MCTR3 reprograms arthritic monocytes to upregulate Arginase-1 and exert pro-resolving and tissue-protective functions in experimental arthritis
Kimberly Pistorius,
Lucy Ly,
Patricia R. Souza,
Esteban A. Gomez,
Duco S. Koenis,
Ana R. Rodriguez,
Julie Foster,
Jane Sosabowski,
Mark Hopkinson,
Vinothini Rajeeve,
Bernd W. Spur,
Andrew Pitsillides,
Costantino Pitzalis,
Jesmond Dalli
Affiliations
Kimberly Pistorius
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK
Lucy Ly
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK
Patricia R. Souza
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK
Esteban A. Gomez
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK
Duco S. Koenis
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK
Ana R. Rodriguez
Rowan University School of Osteopathic Medicine, Department of Cell Biology & Neuroscience, 2 Medical Centre Drive, Stratford NJ 08084, USA
Julie Foster
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
Jane Sosabowski
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
Mark Hopkinson
Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
Vinothini Rajeeve
Mass spectrometry Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom
Bernd W. Spur
Rowan University School of Osteopathic Medicine, Department of Cell Biology & Neuroscience, 2 Medical Centre Drive, Stratford NJ 08084, USA
Andrew Pitsillides
Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
Costantino Pitzalis
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK
Jesmond Dalli
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; Corresponding author: Prof Jesmond Dalli Ph.D, William Harvey Research Institute, John Vane Science Centre, Charterhouse Square, London. EC1M 6BQ. Tel: +44 (0) 207 882 8263
Summary: 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).
