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Among human macrophages polarised to different phenotypes, the M-CSF-oriented cells present the highest pro-inflammatory response to the rheumatoid arthritis-specific immune complexes containing ACPA
  1. Cyril Clavel1,2,3,4,
  2. Laurie Ceccato1,2,3,
  3. Florence Anquetil1,2,3,
  4. Guy Serre1,2,3,4,
  5. Mireille Sebbag1,2,3
  1. 1INSERM Unité 1056, Toulouse, France
  2. 2CNRS Unité Mixte de Recherche 5165, Toulouse, France
  3. 3Laboratory of Epidermis Differentiation and Rheumatoid Autoimmunity, Université de Toulouse, Université Paul Sabatier, Toulouse, France
  4. 4Laboratory of Cell Biology and Cytology, Centre Hospitalier Universitaire (CHU) de Toulouse, Institut Fédératif de Biologie, Toulouse, France
  1. Correspondence to Dr Cyril Clavel, Unité “Différenciation Épidermique et Auto-immunité Rhumatoïde”; UMR 5165 INSERM-CNRS-Université Paul Sabatier, Hôpital Purpan, Place du Dr Baylac, Toulouse 31059, Cedex 9, France; clavel.c{at}


Objectives In the inflamed synovium of patients with rheumatoid arthritis (RA), autoantibodies to citrullinated proteins (ACPA) probably form immune complexes (IC) on deposits of citrullinated fibrin. We showed that in vitro such ACPA-IC activate a pro-inflammatory cytokine response in M-CSF-differentiated macrophages. Our objective was to evaluate how macrophage polarisation influences this response.

Methods CD14-positive monocytes from healthy donors were cultured in the presence of M-CSF, IFN-γ, interleukin (IL)-4 or IL-10. Expression of markers specific for polarised macrophages was analysed by flow cytometry. Their cytokine secretion was prompted by in vitro generated autoantibodies to citrullinated proteins immune complexes (ACPA-IC) and assayed in the culture supernatants.

Results IFN-γ-polarised cells exhibited high levels of CD64 and CD80. Low expression of CD14 and high expression of CD206 characterised the IL-4-polarised cells. Exposure to IL-10 or M-CSF raised the expression of CD14, CD32 and CD163. The two cell types lacked CD80 and exhibited similar expression of CD64, CD200R and CD206. In response to ACPA-IC, the secretion of IL-1β, IL-6 and IL-8 was similar among cells exposed to IFN-γ, IL-4 or IL-10. However, the later cells were associated with the highest IL-1Ra:IL-1β ratio and the lowest tumour necrosis factor (TNF)-α:IL-10 ratio. Conversely, M-CSF-exposed cells secreted the highest levels of pro-inflammatory cytokines, exhibited a high TNF-α:IL-10 ratio and the lowest IL-1Ra:IL-1β ratio.

Conclusions Despite their phenotypic similarity, IL-10-polarised and M-CSF-polarised macrophages clearly differ in their cytokine response to ACPA-IC. M-CSF-polarised cells exhibit the highest pro-inflammatory potential. Since M-CSF is abundant in the RA synovium, therein it probably drives macrophages towards a strong pro-inflammatory cytokine response to the locally formed ACPA-IC.

  • Rheumatoid Arthritis
  • Ant-CCP
  • Cytokines
  • Synovitis
  • TNF-alpha

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  • Handling editor Tore K Kvien

  • GS and MS contributed equally.

  • Contributors CC, MS, FA and GS contributed to conception or design of the study. CC, LC and FA contributed to acquisition of data. CC, LC and MS contributed to their analysis and interpretation. CC and MS wrote the article and revised the final version. GS revised the article. All authors approved the submitted version.

  • Funding This study was supported by grants from the Toulouse III University, the ‘CNRS,’ the ‘INSERM’ and the ‘Société Française de Rhumatologie’.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Author note: Current addresses for FA : La Jolla Institute for Allergy and Immunology, La Jolla, California, USA; MS: Institut de Recherche en Santé Digestive (IRSD), U1220 INSERM-INRA-ENVT-Université Toulouse, France