Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Macrophage heterogeneity in the context of rheumatoid arthritis

Nature Reviews Rheumatology volume 12, pages 472–485 (2016)Cite this article

Subjects

Key Points

  • Macrophages are of critical importance in rheumatoid arthritis (RA), as they generate cytokines that enhance inflammation and contribute to destruction of cartilage and bone

  • Most mouse tissues include both embryonically derived macrophages that can self-renew and macrophages derived from adult bone marrow, but the origin of macrophages in human tissues is not yet known

  • The environment is very important in determining the unique identity and function of tissue-resident macrophages through the regulation of transcription factors and establishment of tissue-specific enhancers

  • Bone-marrow-derived macrophages are capable of adopting the phenotypes of tissue-resident macrophages

  • Seeding and self-renewal of macrophages in the mouse synovium are yet to be determined, but immunophenotyping indicates that macrophages in the synovial lining comprise embryonically derived and bone-marrow-derived populations

  • Future therapies for RA could target specific macrophage subsets, although whether such therapies would interfere with host protective or resolution pathways is not yet known

Abstract

Macrophages are very important in the pathogenesis of rheumatoid arthritis (RA). The increase in the number of sublining macrophages in the synovium is an early hallmark of active rheumatic disease, and high numbers of macrophages are a prominent feature of inflammatory lesions. The degree of synovial macrophage infiltration correlates with the degree of joint erosion, and depletion of these macrophages from inflamed tissue has a profound therapeutic benefit. Research has now uncovered an unexpectedly high level of heterogeneity in macrophage origin and function, and has emphasized the role of environmental factors in their functional specialization. Although the heterogeneous populations of macrophages in RA have not been fully characterized, preliminary results in mouse models of arthritis have contributed to our understanding of the phenotype and ontogeny of synovial macrophages, and to deciphering the properties of monocyte-derived infiltrating and tissue-resident macrophages. Elucidating the molecular mechanisms that drive polarization of macrophages towards proinflammatory or anti-inflammatory phenotypes could lead to identification of signalling pathways that inform future therapeutic strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The role of macrophages in RA.
Figure 2: Embryonic origins of tissue-resident macrophages.
Figure 3: Myelopoiesis in the adult bone marrow and spleen.
Figure 4: PU.1 in the transcriptional control of macrophage development and activation.
Figure 5: The role of Ly6Chi and Ly6Clo monocytes in the development of different mouse models of arthritis.
Figure 6: Lack of IRF5 causes a reduction in neutrophil influx and macrophage-derived CXCL1 in the arthritic knee.

Similar content being viewed by others

References

  1. Takasugi, K. & Hollingsworth, J. W. Morphologic studies of mononuclear cells of human synovial fluid. Arthritis Rheum. 10, 495–501 (1967).

    Article  CAS  PubMed  Google Scholar 

  2. Cooper, N. S., Soren, A., McEwen, C. & Rosenberger, J. L. Diagnostic specificity of synovial lesions. Hum. Pathol. 12, 314–328 (1981).

    Article  CAS  PubMed  Google Scholar 

  3. Janossy, G. et al. Rheumatoid arthritis: a disease of T-lymphocyte/macrophage immunoregulation. Lancet 2, 839–842 (1981).

    Article  CAS  PubMed  Google Scholar 

  4. Bottazzo, G. F., Pujol-Borrell, R., Hanafusa, T. & Feldmann, M. Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet 2, 1115–1119 (1983).

    Article  CAS  PubMed  Google Scholar 

  5. Feldmann, M. & Maini, R. N. Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat. Med. 9, 1245–1250 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Chu, C. Q., Field, M., Feldmann, M. & Maini, R. N. Localization of tumor necrosis factor α in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum. 34, 1125–1132 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. McInnes, I. B. & Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat. Rev. Immunol. 7, 429–442 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Feldmann, M., Brennan, F. M. & Maini, R. N. Rheumatoid arthritis. Cell 85, 307–310 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Wright, H. L., Moots, R. J. & Edwards, S. W. The multifactorial role of neutrophils in rheumatoid arthritis. Nat. Rev. Rheumatol. 10, 593–601 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Murphy, C. A. et al. Divergent pro-and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Miossec, P. & Kolls, J. K. Targeting IL-17 and TH17 cells in chronic inflammation. Nat. Rev. Drug Discov. 11, 763–776 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Shigeyama, Y. et al. Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum. 43, 2523–2530 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Hamilton, J. A., Filonzi, E. L. & Ianches, G. Regulation of macrophage colony-stimulating factor (M-CSF) production in cultured human synovial fibroblasts. Growth Factors 9, 157–165 (1993).

    Article  CAS  PubMed  Google Scholar 

  14. Yoshida, H. et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345, 442–444 (1990).

    Article  CAS  PubMed  Google Scholar 

  15. Dougall, W. C. et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 13, 2412–2424 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bertolini, D. R., Nedwin, G. E., Bringman, T. S., Smith, D. D. & Mundy, G. R. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature 319, 516–518 (1986).

    Article  CAS  PubMed  Google Scholar 

  17. Lam, J. et al. TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J. Clin. Invest. 106, 1481–1488 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sims, N. A. & Gooi, J. H. Bone remodeling: multiple cellular interactions required for coupling of bone formation and resorption. Semin. Cell Dev. Biol. 19, 444–451 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Redlich, K. & Smolen, J. S. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat. Rev. Drug Discov. 11, 234–250 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Koch, A. E. et al. Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. J. Immunol. 147, 2187–2195 (1991).

    CAS  PubMed  Google Scholar 

  21. Koch, A. E. et al. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J. Clin. Invest. 90, 772–779 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Leizer, T., Cebon, J., Layton, J. E. & Hamilton, J. A. Cytokine regulation of colony-stimulating factor production in cultured human synovial fibroblasts: I. Induction of GM-CSF and G-CSF production by interleukin-1 and tumor necrosis factor. Blood 76, 1989–1996 (1990).

    CAS  PubMed  Google Scholar 

  23. Hamilton, J. A. Colony-stimulating factors in inflammation and autoimmunity. Nat. Rev. Immunol. 8, 533–544 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Tak, P. P. & Bresnihan, B. The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis. Arthritis Rheum. 43, 2619–2633 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Haringman, J. J. et al. Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis. Ann. Rheum. Dis. 64, 834–838 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Barrera, P. et al. Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis. Arthritis Rheum. 43, 1951–1959 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Epelman, S. et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40, 91–104 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Hoeffel, G. et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J. Exp. Med. 209, 1167–1181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Merad, M. et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat. Immunol. 3, 1135–1141 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bain, C. C. et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat. Immunol. 15, 929–937 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tamoutounour, S. et al. Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39, 925–938 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Sieweke, M. H. & Allen, J. E. Beyond stem cells: self-renewal of differentiated macrophages. Science 342, 1242974 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Geissmann, F. et al. Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. De Kleer, I., Willems, F., Lambrecht, B. & Goriely, S. Ontogeny of myeloid cells. Front. Immunol. 5, 423 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kumaravelu, P. et al. Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver. Development 129, 4891–4899 (2002).

    CAS  PubMed  Google Scholar 

  40. Kieusseian, A., Brunet de la Grange, P., Burlen-Defranoux, O., Godin, I. & Cumano, A. Immature hematopoietic stem cells undergo maturation in the fetal liver. Development 139, 3521–3530 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Sheng, J., Ruedl, C. & Karjalainen, K. Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity 43, 382–393 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Hoeffel, G. et al. C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Calderon, B. et al. The pancreas anatomy conditions the origin and properties of resident macrophages. J. Exp. Med. 212, 1497–1512 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wilson, A. et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 18, 2747–2763 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Manz, M. G. & Boettcher, S. Emergency granulopoiesis. Nat. Rev. Immunol. 14, 302–314 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Swirski, F. K., Hilgendorf, I. & Robbins, C. S. From proliferation to proliferation: monocyte lineage comes full circle. Semin. Immunopathol. 36, 137–148 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sathe, P. et al. Lymphoid tissue and plasmacytoid dendritic cells and macrophages do not share a common macrophage-dendritic cell-restricted progenitor. Immunity 41, 104–115 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Hettinger, J. et al. Origin of monocytes and macrophages in a committed progenitor. Nat. Immunol. 14, 821–830 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Naik, S. H. et al. Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat. Immunol. 8, 1217–1226 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Onai, N. et al. Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nat. Immunol. 8, 1207–1216 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Swirski, F. K. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Leuschner, F. et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J. Exp. Med. 209, 123–137 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Geissmann, F., Jung, S. & Littman, D. R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Boring, L. et al. Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. J. Clin. Invest. 100, 2552–2561 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311–317 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Croxford, A. L. et al. The cytokine GM-CSF drives the inflammatory signature of CCR2 monocytes and licenses autoimmunity. Immunity 43, 502–514 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Auffray, C. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317, 666–670 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Ziegler-Heitbrock, L. et al. Nomenclature of monocytes and dendritic cells in blood. Blood 116, e74–e80 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Ingersoll, M. A. et al. Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 115, e10–e19 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Martinez, F. O., Gordon, S., Locati, M. & Mantovani, A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J. Immunol. 177, 7303–7311 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. 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).

    Article  CAS  PubMed  Google Scholar 

  62. Rodero, M. P. et al. Immune surveillance of the lung by migrating tissue monocytes. eLife 4, e07847 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Molawi, K. et al. Progressive replacement of embryo-derived cardiac macrophages with age. J. Exp. Med. 211, 2151–2158 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  64. van de Laar, L. et al. Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity 44, 755–768 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Nerlov, C. & Graf, T. PU.1 induces myeloid lineage commitment in multipotent hematopoietic progenitors. Genes Dev. 12, 2403–2412 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Olson, M. C. et al. PU. 1 is not essential for early myeloid gene expression but is required for terminal myeloid differentiation. Immunity 3, 703–714 (1995).

    Article  CAS  PubMed  Google Scholar 

  67. Mossadegh-Keller, N. et al. M-CSF instructs myeloid lineage fate in single haematopoietic stem cells. Nature 497, 239–243 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Alder, J. K. et al. Kruppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo. J. Immunol. 180, 5645–5652 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Feinberg, M. W. et al. The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation. EMBO J. 26, 4138–4148 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Laslo, P. et al. Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell 126, 755–766 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Barozzi, I. et al. Coregulation of transcription factor binding and nucleosome occupancy through DNA features of mammalian enhancers. Mol. Cell 54, 844–857 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ghisletti, S. et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32, 317–328 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gosselin, D. & Glass, C. K. Epigenomics of macrophages. Immunol. Rev. 262, 96–112 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tamura, T., Nagamura-Inoue, T., Shmeltzer, Z., Kuwata, T. & Ozato, K. ICSBP directs bipotential myeloid progenitor cells to differentiate into mature macrophages. Immunity 13, 155–165 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Mancino, A. et al. A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages. Genes Dev. 29, 394–408 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rosas, M. et al. The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal. Science 344, 645–648 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Okabe, Y. & Medzhitov, R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157, 832–844 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Schneider, C. et al. Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat. Immunol. 15, 1026–1037 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ostuni, R. et al. Latent enhancers activated by stimulation in differentiated cells. Cell 152, 157–171 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Garber, M. et al. A high-throughput chromatin immunoprecipitation approach reveals principles of dynamic gene regulation in mammals. Mol. Cell 47, 810–822 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Krausgruber, T. et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat. Immunol. 12, 231–238 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Weiss, M., Blazek, K., Byrne, A. J., Perocheau, D. P. & Udalova, I. A. IRF5 is a specific marker of inflammatory macrophages in vivo. Mediators Inflamm. 2013, 245804 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Saliba, D. G. et al. IRF5:RelA interaction targets inflammatory genes in macrophages. Cell Rep. 8, 1308–1317 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. O'Neill, L. A. & Pearce, E. J. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213, 15–23 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Recalcati, S., Locati, M., Gammella, E., Invernizzi, P. & Cairo, G. Iron levels in polarized macrophages: regulation of immunity and autoimmunity. Autoimmun. Rev. 11, 883–889 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Wang, N., Liang, H. & Zen, K. Molecular mechanisms that influence the macrophage M1–M2 polarization balance. Front. Immunol. 5, 614 (2014).

    PubMed  PubMed Central  Google Scholar 

  91. Gordon, S. & Martinez, F. O. Alternative activation of macrophages: mechanism and functions. Immunity 32, 593–604 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Mantovani, A., Sica, A. & Locati, M. Macrophage polarization comes of age. Immunity 23, 344–346 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Lawrence, T. & Natoli, G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat. Rev. Immunol. 11, 750–761 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Xue, J. et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40, 274–288 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gentek, R., Molawi, K. & Sieweke, M. H. Tissue macrophage identity and self-renewal. Immunol. Rev. 262, 56–73 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Yeadon, C. & Karsh, J. Lymphapheresis in rheumatoid arthritis. The clinical and laboratory effects of a limited course of cell depletion. Clin. Exp. Rheumatol. 1, 119–124 (1983).

    CAS  PubMed  Google Scholar 

  97. Hahn, G. et al. Modulation of monocyte activation in patients with rheumatoid arthritis by leukapheresis therapy. J. Clin. Invest. 91, 862–870 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Salisbury, A. K., Duke, O. & Poulter, L. W. Macrophage-like cells of the pannus area in rheumatoid arthritic joints. Scand. J. Rheumatol. 16, 263–272 (1987).

    Article  CAS  PubMed  Google Scholar 

  99. Cauli, A., Yanni, G. & Panayi, G. S. Interleukin-1, interleukin-1 receptor antagonist and macrophage populations in rheumatoid arthritis synovial membrane. Br. J. Rheumatol. 36, 935–940 (1997).

    Article  CAS  PubMed  Google Scholar 

  100. Ambarus, C. A., Noordenbos, T., de Hair, M. J., Tak, P. P. & Baeten, D. L. Intimal lining layer macrophages but not synovial sublining macrophages display an IL-10 polarized-like phenotype in chronic synovitis. Arthritis Res. Ther. 14, R74 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  102. Ye, L. et al. Interleukin-10 attenuation of collagen-induced arthritis is associated with suppression of interleukin-17 and retinoid-related orphan receptor γt production in macrophages and repression of classically activated macrophages. Arthritis Res. Ther. 16, R96 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. De Rycke, L. et al. Differential expression and response to anti-TNFα treatment of infiltrating versus resident tissue macrophage subsets in autoimmune arthritis. J. Pathol. 206, 17–27 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Asquith, D. L., Miller, A. M., McInnes, I. B. & Liew, F. Y. Animal models of rheumatoid arthritis. Eur. J. Immunol. 39, 2040–2044 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Bruhns, P., Samuelsson, A., Pollard, J. W. & Ravetch, J. V. Colony-stimulating factor-1-dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity 18, 573–581 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Weiss, M. et al. IRF5 controls both acute and chronic inflammation. Proc. Natl Acad. Sci. USA 112, 11001–11006 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Rafei, M. et al. An engineered GM-CSF–CCL2 fusokine is a potent inhibitor of CCR2-driven inflammation as demonstrated in a murine model of inflammatory arthritis. J. Immunol. 183, 1759–1766 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Présumey, J. et al. Nicotinamide phosphoribosyltransferase/visfatin expression by inflammatory monocytes mediates arthritis pathogenesis. Ann. Rheum. Dis. 72, 1717–1724 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Li, J. et al. Treatment of arthritis by macrophage depletion and immunomodulation: testing an apoptosis-mediated therapy in a humanized death receptor mouse model. Arthritis Rheum. 64, 1098–1109 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Brühl, H. et al. Targeting of Gr-1+,CCR2+ monocytes in collagen-induced arthritis. Arthritis Rheum. 56, 2975–2985 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Quinones, M. P. et al. Experimental arthritis in CC chemokine receptor 2-null mice closely mimics severe human rheumatoid arthritis. J. Clin. Invest. 113, 856–866 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Rossol, M., Kraus, S., Pierer, M., Baerwald, C. & Wagner, U. The CD14bright CD16+ monocyte subset is expanded in rheumatoid arthritis and promotes expansion of the Th17 cell population. Arthritis Rheum. 64, 671–677 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Scott, D. L., Wolfe, F. & Huizinga, T. W. Rheumatoid arthritis. Lancet 376, 1094–1108 (2010).

    Article  PubMed  Google Scholar 

  115. Semerano, L. et al. Targeting IL-6 for the treatment of rheumatoid arthritis: phase II investigational drugs. Expert Opin. Investig. Drugs 23, 979–999 (2014).

    Article  CAS  PubMed  Google Scholar 

  116. van Roon, J. A. et al. Selective elimination of synovial inflammatory macrophages in rheumatoid arthritis by an Fcγ receptor I-directed immunotoxin. Arthritis Rheum. 48, 1229–1238 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. van Vuuren, A. J. et al. CD64-directed immunotoxin inhibits arthritis in a novel CD64 transgenic rat model. J. Immunol. 176, 5833–5838 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. U.S. Food & Drug Administration. FDA approves new therapy for certain types of advanced soft tissue sarcoma. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm468832.htm (2015).

  119. Germano, G. et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23, 249–262 (2013).

    Article  CAS  PubMed  Google Scholar 

  120. Getts, D. R. et al. Therapeutic inflammatory monocyte modulation using immune-modifying microparticles. Sci. Transl. Med. 6, 219ra217 (2014).

    Article  CAS  Google Scholar 

  121. Vergunst, C. E. et al. Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum. 58, 1931–1939 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Lebre, M. C. et al. Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the treatment of rheumatoid arthritis. PLoS ONE 6, e21772 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Greven, D. E. et al. Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis. Ann. Rheum. Dis. 74, 1924–1930 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Burmester, G. R., Feist, E. & Dörner, T. Emerging cell and cytokine targets in rheumatoid arthritis. Nat. Rev. Rheumatol. 10, 77–88 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Burmester, G. R. et al. Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis. Ann. Rheum. Dis. 72, 1445–1452 (2013).

    Article  CAS  PubMed  Google Scholar 

  126. Genovese, M. C. et al. Results from a phase IIA parallel group study of JNJ-40346527, an oral CSF-1R inhibitor, in patients with active rheumatoid arthritis despite disease-modifying antirheumatic drug therapy. J. Rheumatol. 42, 1752–1760 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Campbell, I. K., Rich, M. J., Bischof, R. J. & Hamilton, J. A. The colony-stimulating factors and collagen-induced arthritis: exacerbation of disease by M-CSF and G-CSF and requirement for endogenous M-CSF. J. Leukoc. Biol. 68, 144–150 (2000).

    CAS  PubMed  Google Scholar 

  128. Duffau, P. et al. Promotion of inflammatory arthritis by interferon regulatory factor 5 in a mouse model. Arthritis Rheumatol. 67, 3146–3157 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hamilton, J. A. & Achuthan, A. Colony stimulating factors and myeloid cell biology in health and disease. Trends Immunol. 34, 81–89 (2013).

    Article  CAS  PubMed  Google Scholar 

  130. Courties, G. et al. in vivo silencing of the transcription factor IRF5 reprograms the macrophage phenotype and improves infarct healing. J. Am. Coll. Cardiol. 63, 1556–1566 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. Jain, S., Tran, T. H. & Amiji, M. Macrophage repolarization with targeted alginate nanoparticles containing IL-10 plasmid DNA for the treatment of experimental arthritis. Biomaterials 61, 162–177 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Shalek, A. K. et al. Single-cell RNA-seq reveals dynamic paracrine control of cellular variation. Nature 510, 363–369 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Jaitin, D. A. et al. Massively parallel single-cell RNA-seq for marker-free decomposition of tissues into cell types. Science 343, 776–779 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Bendall, S. C. et al. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science 332, 687–696 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Schwanhäusser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).

    Article  CAS  PubMed  Google Scholar 

  136. Becher, B. et al. High-dimensional analysis of the murine myeloid cell system. Nat. Immunol. 15, 1181–1189 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Jaitin, D. A., Keren-Shaul, H., Elefant, N. & Amit, I. Each cell counts: hematopoiesis and immunity research in the era of single cell genomics. Semin. Immunol. 27, 67–71 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Weiss for assistance with figure designs. I.A.U. is supported by the Kennedy Institute Trustees' Research Fund and Arthritis Research UK. A.M. is supported by grants from Fondazione Cassa di Risparmio delle Provincie Lombarde (CARIPLO), the Italian Ministry of Health and European Commission (BTcure).

Author information

Authors and Affiliations

  1. Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, OX3 7LF, UK

    Irina A. Udalova & Marc Feldmann

  2. Humanitas Clinical and Research Centre and Humanitas University, via Manzoni 56, Milan, 20089, Rozzano, Italy

    Alberto Mantovani

Authors
  1. Irina A. Udalova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alberto Mantovani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marc Feldmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

I.A.U. researched the data for the article. I.A.U. and M.F. contributed substantially to discussions of the article content and wrote the manuscript. All authors (I.A.U., A.M. and M.F.) undertook review or editing of the manuscript before submission.

Corresponding author

Correspondence to Irina A. Udalova.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Udalova, I., Mantovani, A. & Feldmann, M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol 12, 472–485 (2016). https://doi.org/10.1038/nrrheum.2016.91

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2016.91

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing