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

Abstract

ObjectiveGout 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.ResultsWe 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.ConclusionsWe propose mTOR inhibition as a novel therapeutic target of interest in gout treatment.

Urate‐induced immune programming: Consequences for gouty arthritis and hyperuricemia

“…Although mTOR activity was enhanced, pro‐IL‐1β protein synthesis was selectively regulated by p38 MAPK signaling and not on mTOR . However, another report showed that gout patients exhibit higher expression of genes involved in mTOR pathway and lower expression of PTEN, an mTOR inhibitor, compared to healthy controls . The group showed that MSU crystals induce mTOR pathway gene expression in monocytes from healthy donors, and this was also reflected at protein level, as well as induction of IL‐1β.…”

“…The effects of MSU crystals were reversed upon induction of autophagy and mTOR inhibition by metformin or rapamycin, which reduced cell death and lowered inflammasome activation and inflammation. In line with these data, in a retrospective cohort analysis, patients who received metformin as comedication were shown to have less frequent gout attacks and patients who were treated with colchicine expressed lower levels of mTOR activation . Metformin exerts its anti‐inflammatory effects by activating AMPK (5′ adenosine monophosphate‐activated protein kinase) which is a negative regulator of NF‐κB via the PI3K (phosphoinositide 3‐kinase)–Akt1 pathway .…”

“…115 However, another report showed that gout patients exhibit higher expression of genes involved in mTOR pathway and lower expression of PTEN, an mTOR inhibitor, compared to healthy controls. 116 The group showed that MSU crystals induce mTOR pathway gene expression in monocytes from healthy donors, and this was also reflected at protein level, as well as induction of IL-1β. They also showed that positively selected CD14+ monocytes undergo pyroptosis upon MSU crystal encounter.…”

“…In line with these data, in a retrospective cohort analysis, patients who received metformin as comedication were shown to have less frequent gout attacks and patients who were treated with colchicine expressed lower levels of mTOR activation. 116 Metformin exerts its anti-inflammatory effects by activating AMPK (5′ adenosine monophosphate-activated protein kinase) which is a negative regulator of NF-κB via the PI3K (phosphoinositide 3-kinase)-Akt1 pathway. 117 It has also been shown that inhibition of mTOR with rapamycin in macrophages induces autophagy and targets pro-IL-1β for degradation, resulting in a decrease of NLRP3 inflammasome activation.…”

Anti-inflammation effects of the total saponin fraction from Dioscorea nipponica Makino on rats with gouty arthritis by influencing MAPK signalling pathway

“…Current drug used to treat GA may have some side effects which could be seen obviously from our previous study, such as stomach injury by indomethacin. It is urgent to identify new drugs to treat GA since it was detrimental to the health of the patients and especially in the condition of comorbidities [6]. Mitogen-activated protein kinases (MAPKs) play an important role during the pathogenesis of GA [7].…”