Inflammation in gout: mechanisms and therapeutic targets

So, Alexander; Martinon, Fabio

doi:10.1038/nrrheum.2017.155

Cited by 402 publications

(401 citation statements)

References 76 publications

(62 reference statements)

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“…Furthermore, these agents are only modestly effective; for example, when NSAIDs are used to treat acute gout, only approximately 50% of patients experience a major clinical response within 2 days (7). A thorough understanding of how MSU crystals trigger inflammation is necessary to uncover new pathways to pharmacologically target and prevent extremely painful and disabling gout flares (8).…”

Section: Introductionmentioning

confidence: 99%

Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation

Hall¹,

Sanderson²,

Lawrence³

et al. 2018

Journal of Clinical Investigation

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Gout is the most common inflammatory arthritis affecting men. Acute gouty inflammation is triggered by monosodium urate (MSU) crystal deposition in and around joints that activates macrophages into a proinflammatory state, resulting in neutrophil recruitment. A complete understanding of how MSU crystals activate macrophages in vivo has been difficult because of limitations of live imaging this process in traditional animal models. By live imaging the macrophage and neutrophil response to MSU crystals within an intact host (larval zebrafish), we reveal that macrophage activation requires mitochondrial ROS (mROS) generated through fatty acid oxidation. This mitochondrial source of ROS contributes to NF-κB-driven production of IL-1β and TNF-α, which promote neutrophil recruitment. We demonstrate the therapeutic utility of this discovery by showing that this mechanism is conserved in human macrophages and, via pharmacologic blockade, that it contributes to neutrophil recruitment in a mouse model of acute gouty inflammation. To our knowledge, this study is the first to uncover an immunometabolic mechanism of macrophage activation that operates during acute gouty inflammation. Targeting this pathway holds promise in the management of gout and, potentially, other macrophage-driven diseases.

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Section: Introductionmentioning

confidence: 99%

Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation

Hall¹,

Sanderson²,

Lawrence³

et al. 2018

Journal of Clinical Investigation

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“…Gout is an inflammatory arthropathy characterized by the deposition of monosodium urate (MSU) crystals in articular and periarticular tissues, often associated with hyperuricemia . Gout attack manifests most commonly as episodes of acute and extremely painful arthritis, classically affecting the first metatarsophalangeal joint, although several other joints can be involved.…”

Section: Introductionmentioning

confidence: 99%

Phosphoinositide-3 kinase gamma regulates caspase-1 activation and leukocyte recruitment in acute murine gout

Tavares

Galvão

Costa

et al. 2019

Journal of Leukocyte Biology

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This study investigates the participation of PI3Kγ in the development of joint inflammation and dysfunction in an experimental model of acute gout in mice. Acute gout was induced by injection of monosodium urate (MSU) crystals into the tibiofemoral joint of mice. The involvement of PI3Kγ was evaluated using a selective inhibitor and mice deficient for PI3Kγ (PI3Kγ−/−) or with loss of kinase activity. Neutrophils recovered from the inflamed joint were quantified and stained for phosphorylated Akt (pAkt) and production of reactive oxygen species (ROS). The adherence of leukocytes to the joint microvasculature was assessed by intravital microscopy and cleaved caspase‐1 by Western blot. Injection of MSU crystals induced massive accumulation of neutrophils expressing phosphorylated Akt. In the absence of PI3Kγ, there was reduction of pAkt expression, chemokine production, and neutrophil recruitment. Genetic or pharmacological inhibition of PI3Kγ reduced the adherence of leukocytes to the joint microvasculature, even in joints with established inflammation. Neutrophils from PI3Kγ−/− mice produced less ROS than wild‐type neutrophils. There was decreased joint damage and dysfunction in the absence of PI3Kγ. In addition, in the absence of PI3Kγ activity, there was reduction of cleaved caspase‐1 and IL‐1β production in synovial tissue after injection of MSU crystals and leukotriene B4. Our studies suggest that PI3Kγ is crucial for MSU crystal–induced acute joint inflammation. It is necessary for regulating caspase‐1 activation and for mediating neutrophil migration and activation. Drugs that impair PI3Kγ function may be useful to control acute gout inflammation.

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“…In recent years, an understanding of additional adverse effects of high levels of serum UA has been advanced [58]. Early scientific literature suggested an association between uric acid concentration and incidence of cardiovascular disease, specifically, the development of hypertension [59], metabolic syndrome [60], endothelial dysfunction [61], and microalbuminuria [62].…”

Section: Discussionmentioning

confidence: 99%

Sensing soluble uric acid by Naip1-Nlrp3 platform

Braga

Davanso

Mendes

et al. 2020

Preprint

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The immune system can recognize microbes and sterile tissue damage. Among the damage-associated molecular patterns (DAMPs), uric acid is considered a major component which can trigger inflammation. It represents a breakpoint in the evolutionary history of humans as our ancestors lost the uricase gene, the enzyme responsible for its cleavage. High soluble uric acid (sUA) concentration is able to increase IL-1β in murine, but not human macrophages. We observed that sUA increased the mRNA expression of Naip1 in murine macrophages, and, therefore, we hypothesized that the recognition of sUA can be made by a Naip1-Nlrp3 inflammasome platform. Additionally, we used genome-wide transcriptome analysis, functional analyses and structural modeling predictions and observed that virus-transduction of murine Naip1 into human macrophages induced IL-1β after sUA stimulus, besides leading to fatty acid production and an inflammationrelated response. Moreover, pharmacologic inhibition and genetic loss of Nlrp3 led to decreased IL-1β production upon sUA stimulus. Surface plasmon resonance and quartz crystal microbalance showed that sUA is able to interact with Naip1.Naip could be a lost receptor for sUA in the evolutionary process and a better understanding of the immune modulatory function of sUA could lead to design rational novel anti-hyperuricemic therapies.

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Inflammation in gout: mechanisms and therapeutic targets

Cited by 402 publications

References 76 publications

Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation

Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation

Phosphoinositide-3 kinase gamma regulates caspase-1 activation and leukocyte recruitment in acute murine gout

Sensing soluble uric acid by Naip1-Nlrp3 platform

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