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Pathogenic stromal cells as therapeutic targets in joint inflammation

An Author Correction to this article was published on 29 November 2018

This article has been updated

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.

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Fig. 1: Embryological origins of mesenchymal tissues in the whole joint organ.
Fig. 2: Molecular features of cells of mesenchymal origin in rheumatoid synovium.
Fig. 3: Crosstalk-related mechanisms that sustain synovial inflammation.

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).

    Google Scholar 

  2. 2.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  9. 9.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

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

    PubMed  PubMed Central  Google Scholar 

  11. 11.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

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

    CAS  PubMed  Google Scholar 

  13. 13.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  17. 17.

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

    CAS  PubMed  Google Scholar 

  18. 18.

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

    CAS  PubMed  Google Scholar 

  19. 19.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

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

    PubMed  PubMed Central  Google Scholar 

  24. 24.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  26. 26.

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

    PubMed  Google Scholar 

  27. 27.

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

    CAS  PubMed  Google Scholar 

  28. 28.

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

    PubMed  PubMed Central  Google Scholar 

  29. 29.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  31. 31.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  40. 40.

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

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  42. 42.

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

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

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

    CAS  PubMed  Google Scholar 

  47. 47.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  52. 52.

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  55. 55.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  57. 57.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  60. 60.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  62. 62.

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

    CAS  PubMed  Google Scholar 

  63. 63.

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

    PubMed  Google Scholar 

  64. 64.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  67. 67.

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

    CAS  Google Scholar 

  68. 68.

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

    CAS  PubMed  Google Scholar 

  69. 69.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  71. 71.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  76. 76.

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

    CAS  PubMed  Google Scholar 

  77. 77.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

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

    CAS  PubMed  Google Scholar 

  81. 81.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  83. 83.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  85. 85.

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

    PubMed  PubMed Central  Google Scholar 

  86. 86.

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

    CAS  PubMed  Google Scholar 

  87. 87.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  91. 91.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  93. 93.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

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

    CAS  PubMed  Google Scholar 

  97. 97.

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

    Google Scholar 

  98. 98.

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

    CAS  PubMed  Google Scholar 

  99. 99.

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  102. 102.

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

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

    PubMed  Google Scholar 

  108. 108.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  120. 120.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  128. 128.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  130. 130.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  132. 132.

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

    PubMed  PubMed Central  Google Scholar 

  133. 133.

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

    CAS  PubMed  Google Scholar 

  134. 134.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  137. 137.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  141. 141.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  143. 143.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  146. 146.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  150. 150.

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

    CAS  PubMed  Google Scholar 

  151. 151.

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

    CAS  PubMed  Google Scholar 

  152. 152.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  154. 154.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  163. 163.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  170. 170.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

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

    PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  188. 188.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

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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.

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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.

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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.

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Correspondence to Christopher D. Buckley.

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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.

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Dakin, S.G., Coles, M., Sherlock, J.P. et al. Pathogenic stromal cells as therapeutic targets in joint inflammation. Nat Rev Rheumatol 14, 714–726 (2018). https://doi.org/10.1038/s41584-018-0112-7

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