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Vazirpanah, Nadia; Ottria, Andrea; van der Linden, Maarten; Wichers, Catharina G K; Schuiveling, Mark; van Lochem, Ellen; Phipps-Green, Amanda; Merriman, Tony; Zimmermann, Maili; Jansen, Matthijs; Radstake, Timothy R D J; Broen, Jasper C A
Annals of the rheumatic diseases, 05/2019, Letnik: 78, Številka: 5Journal Article
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. We used a translational approach starting from ex vivo to in vitro and back to in vivo. 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 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 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. We propose mTOR inhibition as a novel therapeutic target of interest in gout treatment.
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