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MCTR3 reprograms arthritic monocytes to upregulate Arginase-1 and exert pro-resolving and tissue-protective functions in experimental arthritis.
Pistorius, Kimberly; Ly, Lucy; Souza, Patricia R; Gomez, Esteban A; Koenis, Duco S; Rodriguez, Ana R; Foster, Julie; Sosabowski, Jane; Hopkinson, Mark; Rajeeve, Vinothini; Spur, Bernd W; Pitsillides, Andrew; Pitzalis, Costantino; Dalli, Jesmond.
Afiliación
  • Pistorius K; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK.
  • Ly L; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK.
  • Souza PR; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK.
  • Gomez EA; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK.
  • Koenis DS; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK.
  • Rodriguez AR; Rowan University School of Osteopathic Medicine, Department of Cell Biology & Neuroscience, 2 Medical Centre Drive, Stratford NJ 08084, USA.
  • Foster J; Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK.
  • Sosabowski J; Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK.
  • Hopkinson M; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
  • Rajeeve V; Mass spectrometry Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom.
  • Spur BW; Rowan University School of Osteopathic Medicine, Department of Cell Biology & Neuroscience, 2 Medical Centre Drive, Stratford NJ 08084, USA.
  • Pitsillides A; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
  • Pitzalis C; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK.
  • Dalli J; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK; Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, UK. Electronic address: j.dalli@qmul.ac.uk
EBioMedicine ; 79: 103974, 2022 May.
Article en En | MEDLINE | ID: mdl-35430453
BACKGROUND: Rheumatoid arthritis (RA) is a progressive degenerative disorder that leads to joint destruction. Available treatments only target the inflammatory component with minimal impact on joint repair. We recently uncovered a previously unappreciated family of pro-resolving mediators, the maresin conjugate in tissue regeneration (MCTR), that display both immunoregulatory and tissue-protective activities. Thus, we queried whether the production of these autacoids is disrupted in RA patients and whether they can be useful in treating joint inflammation and promoting joint repair. METHODS: Using a highly phenotyped RA cohort we evaluated plasma MCTR concentrations and correlated these to clinical markers of disease activity. To evaluate the immunoregulatory and tissue reparative activities we employed both in vivo models of arthritis and organ culture models. FINDINGS: Herein, we observed that plasma MCTR3 concentrations were negatively correlated with joint disease activity and severity in RA patients. Evaluation of the mechanisms engaged by this mediator in arthritic mice demonstrated that MCTR3 reprograms monocytes to confer enduring joint protective properties. Single cell transcriptomic profiling and flow cytometric evaluation of macrophages from mice treated with MCTR3-reprogrammed monocytes revealed a role for Arginase-1 (Arg-1) in mediating their joint reparative and pro-resolving activities. Arg-1 inhibition reversed both the anti-arthritic and tissue reparative actions of MCTR3-reprogrammed monocytes. INTERPRETATION: Our findings demonstrate that circulating MCTR3 levels are negatively correlated with disease in RA. When administered to mice in vivo, MCTR3 displayed both anti-inflammatory and joint reparative activities, protecting both cartilage and bone in murine arthritis. These activities were, at least in part, mediated via the reprogramming of mononuclear phagocyte responses. FUNDING: This work was supported by funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant no: 677542) and the Barts Charity (grant no: MGU0343) to J.D. J.D. is also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 107613/Z/15/Z).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Artritis Experimental / Artritis Reumatoide Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: EBioMedicine Año: 2022 Tipo del documento: Article Pais de publicación: Países Bajos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Artritis Experimental / Artritis Reumatoide Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: EBioMedicine Año: 2022 Tipo del documento: Article Pais de publicación: Países Bajos