mTOR inhibition by metformin impacts monosodium urate crystal-induced inflammation and cell death in gout: a prelude to a new add-on therapy?

Annals of the Rheumatic Diseases
Nadia VazirpanahJasper C A Broen

Abstract

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 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 ...Continue Reading

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Citations

Dec 12, 2019·Nature Reviews. Rheumatology·Leo A B JoostenRichard J Johnson
May 21, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Lanhai LüHuizhi Wang
Feb 15, 2020·Nature Reviews. Rheumatology·Jasper C A Broen, Jacob M van Laar
Sep 10, 2020·Pharmaceuticals·Teresa SalvatoreFerdinando Carlo Sasso
Dec 20, 2019·Immunological Reviews·Georgiana CabăuLeo A B Joosten
Nov 2, 2020·Joint, Bone, Spine : Revue Du Rhumatisme·Viola KlückLeo A B Joosten
May 19, 2020·Joint, Bone, Spine : Revue Du Rhumatisme·Tristan PascartThomas Bardin
Dec 9, 2021·The Korean Journal of Internal Medicine·Ji-Won KimSung-Hwan Park

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