Scholar 

  11. Koetz, K. et al. T cell homeostasis in patients with rheumatoid arthritis. Proc. Natl Acad. Sci. USA 97, 9203–9208 (2000).

    Article  PubMed  CAS  Google Scholar 

  12. Hale, J. S. & Fink, P. J. Back to the thymus: peripheral T cells come home. Immunol. Cell Biol. 87, 58–64 (2009).

    Article  PubMed  CAS  Google Scholar 

  13. Thiault, N. et al. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nat. Immunol. 16, 628–634 (2015).

    Article  PubMed  CAS  Google Scholar 

  14. Edelmann, S. L., Marconi, P. & Brocker, T. Peripheral T cells re-enter the thymus and interfere with central tolerance induction. J. Immunol. 186, 5612–5619 (2011).

    Article  PubMed  CAS  Google Scholar 

  15. Frommer, F. & Waisman, A. B cells participate in thymic negative selection of murine auto-reactive CD4(+) T cells. PLoS ONE 5, e15372 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Hodge, D. L. et al. MCP-1/CCR2 interactions direct migration of peripheral B and T lymphocytes to the thymus during acute infectious/inflammatory processes. Eur. J. Immunol. 42, 2644–2654 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Cowan, J., McCarthy, N. & Anderson, G. CCR7 controls thymus recirculation, but not production and emigration, of Foxp3(+) T cells. Cell Rep. 14, 1041–1048 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Tracy, A., Buckley, C. D. & Raza, K. Pre-symptomatic autoimmunity in rheumatoid arthritis: when does the disease start? Semin. Immunopathol. 39, 423–435 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Stolt, P. et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann. Rheum. Dis. 62, 835–841 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Izquierdo, E. et al. Immature blood vessels in rheumatoid synovium are selectively depleted in response to anti-TNF therapy. PLoS ONE 4, e8131 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Potempa, J., Mydel, P. & Koziel, J. The case for periodontitis in the pathogenesis of rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 606–620 (2017).

    Article  PubMed  CAS  Google Scholar 

  22. Queiroz-Junior, C. M. et al. Experimental arthritis triggers periodontal disease in mice: involvement of TNF-α and the oral microbiota. J. Immunol. 187, 3821–3830 (2011).

    Article  PubMed  CAS  Google Scholar 

  23. Queiroz-Junior, C. M. et al. Experimental arthritis exacerbates Aggregatibacter actinomycetemcomitans-induced periodontitis in mice. J. Clin. Periodontol. 39, 608–616 (2012).

    Article  PubMed  CAS  Google Scholar 

  24. Ramwadhdoebe, T. H. et al. Human lymph-node CD8(+) T cells display an altered phenotype during systemic autoimmunity. Clin. Transl Immunol. 5, e67 (2016).

    Article  CAS  Google Scholar 

  25. Ramwadhdoebe, T. H. et al. Lymph node biopsy analysis reveals an altered immunoregulatory balance already during the at-risk phase of autoantibody positive rheumatoid arthritis. Eur. J. Immunol. 46, 2812–2821 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Hañhnlein, J. S. et al. Distinctive expression of T cell guiding molecules in human autoimmune lymph node stromal cells upon TLR3 triggering. Sci. Rep. 8, 1736 (2018).

    Article  CAS  Google Scholar 

  27. Hähnlein, J. S. et al. Impaired lymph node stromal cell function during the earliest phases of rheumatoid arthritis. Arthritis Res. Ther. 20, 35 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Li, J. et al. Expanded CD23/CD21 B cells in inflamed lymph nodes are associated with the onset of inflammatory-erosive arthritis in TNF-transgenic mice and are targets of anti-CD20 therapy. J. Immunol. 184, 6142–6150 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Rodríguez-Palmero, M. et al. Alterations of lymphocyte populations in lymph nodes but not in spleen during the latency period of adjuvant arthritis. Inflammation 23, 153–165 (1999).

    Article  Google Scholar 

  30. Nourshargh, S. & Alon, R. Leukocyte migration into inflamed tissues. Immunity 41, 694–707 (2014).

    Article  PubMed  CAS  Google Scholar 

  31. Mellado, M. et al. T cell migration in rheumatoid arthritis. Front. Immunol. 6, 384 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Luo, D., McGettrick, H. M., Stone, P. C., Rainger, G. E. & Nash, G. B. The roles of integrins in function of human neutrophils after their migration through endothelium into interstitial matrix. PLoS ONE 10, e0118593 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. McGettrick, H. M. et al. Chemokine- and adhesion-dependent survival of neutrophils after transmigration through cytokine-stimulated endothelium. J. Leukoc. Biol. 79, 779–788 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Filer, A. et al. Differential survival of leukocyte subsets mediated by synovial, bone marrow, and skin fibroblasts: site-specific versus activation-dependent survival of T cells and neutrophils. Arthritis Rheum. 54, 2096–2108 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Bayley, R. et al. The autoimmune-associated genetic variant PTPN22 R620W enhances neutrophil activation and function in patients with rheumatoid arthritis and healthy individuals. Ann. Rheum. Dis. 74, 1588–1595 (2015).

    Article  PubMed  CAS  Google Scholar 

  36. Burn, G. L. et al. Superresolution imaging of the cytoplasmic phosphatase PTPN22 links integrin-mediated T cell adhesion with autoimmunity. Sci. Signal. 9, ra99 (2016).

    Article  PubMed  CAS  Google Scholar 

  37. Hwang, S. H. et al. Leukocyte-specific protein 1 regulates T cell migration in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 112, E6535–E6543 (2015).

    Article  PubMed  CAS  Google Scholar 

  38. Shen, Y. et al. Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells. Nat. Immunol. 18, 1025–1034 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  39. Demoruelle, M. K. et al. Anti-citrullinated protein antibodies are associated with neutrophil extracellular traps in the sputum in relatives of rheumatoid arthritis patients. Arthritis Rheumatol. 69, 1165–1175 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. McComb, J. G. et al. CX3CL1 up-regulation is associated with recruitment of CX3CR1(+) mononuclear phagocytes and T lymphocytes in the lungs during cigarette smoke-induced emphysema. Am. J. Pathol. 173, 949–961 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Qiu, C. et al. Anti-interleukin-33 inhibits cigarette smoke-induced lung inflammation in mice. Immunology 138, 76–82 (2013).

    Article  PubMed  CAS  Google Scholar 

  42. Qiu, C. et al. Hydrodynamic delivery of IL-28B (IFN-λ3) gene ameliorates lung inflammation induced by cigarette smoke exposure in mice. Biochem. Biophys. Res. Commun. 447, 513–519 (2014).

    Article  PubMed  CAS  Google Scholar 

  43. Nowak, D., Ruta, U. & Piasecka, G. Nicotine increases human polymorphonuclear leukocytes chemotactic response - a possible additional mechanism of lung injury in cigarette smokers. Exp. Pathol. 39, 37–43 (1990).

    Article  PubMed  CAS  Google Scholar 

  44. Ryder, M. I. et al. Alterations of neutrophil L-selection and CD18 expression by tobacco smoke: implications for periodontal diseases. J. Periodont. Res. 33, 359–368 (1998).

    Article  PubMed  CAS  Google Scholar 

  45. Stone, P. C. W., Fisher, A. C., Rainger, G. E. & Nash, G. B. Neutrophil capture by selectins on endothelial cells exposed to cigarette smoke. Biochem. Biophys. Res. Commun. 295, 1150–1155 (2002).

    Article  PubMed  CAS  Google Scholar 

  46. Overbeek, S. A. et al. Cigarette smoke induces β2-integrin-dependent neutrophil migration across human endothelium. Respir. Res. 12, 75–75 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Laan, M., Bozinovski, S. & Anderson, G. P. Cigarette smoke inhibits lipopolysaccharide-induced production of inflammatory cytokines by suppressing the activation of activator protein-1 in bronchial epithelial cells. J. Immunol. 173, 4164–4170 (2004).

    Article  PubMed  CAS  Google Scholar 

  48. Vassallo, R. et al. Cellular and humoral immunity in arthritis are profoundly influenced by the interaction between cigarette smoke effects and host HLA-DR and DQ genes. Clin. Immunol. 152, 25–35 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Allais, L. et al. The effect of cigarette smoke exposure on the development of inflammation in lungs, gut and joints of TNFΔARE mice. PLoS ONE 10, e0141570 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Glossop, J. R., Dawes, P. T. & Mattey, D. L. Association between cigarette smoking and release of tumour necrosis factor-α and its soluble receptors by peripheral blood mononuclear cells in patients with rheumatoid arthritis. Rheumatology 45, 1223–1229 (2006).

    Article  PubMed  CAS  Google Scholar 

  51. Reynisdottir, G. et al. Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis. Ann. Rheum. Dis. 75, 1722–1727 (2016).

    Article  PubMed  CAS  Google Scholar 

  52. Zhang, X. et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat. Med. 21, 895–905 (2015).

    Article  PubMed  CAS  Google Scholar 

  53. Scher, J. U. et al. The lung microbiota in early rheumatoid arthritis and autoimmunity. Microbiome 4, 60 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Morton, A. M. et al. Endoscopic photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut. Proc. Natl Acad. Sci. USA 111, 6696–6701 (2014).

    Article  PubMed  CAS  Google Scholar 

  56. Naskar, D., Teng, F., Felix, K. M., Bradley, C. P. & Wu, H. J. J. Synthetic retinoid AM80 ameliorates lung and arthritic autoimmune responses by inhibiting T follicular helper and Th17 cell responses. J. Immunol. 198, 1855–1864 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Block, K. E., Zheng, Z., Dent, A. L., Kee, B. L. & Huang, H. Gut microbiota regulates K/B×N autoimmune arthritis through Tfh but not Th17 cells. J. Immunol. 196, 1550–1557 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Teng, F. et al. Gut microbiota drive autoimmune arthritis by promoting differentiation and migration of Peyer's patch T follicular helper cells. Immunity 44, 875–888 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Chappert, P., Bouladoux, N., Naik, S. & Schwartz, R. H. Specific gut commensal flora locally alters T cell tuning to endogenous ligands. Immunity 38, 1198–1210 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Salmi, M., Rajala, P. & Jalkanen, S. Homing of mucosal leukocytes to joints. Distinct endothelial ligands in synovium mediate leukocyte-subtype specific adhesion. J. Clin. Invest. 99, 2165–2172 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Tong, B. et al. Sinomenine suppresses collagen-induced arthritis by reciprocal modulation of regulatory T cells and Th17 cells in gut-associated lymphoid tissues. Mol. Immunol. 65, 94–103 (2015).

    Article  PubMed  CAS  Google Scholar 

  62. Yue, M. et al. Berberine ameliorates collagen-induced arthritis in rats by suppressing Th17 cell responses via inducing cortistatin in the gut. FEBS J. 284, 2786–2801 (2017).

    Article  PubMed  CAS  Google Scholar 

  63. Marietta, E. V. et al. Suppression of inflammatory arthritis by human gut-derived Prevotella histicola in humanized mice. Arthritis Rheumatol. 68, 2878–2888 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Smolen, J. S., Aletaha, D. & McInnes, I. B. Rheumatoid arthritis. Lancet 388, 2023–2038 (2016).

    Article  PubMed  CAS  Google Scholar 

  65. Polman, C. H. et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899–910 (2006).

    Article  PubMed  CAS  Google Scholar 

  66. Kaufman, A. & Herold, K. C. Anti-CD3 mAbs for treatment of type 1 diabetes. Diabetes Metab. Res. Rev. 25, 302–306 (2009).

    Article  PubMed  CAS  Google Scholar 

  67. Emery, P. et al. Impact of T cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial). Ann. Rheum. Dis. 69, 510–516 (2010).

    Article  PubMed  CAS  Google Scholar 

  68. Maxwell, L. J. & Singh, J. A. Abatacept for rheumatoid arthritis: a Cochrane systematic review. J. Rheumatol. 37, 234–245 (2010).

    Article  PubMed  CAS  Google Scholar 

  69. Asquith, D. L., Bryce, S. A. & Nibbs, R. J. B. Targeting cell migration in rheumatoid arthritis. Curr. Opin. Rheumatol. 27, 204–211 (2015).

    Article  PubMed  CAS  Google Scholar 

  70. de Hair, M. J. H. et al. Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis. Arthritis Rheumatol. 66, 513–522 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Choi, I. Y. et al. Stromal cell markers are differentially expressed in the synovial tissue of patients with early arthritis. PLoS ONE 12, e0182751 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Filer, A. et al. Identification of a transitional fibroblast function in very early rheumatoid arthritis. Ann. Rheum. Dis. 76, 2105–2112 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Lally, F. et al. A novel mechanism of neutrophil recruitment in a coculture model of the rheumatoid synovium. Arthritis Rheum. 52, 3460–3649 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. McGettrick, H. M. et al. Fibroblasts from different sites may promote or inhibit recruitment of flowing lymphocytes by endothelial cells. Eur. J. Immunol. 39, 113–125 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Smith, E. et al. Duffy antigen receptor for chemokines and CXCL5 are essential for the recruitment of neutrophils in a multicellular model of rheumatoid arthritis synovium. Arthritis Rheum. 58, 1968–1973 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Allen, M. & Louise Jones, J. Jekyll and Hyde: the role of the microenvironment on the progression of cancer. J. Pathol. 223, 163–177 (2011).

    Article  CAS  Google Scholar 

  77. Klimiuk, P. A., Goronzy, J. J., Bjornsson, J., Beckenbaugh, R. D. & Weyand, C. M. Tissue cytokine patterns distinguish variants of rheumatoid synovitis. Am. J. Pathol. 151, 1311–1319 (1997).

    PubMed  PubMed Central  CAS  Google Scholar 

  78. Pitzalis, C., Kelly, S. & Humby, F. New learnings on the pathophysiology of RA from synovial biopsies. Curr. Opin. Rheumatol. 25, 334–344 (2013).

    Article  PubMed  Google Scholar 

  79. Dennis, G. et al. Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics. Arthritis Res. Ther. 16, R90–R90 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat. Commun. 9, 789 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Croft, A. P. et al. Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage. Arthritis Res. Ther. 18, 270 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. van Oosterhout, M. et al. Differences in synovial tissue infiltrates between anti–cyclic citrullinated peptide–positive rheumatoid arthritis and anti–cyclic citrullinated peptide–negative rheumatoid arthritis. Arthritis Rheum. 58, 53–60 (2008).

    Article  PubMed  Google Scholar 

  83. Tineke, C. et al. Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis. Arthritis Rheum. 60, 1944–1956 (2009).

    Article  CAS  Google Scholar 

  84. Gómez-Puerta, J. A. et al. Differences in synovial fluid cytokine levels but not in synovial tissue cell infiltrate between anti-citrullinated peptide/protein antibody-positive and –negative rheumatoid arthritis patients. Arthritis Res. Ther. 15, R182–R182 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Abbot, S. E., Whish, W. J., Jennison, C., Blake, D. R. & Stevens, C. R. Tumour necrosis factor alpha stimulated rheumatoid synovial microvascular endothelial cells exhibit increased shear rate dependent leucocyte adhesion in vitro. Ann. Rheum. Dis. 58, 573–581 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Leick, M., Azcutia, V., Newton, G. & Luscinskas, F. W. Leukocyte recruitment in inflammation: basic concepts and new mechanistic insights based on new models and microscopic imaging technologies. Cell Tissue Res. 355, 647–656 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Tak, P. P. et al. Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor-α monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum. 39, 1077–1081 (1996).

    Article  PubMed  CAS  Google Scholar 

  88. Szekanecz, Z. & Koch, A. E. Successes and failures of chemokine-pathway targeting in rheumatoid arthritis. Nat. Rev. Rheumatol. 12, 5–13 (2016).

    Article  PubMed  CAS  Google Scholar 

  89. McNaughton, E. F. et al. Novel anti-inflammatory peptides based on chemokine–glycosaminoglycan interactions reduce leukocyte migration and disease severity in a model of rheumatoid arthritis. J. Immunol. 200, 3201–3217 (2018).

    Article  PubMed  CAS  Google Scholar 

  90. Chimen, M. et al. Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in autoimmune and chronic inflammatory disease. Nat. Med. 21, 467–475 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Kemble, S., Harford, L. & McGettrick, H. New therapeutic avenues in rheumatoid arthritis: exploring the role of the adiponectin-PEPITEM axis [abstract]. Ann. Rheum. Dis. 77 (Suppl. 1), A7 (2018).

    Google Scholar 

  92. McGettrick, H. M., Butler, L. M., Buckley, C. D., Rainger, G. E. & Nash, G. B. Tissue stroma as a regulator of leukocyte recruitment in inflammation. J. Leuk. Biol. 91, 385–400 (2012).

    Article  Google Scholar 

  93. Parsonage, G. et al. A stromal address code defined by fibroblasts. Trends Immunol. 26, 150–156 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Luu, N.-T. et al. Crosstalk between mesenchymal stem cells and endothelial cells leads to downregulation of cytokine-induced leukocyte recruitment. Stem Cells 31, 2690–2702 (2013).

    Article  PubMed  CAS  Google Scholar 

  95. Munir, H., Luu, N. T., Clarke, L. S. C., Nash, G. B. & McGettrick, H. M. Comparative ability of mesenchymal stromal cells from different tissues to limit neutrophil recruitment to inflamed endothelium. PLoS ONE 11, e0155161 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. McGettrick, H. M. et al. Functional pathways in endothelial cells are differentially regulated by fibroblasts from patients with RA and resolving disease [abstract]. Ann. Rheum. Dis. 74 (Suppl. 1), A57 (2015).

    Google Scholar 

  97. Davis, G. E., Norden, P. R. & Bowers, S. L. K. Molecular control of capillary morphogenesis and maturation by recognition and remodeling of the extracellular matrix: functional roles of endothelial cells and pericytes in health and disease. Connective Tissue Res. 56, 392–402 (2015).

    Article  CAS  Google Scholar 

  98. Alon, R. & Nourshargh, S. Learning in motion: pericytes instruct migrating innate leukocytes. Nat. Immunol. 14, 14–15 (2012).

    Article  CAS  Google Scholar 

  99. Slowikowski, K., Wei, K., Brenner, M. B. & Raychaudhuri, S. Functional genomics of stromal cells in chronic inflammatory diseases. Curr. Opin. Rheumatol. 30, 65–71 (2018).

    Article  PubMed  Google Scholar 

  100. Williams, B., Dharmapatni, A. & Crotti, T. Intracellular apoptotic pathways: a potential target for reducing joint damage in rheumatoid arthritis. Inflamm Res. 67, 219–231 (2018).

    Article  PubMed  CAS  Google Scholar 

  101. Croft, M. & Siegel, R. M. Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat. Rev. Rheumatol. 13, 217–233 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Cuda, C. M., Pope, R. M. & Perlman, H. The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases. Nat. Rev. Rheumatol. 12, 543–558 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Liu, H. & Pope, R. M. The role of apoptosis in rheumatoid arthritis. Curr. Opin. Pharmacol. 3, 317–322 (2003).

    Article  PubMed  CAS  Google Scholar 

  104. Prendergast, C. T. et al. Visualising the interaction of CD4 T cells and DCs in the evolution of inflammatory arthritis. Ann. Rheum. Dis. 77, 579–588 (2018).

    Article  PubMed  Google Scholar 

  105. Jaigirdar, S. A. et al. Sphingosine-1-phosphate promotes the persistence of activated CD4 T cells in inflamed sites. Front. Immunol. 8, 1627 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Wang, F., Tan, W., Guo, D. & He, S. Reduction of CD4 positive T cells and improvement of pathological changes of collagen-induced arthritis by FTY720. Eur. J. Pharmacol. 573, 230–240 (2007).

    Article  PubMed  CAS  Google Scholar 

  107. Matsuura, M., Imayoshi, T. & Okumoto, T. Effect of FTY720, a novel immunosuppressant, on adjuvant- and collagen-induced arthritis in rats. Int. J. Immunopharmacol. 22, 323–331 (2000).

    Article  PubMed  CAS  Google Scholar 

  108. Han, Y. et al. FTY720 abrogates collagen-induced arthritis by hindering dendritic cell migration to local lymph nodes. J. Immunol. 195, 4126–4135 (2015).

    Article  PubMed  CAS  Google Scholar 

  109. Tsunemi, S. et al. Effects of the novel immunosuppressant FTY720 in a murine rheumatoid arthritis model. Clin. Immunol. 136, 197–204 (2010).

    Article  PubMed  CAS  Google Scholar 

  110. Fujii, Y. et al. Amelioration of collagen-induced arthritis by a novel S1P1 antagonist with immunomodulatory activities. J. Immunol. 188, 206–215 (2012).

    Article  PubMed  CAS  Google Scholar 

  111. Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002).

    Article  PubMed  CAS  Google Scholar 

  112. Chiba, K. FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol. Ther. 108, 308–319 (2005).

    Article  PubMed  CAS  Google Scholar 

  113. Bouta, E. M. et al. Targeting lymphatic function as a novel therapeutic intervention for rheumatoid arthritis. Nat. Rev. Rheumatol. 14, 94–106 (2018).

    Article  PubMed  CAS  Google Scholar 

  114. Bouta, E. M. et al. The role of the lymphatic system in inflammatory-erosive arthritis. Semin. Cell Dev. Biol. 38, 90–97 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Taylor, P. C. et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor a blockade in patients with rheumatoid arthritis. Arthritis Rheum. 43, 38–47 (2000).

    Article  PubMed  CAS  Google Scholar 

  116. den Broeder, A. A. et al. Neutrophil migration and production of reactive oxygen species during treatment with a fully human anti-tumor necrosis factor-α monoclonal antibody in patients with rheumatoid arthritis. J. Rheumatol. 30, 232–237 (2003).

    Google Scholar 

  117. Herenius, M. M. J. et al. Monocyte migration to the synovium in rheumatoid arthritis patients treated with adalimumab. Ann. Rheum. Dis. 70, 1160–1162 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Mitchell, T. S., Moots, R. J. & Wright, H. L. Janus kinase inhibitors prevent migration of rheumatoid arthritis neutrophils towards interleukin-8, but do not inhibit priming of the respiratory burst or reactive oxygen species production. Clin. Exp. Immunol. 189, 250–258 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgements

The work of the authors is supported by an Arthritis Research UK Career Development Fellowship (grant number 19899 to H.M.M.) and by an Arthritis Research UK programme grant (grant number 19791 to C.D.B.). The Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence is partially funded by Arthritis Research UK (grant number 20298); this centre is a collaboration between the University of Glasgow, the University of Newcastle and the University of Birmingham in the UK. The MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research (grant number MR/P021220/1) is a collaboration between the University of Birmingham, the University of Nottingham and Oxford University in the UK.

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Nature Reviews Rheumatology thanks S. Jalkanen, M. Perretti and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Rheumatology Research Group, Arthritis Research UK Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK

    Christopher D. Buckley & Helen M. McGettrick

  2. Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK

    Christopher D. Buckley

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  1. Christopher D. Buckley
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  2. Helen M. McGettrick
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H.M.M. researched data for this article. Both authors provided substantial contributions to discussions of its content, wrote the article and reviewed or edited the manuscript before submission.

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Correspondence to Helen M. McGettrick.

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C.D.B. declares that he has received research funding from Roche. H.M.M. declares that she has received research funding from Pfizer.

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Buckley, C.D., McGettrick, H.M. Leukocyte trafficking between stromal compartments: lessons from rheumatoid arthritis. Nat Rev Rheumatol 14, 476–487 (2018). https://doi.org/10.1038/s41584-018-0042-4

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