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Macrophage heterogeneity in the context of rheumatoid arthritis

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.

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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.

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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).

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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.

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Correspondence to Irina A. Udalova.

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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

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