Review Article | Published:

Pathogenic stromal cells as therapeutic targets in joint inflammation

Nature Reviews Rheumatologyvolume 14pages714726 (2018) | Download Citation

Abstract

Knowledge of how the joint functions as an integrated unit in health and disease requires an understanding of the stromal cells populating the joint mesenchyme, including fibroblasts, tissue-resident macrophages and endothelial cells. Knowledge of the physiological and pathological mechanisms that involve joint mesenchymal stromal cells has begun to cast new light on why joint inflammation persists. The shared embryological origins of fibroblasts and endothelial cells might shape the behaviour of these cell types in diseased adult tissues. Cells of mesenchymal origin sustain inflammation in the synovial membrane and tendons by various mechanisms, and the important contribution of newly discovered fibroblast subtypes and their associated crosstalk with endothelial cells, tissue-resident macrophages and leukocytes is beginning to emerge. Knowledge of these mechanisms should help to shape the future therapeutic landscape and emphasizes the requirement for new strategies to address the pathogenic stroma and associated crosstalk between leukocytes and cells of mesenchymal origin.

Key points

  • Joint inflammation and tissue damage are mediated by stromal cells of mesodermal origin.

  • Stromal activation and memory of previous inflammatory insults are shared mechanisms exhibited by fibroblasts, tissue-resident macrophages and endothelial cells.

  • Data characterizing the phenotype and function of cells of mesenchymal origin highlight the distinct fibroblast subtypes that mediate joint inflammation and tissue damage.

  • Mesenchymal stromal cell niches and their interactions with leukocytes are implicated in the persistence of joint inflammation.

  • For effective treatment of residual joint disease, strategies are needed that target the pathogenic stroma and associated immune cell crosstalk.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

  • 29 November 2018

    In the originally published version of this article, the acknowledgements and affiliations contained errors. In the acknowledgements, “NIHR Oxford and Birmingham Biomedical Research Centres” and “the Department of Health and Social Care” were incorrectly presented as “NIHR Oxford Biomedical Research Centres” and “the Department of Health”. For affiliation 4, “NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Institute of Inflammation and Ageing, Birmingham, UK” was incorrectly presented as “Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK”. For affiliation 3, "Institute" was incorrectly spelt. These errors have now been corrected in the HTML and PDF versions of the manuscript.

References

  1. 1.

    Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386, 743–800 (2015).

  2. 2.

    Ospelt, C. Synovial fibroblasts in 2017. RMD Open 3, e000471 (2017).

  3. 3.

    Plein, A., Fantin, A., Denti, L., Pollard, J. W. & Ruhrberg, C. Erythro-myeloid progenitors contribute endothelial cells to blood vessels. Nature 562, 223–228 (2018).

  4. 4.

    Crowley, T. et al. Priming in response to pro-inflammatory cytokines is a feature of adult synovial but not dermal fibroblasts. Arthritis Res. Ther. 19, 35 (2017).

  5. 5.

    Wolff, B., Burns, A. R., Middleton, J. & Rot, A. Endothelial cell “memory” of inflammatory stimulation: human venular endothelial cells store interleukin 8 in Weibel-Palade bodies. J. Exp. Med. 188, 1757–1762 (1998).

  6. 6.

    Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).

  7. 7.

    Davies, L. C., Jenkins, S. J., Allen, J. E. & Taylor, P. R. Tissue-resident macrophages. Nat. Immunol. 14, 986–995 (2013).

  8. 8.

    Davies, L. C. et al. Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat. Commun. 4, 1886 (2013).

  9. 9.

    Epelman, S., Lavine, K. J. & Randolph, G. J. Origin and functions of tissue macrophages. Immunity 41, 21–35 (2014).

  10. 10.

    Hoeffel, G. & Ginhoux, F. Ontogeny of tissue-resident macrophages. Front. Immunol. 6, 486 (2015).

  11. 11.

    Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

  12. 12.

    Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

  13. 13.

    Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

  14. 14.

    Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

  15. 15.

    Guilliams, M. et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J. Exp. Med. 210, 1977–1992 (2013).

  16. 16.

    Jakubzick, C. et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39, 599–610 (2013).

  17. 17.

    Samokhvalov, I. M. Deconvoluting the ontogeny of hematopoietic stem cells. Cell. Mol. Life Sci. 71, 957–978 (2014).

  18. 18.

    Jung, S. Macrophages and monocytes in 2017: macrophages and monocytes: of tortoises and hares. Nat. Rev. Immunol. 18, 85–86 (2018).

  19. 19.

    Dakin, S. G. et al. Persistent stromal fibroblast activation is present in chronic tendinopathy. Arthritis Res. Ther. 19, 16 (2017).

  20. 20.

    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).

  21. 21.

    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).

  22. 22.

    Wynn, T. A. & Vannella, K. M. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44, 450–462 (2016).

  23. 23.

    Dakin, S. G. et al. Inflammation activation and resolution in human tendon disease. Sci. Transl Med. 7, 311ra173 (2015).

  24. 24.

    Buckley, C. D. Why does chronic inflammation persist: an unexpected role for fibroblasts. Immunol. Lett. 138, 12–14 (2011).

  25. 25.

    Scherer, H. U., Huizinga, T. W. J., Kronke, G., Schett, G. & Toes, R. E. M. The B cell response to citrullinated antigens in the development of rheumatoid arthritis. Nat. Rev. Rheumatol. 14, 157–169 (2018).

  26. 26.

    Orr, C. et al. Synovial tissue research: a state-of-the-art review. Nat. Rev. Rheumatol. 13, 463–475 (2017).

  27. 27.

    Lubberts, E. The IL-23-IL-17 axis in inflammatory arthritis. Nat. Rev. Rheumatol. 11, 415–429 (2015).

  28. 28.

    Filer, A., Raza, K., Salmon, M. & Buckley, C. D. Targeting stromal cells in chronic inflammation. Discov. Med. 7, 20–26 (2007).

  29. 29.

    Tarin, D. & Croft, C. B. Ultrastructural features of wound healing in mouse skin. J. Anat. 105, 189–190 (1969).

  30. 30.

    Abe, R., Donnelly, S. C., Peng, T., Bucala, R. & Metz, C. N. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J. Immunol. 166, 7556–7562 (2001).

  31. 31.

    Kalluri, R. & Neilson, E. G. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 112, 1776–1784 (2003).

  32. 32.

    Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341–350 (2002).

  33. 33.

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

  34. 34.

    Marinkovich, M. P., Keene, D. R., Rimberg, C. S. & Burgeson, R. E. Cellular origin of the dermal-epidermal basement membrane. Dev. Dyn. 197, 255–267 (1993).

  35. 35.

    Sabatelli, P. et al. Collagen VI deficiency affects the organization of fibronectin in the extracellular matrix of cultured fibroblasts. Matrix Biol. 20, 475–486 (2001).

  36. 36.

    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).

  37. 37.

    Estell, E. G. et al. Fibroblast-like synoviocyte mechanosensitivity to fluid shear is modulated by interleukin-1α. J. Biomech. 60, 91–99 (2017).

  38. 38.

    Buckley, C. D. et al. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends Immunol. 22, 199–204 (2001).

  39. 39.

    Buckley, C. D., Barone, F., Nayar, S., Benezech, C. & Caamano, J. Stromal cells in chronic inflammation and tertiary lymphoid organ formation. Annu. Rev. Immunol. 33, 715–745 (2015).

  40. 40.

    Dang, Q., Liu, J., Li, J. & Sun, Y. Podoplanin: a novel regulator of tumor invasion and metastasis. Med. Oncol. 31, 24 (2014).

  41. 41.

    Zimmermann, T. et al. Isolation and characterization of rheumatoid arthritis synovial fibroblasts from primary culture—primary culture cells markedly differ from fourth-passage cells. Arthritis Res. 3, 72–76 (2001).

  42. 42.

    Juarez, M., Filer, A. & Buckley, C. D. Fibroblasts as therapeutic targets in rheumatoid arthritis and cancer. Swiss Med. Wkly 142, w13529 (2012).

  43. 43.

    Patel, R., Filer, A., Barone, F. & Buckley, C. D. Stroma: fertile soil for inflammation. Best Pract. Res. Clin. Rheumatol. 28, 565–576 (2014).

  44. 44.

    Chang, H. Y. et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc. Natl Acad. Sci. USA 99, 12877–12882 (2002).

  45. 45.

    Sohn, C. et al. Prolonged tumor necrosis factor alpha primes fibroblast-like synoviocytes in a gene-specific manner by altering chromatin. Arthritis Rheumatol. 67, 86–95 (2015).

  46. 46.

    Seeley, J. J. & Ghosh, S. Molecular mechanisms of innate memory and tolerance to LPS. J. Leukoc. Biol. 101, 107–119 (2017).

  47. 47.

    Kawasaki, T. & Kawai, T. Toll-like receptor signaling pathways. Front. Immunol. 5, 461 (2014).

  48. 48.

    Crowley, T., Buckley, C. D. & Clark, A. R. Stroma: the forgotten cells of innate immune memory. Clin. Exp. Immunol. 193, 24–36 (2018).

  49. 49.

    Heinemeier, K. M., Schjerling, P., Heinemeier, J., Magnusson, S. P. & Kjaer, M. Lack of tissue renewal in human adult Achilles tendon is revealed by nuclear bomb 14C. FASEB J. 27, 2074–2079 (2013).

  50. 50.

    Klein, K. et al. The epigenetic architecture at gene promoters determines cell type-specific LPS tolerance. J. Autoimmun. 83, 122–133 (2017).

  51. 51.

    Koch, S. R., Lamb, F. S., Hellman, J., Sherwood, E. R. & Stark, R. J. Potentiation and tolerance of toll-like receptor priming in human endothelial cells. Transl. Res. 180, 53–67 (2017).

  52. 52.

    Ballestar, E. & Li, T. New insights into the epigenetics of inflammatory rheumatic diseases. Nat. Rev. Rheumatol. 13, 593–605 (2017).

  53. 53.

    Karouzakis, E. et al. Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis. Sci. Rep. 8, 7370 (2018).

  54. 54.

    Karouzakis, E., Gay, R. E., Michel, B. A., Gay, S. & Neidhart, M. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 60, 3613–3622 (2009).

  55. 55.

    Gaur, N. et al. MicroRNAs interfere with DNA methylation in rheumatoid arthritis synovial fibroblasts. RMD Open 2, e000299 (2016).

  56. 56.

    Ospelt, C., Reedquist, K. A., Gay, S. & Tak, P. P. Inflammatory memories: is epigenetics the missing link to persistent stromal cell activation in rheumatoid arthritis? Autoimmun. Rev. 10, 519–524 (2011).

  57. 57.

    Frank-Bertoncelj, M. et al. Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions. Nat. Commun. 8, 14852 (2017).

  58. 58.

    Ospelt, C. & Frank-Bertoncelj, M. Why location matters - site-specific factors in rheumatic diseases. Nat. Rev. Rheumatol. 13, 433–442 (2017).

  59. 59.

    Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat. Med. 18, 1069–1076 (2012).

  60. 60.

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

  61. 61.

    Alexander, T., Nolte, C. & Krumlauf, R. Hox genes and segmentation of the hindbrain and axial skeleton. Annu. Rev. Cell Dev. Biol. 25, 431–456 (2009).

  62. 62.

    Krumlauf, R. Hox genes in vertebrate development. Cell 78, 191–201 (1994).

  63. 63.

    Ospelt, C., Gay, S. & Klein, K. Epigenetics in the pathogenesis of RA. Semin. Immunopathol. 39, 409–419 (2017).

  64. 64.

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

  65. 65.

    Stephenson, W. et al. Single-cell RNA-seq of rheumatoid arthritis synovial tissue using low-cost microfluidic instrumentation. Nat. Commun. 9, 791 (2018).

  66. 66.

    Jackson, J. R., Seed, M. P., Kircher, C. H., Willoughby, D. A. & Winkler, J. D. The codependence of angiogenesis and chronic inflammation. FASEB J. 11, 457–465 (1997).

  67. 67.

    Ley, K. & Reutershan, J. Leucocyte-endothelial interactions in health and disease. Handb. Exp. Pharmacol. 176 Pt 2, 97–133 (2006).

  68. 68.

    Bazzoni, G. Endothelial tight junctions: permeable barriers of the vessel wall. Thromb. Haemost. 95, 36–42 (2006).

  69. 69.

    Pober, J. S. & Sessa, W. C. Evolving functions of endothelial cells in inflammation. Nat. Rev. Immunol. 7, 803–815 (2007).

  70. 70.

    Weber, A. J., De Bandt, M. & Gaudry, M. Immunohistochemical analysis of vascular endothelial growth factor expression in severe and destructive rheumatoid arthritis. J. Rheumatol. 27, 2284–2286 (2000).

  71. 71.

    Girard, J. P. & Springer, T. A. High endothelial venules (HEVs): specialized endothelium for lymphocyte migration. Immunol. Today 16, 449–457 (1995).

  72. 72.

    Middleton, J. et al. Endothelial cell phenotypes in the rheumatoid synovium: activated, angiogenic, apoptotic and leaky. Arthritis Res. Ther. 6, 60–72 (2004).

  73. 73.

    Johnson, B. A., Haines, G. K., Harlow, L. A. & Koch, A. E. Adhesion molecule expression in human synovial tissue. Arthritis Rheum. 36, 137–146 (1993).

  74. 74.

    Szekanecz, Z. et al. Differential distribution of intercellular adhesion molecules (ICAM-1, ICAM-2, and ICAM-3) and the MS-1 antigen in normal and diseased human synovia. Their possible pathogenetic and clinical significance in rheumatoid arthritis. Arthritis Rheum. 37, 221–231 (1994).

  75. 75.

    Wilkinson, L. S., Edwards, J. C., Poston, R. N. & Haskard, D. O. Expression of vascular cell adhesion molecule-1 in normal and inflamed synovium. Lab Invest. 68, 82–88 (1993).

  76. 76.

    Bordy, R. et al. Microvascular endothelial dysfunction in rheumatoid arthritis. Nat. Rev. Rheumatol. 14, 404–420 (2018).

  77. 77.

    Liao, J. K. Linking endothelial dysfunction with endothelial cell activation. J. Clin. Invest. 123, 540–541 (2013).

  78. 78.

    Brenchley, P. E. Angiogenesis in inflammatory joint disease: a target for therapeutic intervention. Clin. Exp. Immunol. 121, 426–429 (2000).

  79. 79.

    Chyou, S. et al. Fibroblast-type reticular stromal cells regulate the lymph node vasculature. J. Immunol. 181, 3887–3896 (2008).

  80. 80.

    Alitalo, K. The lymphatic vasculature in disease. Nat. Med. 17, 1371–1380 (2011).

  81. 81.

    Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

  82. 82.

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

  83. 83.

    Zheng, W., Aspelund, A. & Alitalo, K. Lymphangiogenic factors, mechanisms, and applications. J. Clin. Invest. 124, 878–887 (2014).

  84. 84.

    Zhou, Q., Wood, R., Schwarz, E. M., Wang, Y. J. & Xing, L. Near-infrared lymphatic imaging demonstrates the dynamics of lymph flow and lymphangiogenesis during the acute versus chronic phases of arthritis in mice. Arthritis Rheum. 62, 1881–1889 (2010).

  85. 85.

    Rahimi, H. et al. Lymphatic imaging to assess rheumatoid flare: mechanistic insights and biomarker potential. Arthritis Res. Ther. 18, 194 (2016).

  86. 86.

    Fullerton, J. N. & Gilroy, D. W. Resolution of inflammation: a new therapeutic frontier. Nat. Rev. Drug Discov. 15, 551–567 (2016).

  87. 87.

    Kennedy, A., Fearon, U., Veale, D. J. & Godson, C. Macrophages in synovial inflammation. Front. Immunol. 2, 52 (2011).

  88. 88.

    Burmester, G. R., Stuhlmuller, B., Keyszer, G. & Kinne, R. W. Mononuclear phagocytes and rheumatoid synovitis. Mastermind or workhorse in arthritis? Arthritis Rheum. 40, 5–18 (1997).

  89. 89.

    Vallejo, A. N., Yang, H., Klimiuk, P. A., Weyand, C. M. & Goronzy, J. J. Synoviocyte-mediated expansion of inflammatory T cells in rheumatoid synovitis is dependent on CD47-thrombospondin 1 interaction. J. Immunol. 171, 1732–1740 (2003).

  90. 90.

    Abeles, A. M. & Pillinger, M. H. The role of the synovial fibroblast in rheumatoid arthritis: cartilage destruction and the regulation of matrix metalloproteinases. Bull. NYU Hosp. Jt Dis. 64, 20–24 (2006).

  91. 91.

    Misharin, A. V. et al. Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice. Cell Rep. 9, 591–604 (2014).

  92. 92.

    Mandelin, A. M. 2nd et al. Transcriptional profiling of synovial macrophages using minimally invasive ultrasound-guided synovial biopsies in rheumatoid arthritis. Arthritis Rheumatol. 70, 841–854 (2018).

  93. 93.

    Serhan, C. N. et al. Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. J. Exp. Med. 206, 15–23 (2009).

  94. 94.

    Dalli, J. & Serhan, C. Macrophage proresolving mediators-the when and where. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.MCHD-0001-2014 (2016).

  95. 95.

    Serhan, C. N., Chiang, N. & Van Dyke, T. E. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat. Rev. Immunol. 8, 349–361 (2008).

  96. 96.

    Perretti, M., Cooper, D., Dalli, J. & Norling, L. V. Immune resolution mechanisms in inflammatory arthritis. Nat. Rev. Rheumatol. 13, 87–99 (2017).

  97. 97.

    Stables, M. J. et al. Transcriptomic analyses of murine resolution-phase macrophages. Blood 118, e192–208 (2011).

  98. 98.

    Millar, N. L., Murrell, G. A. & McInnes, I. B. Inflammatory mechanisms in tendinopathy - towards translation. Nat. Rev. Rheumatol. 13, 110–122 (2017).

  99. 99.

    Nefla, M., Holzinger, D., Berenbaum, F. & Jacques, C. The danger from within: alarmins in arthritis. Nat. Rev. Rheumatol. 12, 669–683 (2016).

  100. 100.

    Pisetsky, D. S., Erlandsson-Harris, H. & Andersson, U. High-mobility group box protein 1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease. Arthritis Res. Ther. 10, 209 (2008).

  101. 101.

    Carrion, M. et al. IL-22/IL-22R1 axis and S100A8/A9 alarmins in human osteoarthritic and rheumatoid arthritis synovial fibroblasts. Rheumatology 52, 2177–2186 (2013).

  102. 102.

    Bertheloot, D. & Latz, E. HMGB1, IL-1alpha, IL-33 and S100 proteins: dual-function alarmins. Cell. Mol. Immunol. 14, 43–64 (2017).

  103. 103.

    Zuliani-Alvarez, L. et al. Mapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers. Nat. Commun. 8, 1595 (2017).

  104. 104.

    Midwood, K. et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat. Med. 15, 774–780 (2009).

  105. 105.

    Lee, G. et al. Fully reduced HMGB1 accelerates the regeneration of multiple tissues by transitioning stem cells to GAlert. Proc. Natl Acad. Sci. USA 115, E4463–E4472 (2018).

  106. 106.

    Burman, A. et al. A chemokine-dependent stromal induction mechanism for aberrant lymphocyte accumulation and compromised lymphatic return in rheumatoid arthritis. J. Immunol. 174, 1693–1700 (2005).

  107. 107.

    Buckley, C. D. & McGettrick, H. M. Leukocyte trafficking between stromal compartments: lessons from rheumatoid arthritis. Nat. Rev. Rheumatol. 14, 476–487 (2018).

  108. 108.

    Kalinski, P. Regulation of immune responses by prostaglandin E2. J. Immunol. 188, 21–28 (2012).

  109. 109.

    Ivanov, I. I. et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

  110. 110.

    Fleetwood, A. J., Lawrence, T., Hamilton, J. A. & Cook, A. D. Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J. Immunol. 178, 5245–5252 (2007).

  111. 111.

    Nguyen, H. N. et al. Autocrine loop involving IL-6 family member LIF, LIF receptor, and STAT4 drives sustained fibroblast production of inflammatory mediators. Immunity 46, 220–232 (2017).

  112. 112.

    Buckley, C. D. et al. Persistent induction of the chemokine receptor CXCR4 by TGF-beta 1 on synovial T cells contributes to their accumulation within the rheumatoid synovium. J. Immunol. 165, 3423–3429 (2000).

  113. 113.

    Bradfield, P. F. et al. Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. Arthritis Rheum. 48, 2472–2482 (2003).

  114. 114.

    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).

  115. 115.

    Nash, G. B., Buckley, C. D. & Ed Rainger, G. The local physicochemical environment conditions the proinflammatory response of endothelial cells and thus modulates leukocyte recruitment. FEBS Lett. 569, 13–17 (2004).

  116. 116.

    Gawronska-Kozak, B., Bogacki, M., Rim, J. S., Monroe, W. T. & Manuel, J. A. Scarless skin repair in immunodeficient mice. Wound Repair Regen. 14, 265–276 (2006).

  117. 117.

    Cowin, A. J., Brosnan, M. P., Holmes, T. M. & Ferguson, M. W. Endogenous inflammatory response to dermal wound healing in the fetal and adult mouse. Dev. Dyn. 212, 385–393 (1998).

  118. 118.

    Hopkinson-Woolley, J., Hughes, D., Gordon, S. & Martin, P. Macrophage recruitment during limb development and wound healing in the embryonic and foetal mouse. J. Cell Sci. 107, 1159–1167 (1994).

  119. 119.

    Cowin, A. J., Holmes, T. M., Brosnan, P. & Ferguson, M. W. Expression of TGF-β and its receptors in murine fetal and adult dermal wounds. Eur. J. Dermatol. 11, 424–431 (2001).

  120. 120.

    Rolfe, K. J. & Grobbelaar, A. O. A review of fetal scarless healing. ISRN Dermatol. 2012, 698034 (2012).

  121. 121.

    Whitby, D. J. & Ferguson, M. W. Immunohistochemical localization of growth factors in fetal wound healing. Dev. Biol. 147, 207–215 (1991).

  122. 122.

    Martin, P., Dickson, M. C., Millan, F. A. & Akhurst, R. J. Rapid induction and clearance of TGFβ1 is an early response to wounding in the mouse embryo. Dev. Genet. 14, 225–238 (1993).

  123. 123.

    Frank, S., Madlener, M. & Werner, S. Transforming growth factors β1, β2, and β3 and their receptors are differentially regulated during normal and impaired wound healing. J. Biol. Chem. 271, 10188–10193 (1996).

  124. 124.

    Coolen, N. A., Schouten, K. C., Boekema, B. K., Middelkoop, E. & Ulrich, M. M. Wound healing in a fetal, adult, and scar tissue model: a comparative study. Wound Repair Regen. 18, 291–301 (2010).

  125. 125.

    Coolen, N. A., Schouten, K. C., Middelkoop, E. & Ulrich, M. M. Comparison between human fetal and adult skin. Arch. Dermatol. Res. 302, 47–55 (2010).

  126. 126.

    Stalling, S. S. & Nicoll, S. B. Fetal ACL fibroblasts exhibit enhanced cellular properties compared with adults. Clin. Orthop. Relat. Res. 466, 3130–3137 (2008).

  127. 127.

    Clark, I. M., Powell, L. K., Ramsey, S., Hazleman, B. L. & Cawston, T. E. The measurement of collagenase, tissue inhibitor of metalloproteinases (TIMP), and collagenase-TIMP complex in synovial fluids from patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum. 36, 372–379 (1993).

  128. 128.

    Sato, H. et al. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370, 61–65 (1994).

  129. 129.

    Grassi, F. et al. CXCL12 chemokine up-regulates bone resorption and MMP-9 release by human osteoclasts: CXCL12 levels are increased in synovial and bone tissue of rheumatoid arthritis patients. J. Cell. Physiol. 199, 244–251 (2004).

  130. 130.

    Bauer, S. et al. Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes. Arthritis Res. Ther. 8, R171 (2006).

  131. 131.

    Huet, G. et al. Measurement of elastase and cysteine proteinases in synovial fluid of patients with rheumatoid arthritis, sero-negative spondylarthropathies, and osteoarthritis. Clin. Chem. 38, 1694–1697 (1992).

  132. 132.

    Carmona-Rivera, C. et al. Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci. Immunol. 2, eaag3358 (2017).

  133. 133.

    Brabletz, T., Kalluri, R., Nieto, M. A. & Weinberg, R. A. EMT in cancer. Nat. Rev. Cancer 18, 128–134 (2018).

  134. 134.

    Lefevre, S. et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15, 1414–1420 (2009).

  135. 135.

    Jutley, G., Raza, K. & Buckley, C. D. New pathogenic insights into rheumatoid arthritis. Curr. Opin. Rheumatol. 27, 249–255 (2015).

  136. 136.

    Whittle, S. L. et al. Multinational evidence-based recommendations for pain management by pharmacotherapy in inflammatory arthritis: integrating systematic literature research and expert opinion of a broad panel of rheumatologists in the 3e Initiative. Rheumatology 51, 1416–1425 (2012).

  137. 137.

    FitzGerald, G. A. & Patrono, C. The coxibs, selective inhibitors of cyclooxygenase-2. N. Engl. J. Med. 345, 433–442 (2001).

  138. 138.

    Gotzsche, P. C. & Johansen, H. K. Meta-analysis of short-term low dose prednisolone versus placebo and non-steroidal anti-inflammatory drugs in rheumatoid arthritis. BMJ 316, 811–818 (1998).

  139. 139.

    Wassenberg, S., Rau, R., Steinfeld, P. & Zeidler, H. Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 52, 3371–3380 (2005).

  140. 140.

    Gilroy, D. W. & Perretti, M. Aspirin and steroids: new mechanistic findings and avenues for drug discovery. Curr. Opin. Pharmacol. 5, 405–411 (2005).

  141. 141.

    Gilroy, D. W. et al. Inducible cyclooxygenase may have anti-inflammatory properties. Nat. Med. 5, 698–701 (1999).

  142. 142.

    Gilroy, D. W., Lawrence, T., Perretti, M. & Rossi, A. G. Inflammatory resolution: new opportunities for drug discovery. Nat. Rev. Drug Discov. 3, 401–416 (2004).

  143. 143.

    Scholten, D. J. et al. Pharmacological modulation of chemokine receptor function. Br. J. Pharmacol. 165, 1617–1643 (2012).

  144. 144.

    Filer, A. The fibroblast as a therapeutic target in rheumatoid arthritis. Curr. Opin. Pharmacol. 13, 413–419 (2013).

  145. 145.

    Cornish, A. L., Campbell, I. K., McKenzie, B. S., Chatfield, S. & Wicks, I. P. G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis. Nat. Rev. Rheumatol. 5, 554–559 (2009).

  146. 146.

    Wicks, I. P. & Roberts, A. W. Targeting GM-CSF in inflammatory diseases. Nat. Rev. Rheumatol. 12, 37–48 (2016).

  147. 147.

    Burmester, G. R. et al. Mavrilimumab, a fully human granulocyte-macrophage colony-stimulating factor receptor alpha monoclonal antibody: long-term safety and efficacy in patients with rheumatoid arthritis. Arthritis Rheumatol. 70, 679–689 (2018).

  148. 148.

    Weinblatt, M. E. et al. Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial. Arthritis Rheum. 58, 3309–3318 (2008).

  149. 149.

    Weinblatt, M. E. et al. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N. Engl. J. Med. 363, 1303–1312 (2010).

  150. 150.

    Taylor, P. C. et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N. Engl. J. Med. 376, 652–662 (2017).

  151. 151.

    Munoz, L. Non-kinase targets of protein kinase inhibitors. Nat. Rev. Drug Discov. 16, 424–440 (2017).

  152. 152.

    Sund, M. & Kalluri, R. Tumor stroma derived biomarkers in cancer. Cancer Metastasis Rev. 28, 177–183 (2009).

  153. 153.

    Sherlock, J. P., Filer, A. D., Isaacs, J. D. & Buckley, C. D. What can rheumatologists learn from translational cancer therapy? Arthritis Res. Ther. 15, 114 (2013).

  154. 154.

    Chang, S. K. et al. Cadherin-11 regulates fibroblast inflammation. Proc. Natl Acad. Sci. USA 108, 8402–8407 (2011).

  155. 155.

    Nair, B. C., Vallabhaneni, S., Tekmal, R. R. & Vadlamudi, R. K. Roscovitine confers tumor suppressive effect on therapy-resistant breast tumor cells. Breast Cancer Res. 13, R80 (2011).

  156. 156.

    Perlman, H. et al. IL-6 and matrix metalloproteinase-1 are regulated by the cyclin-dependent kinase inhibitor p21 in synovial fibroblasts. J. Immunol. 170, 838–845 (2003).

  157. 157.

    Hammaker, D. et al. LBH gene transcription regulation by the interplay of an enhancer risk allele and DNA methylation in rheumatoid arthritis. Arthritis Rheumatol. 68, 2637–2645 (2016).

  158. 158.

    Serhan, C. N., Hamberg, M. & Samuelsson, B. Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proc. Natl Acad. Sci. USA 81, 5335–5339 (1984).

  159. 159.

    Serhan, C. N., Levy, B. D., Clish, C. B., Gronert, K. & Chiang, N. Lipoxins, aspirin-triggered 15-epi-lipoxin stable analogs and their receptors in anti-inflammation: a window for therapeutic opportunity. Ernst Schering Res. Found. Workshop 31, 143–185 (2000).

  160. 160.

    Serhan, C. N., Gotlinger, K., Hong, S. & Arita, M. Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis. Prostaglandins Other Lipid Mediat. 73, 155–172 (2004).

  161. 161.

    Norris, P. C., Libreros, S., Chiang, N. & Serhan, C. N. A cluster of immunoresolvents links coagulation to innate host defense in human blood. Sci. Signal. 10, eaan1471 (2017).

  162. 162.

    Serhan, C. N. Discovery of specialized pro-resolving mediators marks the dawn of resolution physiology and pharmacology. Mol. Aspects Med. 58, 1–11 (2017).

  163. 163.

    Serhan, C. N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92–101 (2014).

  164. 164.

    Herrera, B. S. et al. LXA4 actions direct fibroblast function and wound closure. Biochem. Biophys. Res. Commun. 464, 1072–1077 (2015).

  165. 165.

    Tabas, I. & Glass, C. K. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339, 166–172 (2013).

  166. 166.

    Merched, A. J., Ko, K., Gotlinger, K. H., Serhan, C. N. & Chan, L. Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J. 22, 3595–3606 (2008).

  167. 167.

    Arnardottir, H. H. et al. Resolvin D3 is dysregulated in arthritis and reduces arthritic inflammation. J. Immunol. 197, 2362–2368 (2016).

  168. 168.

    Norling, L. V. et al. Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis. JCI Insight 1, e85922 (2016).

  169. 169.

    Dakin, S. G. et al. Increased 15-PGDH expression leads to dysregulated resolution responses in stromal cells from patients with chronic tendinopathy. Sci. Rep. 7, 11009 (2017).

  170. 170.

    Bresnihan, B. et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 41, 2196–2204 (1998).

  171. 171.

    Jiang, Y. et al. A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum. 43, 1001–1009 (2000).

  172. 172.

    Nishimoto, N. et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann. Rheum. Dis. 66, 1162–1167 (2007).

  173. 173.

    Nishimoto, N. et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod. Rheumatol. 19, 12–19 (2009).

  174. 174.

    Genovese, M. C. et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 58, 2968–2980 (2008).

  175. 175.

    Emery, P. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann. Rheum. Dis. 67, 1516–1523 (2008).

  176. 176.

    Smolen, J. S. et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371, 987–997 (2008).

  177. 177.

    Bathon, J. M. et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N. Engl. J. Med. 343, 1586–1593 (2000).

  178. 178.

    Moreland, L. W. et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N. Engl. J. Med. 337, 141–147 (1997).

  179. 179.

    Weinblatt, M. E. et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N. Engl. J. Med. 340, 253–259 (1999).

  180. 180.

    Lipsky, P. E. et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N. Engl. J. Med. 343, 1594–1602 (2000).

  181. 181.

    Keystone, E. C. et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 50, 1400–1411 (2004).

  182. 182.

    van de Putte, L. B. et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann. Rheum. Dis. 63, 508–516 (2004).

  183. 183.

    Burmester, G. R. et al. Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-alpha, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study. Ann. Rheum. Dis. 70, 1542–1549 (2011).

  184. 184.

    Avci, A. B., Feist, E. & Burmester, G. R. Targeting GM-CSF in rheumatoid arthritis. Clin. Exp. Rheumatol. 34, 39–44 (2016).

  185. 185.

    Langley, R. G. et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N. Engl. J. Med. 371, 326–338 (2014).

  186. 186.

    Mrowietz, U. et al. Secukinumab retreatment-as-needed versus fixed-interval maintenance regimen for moderate to severe plaque psoriasis: a randomized, double-blind, noninferiority trial (SCULPTURE). J. Am. Acad. Dermatol. 73, 27–36 (2015).

  187. 187.

    Blauvelt, A. et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: results from the CLEAR study. J. Am. Acad. Dermatol. 76, 60–69 (2017).

  188. 188.

    Fleischmann, R. et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N. Engl. J. Med. 367, 495–507 (2012).

  189. 189.

    Kremer, J. M. et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 60, 1895–1905 (2009).

  190. 190.

    Lee, A. et al. Tumor necrosis factor alpha induces sustained signaling and a prolonged and unremitting inflammatory response in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 65, 928–938 (2013).

  191. 191.

    Lin, J. et al. A novel p53/microRNA-22/Cyr61 axis in synovial cells regulates inflammation in rheumatoid arthritis. Arthritis Rheumatol. 66, 49–59 (2014).

  192. 192.

    Philippe, L. et al. MiR-20a regulates ASK1 expression and TLR4-dependent cytokine release in rheumatoid fibroblast-like synoviocytes. Ann. Rheum. Dis. 72, 1071–1079 (2013).

  193. 193.

    Stanczyk, J. et al. Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum. 63, 373–381 (2011).

  194. 194.

    Headland, S. E. et al. Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis. Sci. Transl. Med. 7, 315ra190 (2015).

Download references

Acknowledgements

The work of S.G.D. is funded by an Oxford-UCB Prize Fellowship in Biomedical Sciences. The work of the authors is supported by NIHR Oxford and Birmingham Biomedical Research Centres. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Reviewer information

Nature Reviews Rheumatology thanks H. -G. Schaible, J. D. Cañete and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Affiliations

  1. Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK

    • Stephanie G. Dakin
    • , Jonathan P. Sherlock
    •  & Andrew J. Carr
  2. NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK

    • Stephanie G. Dakin
    • , Mark Coles
    • , Jonathan P. Sherlock
    • , Fiona Powrie
    • , Andrew J. Carr
    •  & Christopher D. Buckley
  3. Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK

    • Mark Coles
    • , Jonathan P. Sherlock
    • , Fiona Powrie
    •  & Christopher D. Buckley
  4. NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Institute of Inflammation and Ageing, Birmingham, UK

    • Christopher D. Buckley

Authors

  1. Search for Stephanie G. Dakin in:

  2. Search for Mark Coles in:

  3. Search for Jonathan P. Sherlock in:

  4. Search for Fiona Powrie in:

  5. Search for Andrew J. Carr in:

  6. Search for Christopher D. Buckley in:

Contributions

C.D.B., S.G.D., M.C. and J.P.S researched data for the article and wrote the article. C.D.B., S.G.D., M.C., J.P.S and A.J.C made substantial contributions to discussions of the content. All authors reviewed and/or edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Christopher D. Buckley.

Glossary

Mesenchymal

Describes the embryonic connective tissue derived from the mesoderm; mesenchymal tissue includes the tissue of the musculoskeletal, circulatory and lymphatic systems.

Parenchyma

The important functional elements of each body system.

Stromal cells

Non-haematopoietic, tissue-resident cells.

Mesoderm

The middle embryonic primary germ layer that resides between the ectoderm and the endoderm.

Stromal cell activation

A process whereby stromal cells, including fibroblasts, tissue-resident macrophages and endothelial cells, adopt a pro-inflammatory phenotype and express distinct molecular markers after exposure to an inflammatory stimulus.

Stromal cell memory

A change in the capacity of stromal cells to respond to inflammatory stimuli that persists for future exposures.

Positional memory

Refers to the topographic memory of a cell across different tissues and joints, which for fibroblasts is regulated by homeobox (HOX) genes during development.

Neoangiogenesis

The process by which new blood vessels develop by sprouting from existing vessels.

Lipid mediator class switching

A process whereby eicosanoids at the site of inflammation trigger the release of specialized pro-resolving lipid mediators involved in resolving inflammation.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/s41584-018-0112-7