Modulation of the immune response in rheumatoid arthritis with strategically released rapamycin

Shao, Ping; Ma, Linxiao; Ren, Yifei; Liu, Huijie

doi:10.3892/mmr.2017.7285

Cited by 23 publications

(17 citation statements)

References 34 publications

(35 reference statements)

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“…The most potent clinically approved drug that inhibits mTOR is rapamycin, which is used as an immunosuppressant agent in transplant patients and as a coating for coronary stents 19. In addition, a number of reports have been published on using rapamycin as an add-on therapy in rheumatoid arthritis, systemic lupus erythematosus and Sjögren’s disease 20–22. A less well-known, weak inhibitor of mTOR but more widely used is metformin.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Rapamycin downregulates the activation of dendritic cells and macrophages, thus reduces the secretion of inflammatory cytokines and clinical scores in mice RA model. [147] It blocks the increases in T cell activation, IL-13 and leukotriene levels, and AHR in a clinically relevant asthma model. [148] It can attenuate the pulmonary and systemic Tc1 and Tc17 cell responses, leading to the amelioration of cigarette smoke-induced emphysema, a major hallmark of COPD, in mice.…”

Section: Macrolidesmentioning

confidence: 99%

The Role of Chronic Inflammation in Various Diseases and Anti‐inflammatory Therapies Containing Natural Products

Wang

Zhou

et al. 2021

ChemMedChem

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Chronic inflammation represents a long-term reaction of the body's immune system to noxious stimuli. Such a sustained inflammatory response sometimes results in lasting damage to healthy tissues and organs. In fact, chronic inflammation is implicated in the development and progression of various diseases, including cardiovascular diseases, respiratory diseases, metabolic diseases, neurodegenerative diseases, and even cancers. Targeting nonresolving inflammation thus provides new opportunities for treating relevant diseases. In this review, we will go over several chronic inflammation-associated diseases first with emphasis on the role of inflammation in their pathogenesis. Then, we will summarize a number of natural products that exhibit therapeutic effects against those diseases by acting on different markers in the inflammatory response. We envision that natural products will remain a rich resource for the discovery of new drugs treating diseases associated with chronic inflammation.

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“…Increased mTOR signaling is involved in multiple pathological conditions [15]. Moreover, rapamycin, the most potent mTOR inhibitor, was suggested as an add-on therapy in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) [16,17]. Even metformin was proven to be able to significantly inhibit mTOR phosphorylation through AMPK activation [18].…”

Section: Anti-inflammatory and Immuno-modulating Effects Of Ampkmentioning

confidence: 99%

Metformin: A Potential Therapeutic Tool for Rheumatologists

et al. 2020

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Metformin is an oral antihyperglycemic drug widely used to treat type 2 diabetes, acting via indirect activation of 5′ Adenosine Monophosphate-activated Protein Kinase (AMPK). Actually, evidence has accumulated of an intriguing anti-inflammatory activity, mainly mediated by AMPK through a variety of mechanisms such as the inhibition of cytokine-stimulated Nuclear Factor-κB (NF-κB) and the downregulation of the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathways. Moreover, AMPK plays an important role in the modulation of T lymphocytes and other pivotal cells of the innate immune system. The current understanding of these AMPK effects provides a strong rationale for metformin repurposing in the management of autoimmune and inflammatory conditions. Several studies demonstrated metformin’s beneficial effects on both animal and human rheumatologic diseases, especially on rheumatoid arthritis. Unfortunately, even though data are large and remarkable, they almost exclusively come from experimental investigations with only a few from clinical trials. The lack of support from prospective placebo-controlled trials does not allow metformin to enter the therapeutic repertoire of rheumatologists. However, a large proportion of rheumatologic patients can currently benefit from metformin, such as those with concomitant obesity and type 2 diabetes, two conditions strongly associated with rheumatoid arthritis, osteoarthritis, and gout, as well as those with diabetes secondary to steroid therapy.

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Modulation of the immune response in rheumatoid arthritis with strategically released rapamycin

Cited by 23 publications

References 34 publications

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

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

The Role of Chronic Inflammation in Various Diseases and Anti‐inflammatory Therapies Containing Natural Products

Metformin: A Potential Therapeutic Tool for Rheumatologists

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