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mTOR inhibition by metformin impacts monosodium urate crystal–induced inflammation and cell death in gout: a prelude to a new add-on therapy?
  1. Nadia Vazirpanah1,
  2. Andrea Ottria1,
  3. Maarten van der Linden1,
  4. Catharina G K Wichers1,
  5. Mark Schuiveling1,
  6. Ellen van Lochem2,
  7. Amanda Phipps-Green3,
  8. Tony Merriman3,
  9. Maili Zimmermann1,
  10. Matthijs Jansen4,
  11. Timothy R D J Radstake1,5,
  12. Jasper C A Broen1,5
  1. 1 Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
  2. 2 Medical Microbiology and Immunology, Rijnstate Hospital, Arnhem, The Netherlands
  3. 3 Department of Biochemistry, University of Otago, Dunedin, New Zealand
  4. 4 Department of Immunology, Rijnstate Hospital, Arnhem, The Netherlands
  5. 5 Department of Rheumatology and Clinical Immunology, University Medical Center, Utrech, The Netherlands
  1. Correspondence to Dr Nadia Vazirpanah, Universitair Medisch Centrum Utrecht, Utrecht 3584EA, The Netherlands; nadiavazirpanah{at}gmail.com

Abstract

Objective Gout is the most common inflammatory arthritis worldwide, and patients experience a heavy burden of cardiovascular and metabolic diseases. The inflammation is caused by the deposition of monosodium urate (MSU) crystals in tissues, especially in the joints, triggering immune cells to mount an inflammatory reaction. Recently, it was shown that MSU crystals can induce mechanistic target of rapamycin (mTOR) signalling in monocytes encountering these crystals in vitro. The mTOR pathway is strongly implicated in cardiovascular and metabolic disease. We hypothesised that inhibiting this pathway in gout might be a novel avenue of treatment in these patients, targeting both inflammation and comorbidities.

Methods We used a translational approach starting from ex vivo to in vitro and back to in vivo.

Results We show that ex vivo immune cells from patients with gout exhibit higher expression of the mTOR pathway, which we can mimic in vitro by stimulating healthy immune cells (B lymphocytes, monocytes, T lymphocytes) with MSU crystals. Monocytes are the most prominent mTOR expressers. By using live imaging, we demonstrate that monocytes, on encountering MSU crystals, initiate cell death and release a wide array of proinflammatory cytokines. By inhibiting mTOR signalling with metformin or rapamycin, a reduction of cell death and release of inflammatory mediators was observed. Consistent with this, we show that patients with gout who are treated with the mTOR inhibitor metformin have a lower frequency of gout attacks.

Conclusions We propose mTOR inhibition as a novel therapeutic target of interest in gout treatment.

  • gout
  • monosodium urate crystal
  • monocyte
  • mTOR
  • rapamycin
  • metformin

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors All authors approved the final version after being involved in drafting and revising the article for important intellectual content. As the corresponding author, NV had full access to the data and takes responsibility for the accuracy of the performed analysis and the integrity of the data. NV, TRDJR and JCAB were involved in design of the study. Execution, analysis and writing of the manuscript was performed by NV. AO and MvdL respectively contributed in FACS and Live Imaging of this study. CGKW was involved in performing gene arrays. MS and MZ thought along on rapamycin and metformin stimulations. EvL and MJ were involved in inclusion of Dutch patients with gout and TM participated by including patients with gout from New Zealand.

  • Funding This study was funded by Nederlandse Organisatie voor Wetenschappelijk Onderzoek (91614041).

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval This study was performed according to the guidelines of the Declaration of Helsinki and study meets the approval of ethical and review committees of the the Rijnstate hospital (Nijmegen, the Netherlands), University Medical Center of Utrecht in the Netherlands, VieCuri Hospital of Venlo in the Netherlands and University of Otago in Dunedin, New Zealand.

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

  • Data sharing statement Not applicable.

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