REVIEWS

Inflammation in gout: mechanisms

and therapeutic targets
Alexander K. So1 and Fabio Martinon2
Abstract | The acute symptoms of gout are triggered by the inflammatory response to
monosodium urate crystals, mediated principally by macrophages and neutrophils. Innate
immune pathways are of key importance in the pathogenesis of gout, in particular the activation
of the NLRP3 inflammasome, which leads to the release of IL‑1β and other pro-inflammatory
cytokines. The orchestration of this pro-inflammatory cascade involves multiple intracellular and
extracellular receptors and enzymes interacting with environmental influences that modulate
the inflammatory state. Furthermore, the resolution of inflammation in gout is becoming better
understood. This Review highlights recent advances in our understanding of both positive and
negative regulatory pathways, as well as the genetic and environmental factors that modulate
the inflammatory response. Some of these pathways can be manipulated and present novel
therapeutic opportunities for the treatment of acute gout attacks.

Autoinflammatory disease
Inflammatory diseases not due
to infections or injuries, mostly
caused by malfunction in the
innate immune system.
Inflammasome
A multiprotein cytoplasmic
complex that activates one or
more inflammatory caspases,
such as caspase‑1, leading
to the processing and secretion
of the pro-inflammatory
cytokines IL‑1β and IL‑18, and
the processing and activation
of factors triggering pyroptosis
such as gasdermin D.
1
Service of Rheumatology,
Centre Hospitalier
Universitaire Vaudois and
University of Lausanne,
Avenue Pierre Decker 4,
1011 Lausanne, Switzerland.
2
Department of
Biochemistry, University of
Lausanne, 155 Chemin des
Boveresses, 1066 Epalinges,
Switzerland.
Correspondence to A.K.S.  trol of the inflammasome and pro-inflammatory cytokine
alexanderkai-lik.so@chuv.ch
doi:10.1038/nrrheum.2017.155
Published online 28 Sep 2017
Gout is now the most common cause of inflammatory
arthritis, and its epidemiology worldwide points to an
increase in incidence and prevalence in both developed
and developing countries1. Gout is caused by hyper­
uricaemia (serum urate levels >7 mg/l (420 μmol/l)) lead­
ing to the formation and deposition of monosodium urate
(MSU) crystals. Clinically, the disease is characterized by
acute episodes of joint inflammation, usually affecting a
single joint, interspersed with symptom-free periods of
variable duration. If untreated, gout typically progresses
to the formation of urate deposits (tophi) in soft tissues,
recurrent attacks of arthritis affecting multiple joints and
progressive joint destruction. Other complications include
renal deposits of uric acid that can provoke renal failure
and the formation of renal stones. These and other clinical
features have been reviewed elsewhere2.
Gout is now regarded as a prototypical inflamma­
tory disease driven by activation of the innate immune
system. Gout has also been termed an autoinflammatory
disease3; however, this classification is misleading as,
unlike hereditary autoinflammatory diseases, the acute
trigger of gout is MSU crystals. Uric acid itself is an endo­
genous and ubiquitous metabolite that is not considered
to be pro-inflammatory, and MSU crystal formation is
required to provoke clinically observed inflammation.
The study of the underlying mechanisms of gouty
inflammation has led to remarkable insights into the con­
release. Nevertheless, we must bear in mind some of the
other distinguishing features of gout: firstly, that the attack
is usually self-limiting and, secondly, that MSU crystals
can be present without an inflammatory response. These
observations suggest that regulatory mechanisms exists
that modify the acute inflammatory response, and a
thorough understanding of pro-­inflammatory as well
as anti-inflammatory pathways could help to develop
new strategies for the treatment of gout. In this Review,
we discuss advances over the past decade in the field of
gout inflammation research and emerging therapeutic
strategies to manage acute gout attacks.
Uric acid-mediated inflammation
IL‑1β–mediated inflammation is a key aspect of gouty
inflammation. In gout, IL‑1β production is mediated
by MSU crystals triggering the inflammasome, a multi­
molecular complex whose dysregulation is central to
many pathological inflammatory conditions.
Inflammasome activation by MSU crystals
MSU crystals trigger an inflammatory response from
macrophages. The crystals are first taken up by macro­
phages and promote the assembly and activation of the
NLRP3 inflammasome4. Inflammasomes are cytosolic
multiprotein complexes that can initiate inflammatory
responses5,6.
Inflammasomes assemble when cytosolic pattern-­
recognition receptors (PRRs) such as NLRP3 sense acti­
vating signals that have reached the cytosol of the cell.
This signalling leads to the oligomerization of the PRR
and its recruitment to a complex of adaptor proteins and
effector enzymes (FIG. 1). NLRP3 inflammasomes are
formed by the recruitment of the adaptor protein ASC

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Key points Mechanisms of inflammasome engagement

Despite the fact that activation of IL‑1β production and
• Inflammatory cytokines, in particular IL‑1β, are the key mediators of gouty the role of the NLRP3 inflammasome in gout is well-­
inflammation described, the upstream pathway that links MSU crystals
• The NLRP3 inflammasome is the major pathway by which MSU crystals trigger to NLRP3 activation is poorly understood. Inflammasome
the cellular inflammatory response engagement can be dissected into two prerequisite steps:
• Multiple regulatory pathways modulate the activity of the inflammasome priming and activation. Reliance on two signals is a key
and the release of IL‑1β; this may explain in part the clinical origins of gouty feature of most inflammasomes and increases the speci­
inflammation ficity of the response while avoiding inappropriate firing
• Diet influences hyperuricaemia as well as the inflammatory state of macrophages of the pathway. In gout, the nature of signal 1 is unclear but
in gout might rely on the activation of Toll-like receptors (TLRs)14.
• Nutrients can modulate inflammasome activity and IL‑1β release and participate Signal 2 is provided by the interaction of MSU crystals
in the regulation of pro-inflammatory as well as anti-inflammatory pathways with inflammasome-competent cells15.
in gout
• The resolution of gouty inflammation is regulated at the cellular level as well as at the Signal 1 of inflammasome engagement primes cells for
level of activation of the inflammasome; these pathways provide promising new
inflammasome assembly. Priming of the cell, also known
avenues for therapeutic intervention
as signal 116, controls the expression of all components
required for the assembly and activation of the inflam­
masome and contributes to the expression of the pre­
and subsequent recruitment of caspase‑1. Following cursor proteins that are the substrates of inflammatory
initial oligomerization within the inflammasome, caspases. This inflammasome-competent stage, which is
ASC monomers can further auto-assemble into high-­ achieved as a result of an inflammatory milieu, can orig­
molecular-weight oligomers. This process, referred to as inate by the engagement of innate immune receptors on
‘prion-like’ polymerization, amplifies the signals sensed the cell surface or as part of an auto-amplification loop
by the PRR and engages virtually all ASC molecules into via IL‑1β itself.
one active cellular complex 7. Recruitment and oligo­ Signalling pathways mediated by cell-surface recep­
merization of caspase‑1 by this structure leads to the tors coordinate the innate immune response. The best
activation and proteolytic processing of its substrates. known of these receptors are the TLR family, of which
Caspase‑1 activates the pro-inflammatory cytokines TLR2 and TLR4 in particular have been implicated in
IL‑1β and IL‑18 by cleaving their respective pre­ gouty inflammation. Work published in 2005 showed
cursor proteins, pro‑IL‑1β and pro‑IL‑18. In gout, that mice deficient in TLR2 or TLR4 have an impaired
inflammasome-­mediated IL‑1β‑release triggers an impor­ neutrophil response to MSU crystals in the air-pouch
tant inflammatory response, with vasodilatation and rapid model of gout14. A direct interaction between MSU crys­
recruitment of neutrophils to the site of crystal deposition, tals and the TLRs was postulated, as macrophages defi­
and thereby drives acute inflammatory episodes8. cient for these receptors did not take up MSU crystals as
Additional caspase‑1 substrates, such as gasdermins, efficiently as wild-type macrophages; however, no clear
are emerging as downstream targets of inflammasome evidence demonstrated that MSU crystals could directly
engagement 9. Gasdermins promote cell death upon activate TLRs. Subsequent data suggested that TLRs
the activation of inflammatory caspases10,11. Caspase‑1 regulate gouty inflammation by recognition of ligands
and caspase‑11 can cleave gasdermin D to release its that prime monocytes and macro­phages to produce
N‑terminal portion that then polymerizes at the plasma pro‑IL‑1β. Proteins S100A8 and S100A9 are endo­
membrane, forming cytotoxic pores. These pores alter genous ligands of TLR4 and are secreted upon activa­
cellular integrity and result in cell death by pyroptosis, tion of phagocytes. Patients with gout and mice injected
which is mediated by inflammatory caspases and differs with MSU crystals produced high levels of S100A8
from cell death mediated by apoptotic caspases in that and S100A9, and genetic deletion of S100A9 reduced
it results in the release of the cytosolic contents of cells, the response to MSU crystals in mice17. Another TLR
including a plethora of pro-inflammatory mediators ligand that might have a role in macrophage priming in
and danger signals. Pyroptosis can therefore amplify gout is long-chain free fatty acids (FFAs). In a murine
the inflammatory response and facilitate the release of model of gout, arthritis was only observed when mice
cytokines, including IL‑1β. Whether this pathway con­ were injected with both long-chain FFAs and MSU
tributes to inflammation in gout remains to be estab­ crystals, whereas injection of MSU alone or long-chain
lished. Uric acid crystals have also been proposed to FFAs alone was not sufficient to elicit inflammation.
trigger necroptosis, another pro-inflammatory type Furthermore, it was demonstrated that TLR2 is the
of cell death that is mediated by the activation of the receptor that mediated the effects of long-chain FFAs
Pyroptosis
Inflammatory form of cell receptor-interacting serine/threonine-protein kinase 3 on macrophages18. The mechanisms by which TLRs can
death mediated by (RIPK3) and mixed lineage kinase domain-like protein regulate inflammation have been reviewed elsewhere19.
inflammatory caspases such as (MLKL) pathways12. Interestingly, disruption of cellular Other factors such as granulocyte-macrophage
caspase‑1 and caspase‑11 that integrity during necroptosis can elicit NLRP3 inflamma­ colony-­stimulating factor (GM‑CSF) and the comple­
results in the extracellular
release of cellular content,
some assembly 13. Thus, necroptosis and pyroptosis ment protein C5a have been proposed to affect cell prim­
including inflammatory might cooperate to amplify the release of inflammatory ing in gout. In monocytes from GM‑CSF-neutralized
mediators and danger signals. mediators in gout. mice, decreased levels of IL‑1β were observed following

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Signal 1 Signal 2

TLR
Potassium efflux IL-1β

Plasma
membrane MSU crystals Pyroptotic pore

Pyroptosis
Inflammasome K+
activation

ROS
Mitochondria

N-terminal
Inflammasome Nek7 Gasdermin D cleavage product
components
NF-κB

Caspase-1
activation

Pro-IL-1β IL-1β
Nucleus
Inflammasome

Figure 1 | NLRP3 inflammasome activation by monosodium urate crystals. The NLRP3 inflammasome Nature Reviews | Rheumatology
must be primed
before activation. Priming (signal 1) is mediated by NF‑κB–activating pathways, such as those activated by a member of the
Toll-like receptor (TLR) family. This signalling cascade induces the expression of functional inflammasome components such
as NLRP3. Monosdium urate (MSU) crystals provide signal 2, triggering the assembly of the inflammasome. The interaction
of MSU crystals with the plasma membrane promotes a cellular response that is still poorly understood but includes
hallmarks of NLRP3 activation, including potassium efflux through ion channels and mitochondrial perturbations leading to
the production and release of mitochondrial reactive oxygen species (ROS) into the cytosol. NLRP3‑activating factors such
as the mammalian NIMA-related Ser/Thr (Nek) kinase Nek7 are then engaged, promoting NLRP3 oligomerization and
inflammasome assembly. The adaptor protein ASC is recruited to the inflammasome and nucleates into prion-like filaments.
Caspase‑1 is recruited by ASC and oligomerizes along the ASC filaments, leading to the autoproteolytic activation of
caspase‑1. Active caspase‑1 then promotes the proteolytic cleavage and maturation of pro‑IL‑1β into biologically active
IL‑1β. Caspase‑1 also promotes the cleavage of gasdermin D to generate an N‑terminal cleavage product that oligomerizes
at the plasma membrane, causing the formation of pyroptotic pores. These pores disrupt the integrity of the cellular plasma
membrane, and might contribute to the release of inflammatory mediators including IL‑1β.

ex vivo stimulation with MSU crystals. These mono­
cytes also exhibited decreased expression of NLRP3 and
pro‑IL‑1β20. Conversely, treatment with C5a increased
the expression of IL‑1β and IL‑18 and exacerbated MSU
crystal-mediated peritonitis in a mouse model of gout20,21.
Although priming is necessary for inflammasome
assembly, this step is nonspecific and can result from
various conditions and signals that promote an under­
lining inflammatory response. Priming provides an envi­
ronment for inflammasome engagement, but on its own
is not sufficient to trigger the inflammasome pathway.
Signal 2 catalyses inflammasome assembly. A second
signal, signal 2, is required for inflammasome activation.
This signal is more specific than signal 1 and directly
drives post-transcriptional and translational aggregation
and polymerization of inflammasome components. The
mechanisms by which MSU crystals trigger signal 2 to
promote NLRP3 activation are still poorly understood.
However, several steps commonly found upstream of
NLRP3 activation are involved.
Perturbation of cellular ionic balances, in particular
potassium efflux and calcium influx, is a characteristic
feature of NLRP3 inducers22,23. This ionic perturbation
is necessary for the generation of mitochondrial reactive
oxygen species (ROS) upstream of NLRP3 inflamma­
some assembly. ROS production is also an essential step
for inflammasome formation, and is increased by MSU-
mediated leukotriene B4 (REF. 24) and might contribute
to engage Nek7, a member of the family of mammalian
NIMA-related Ser/Thr (Nek) kinases. Nek7 directly binds
NLRP3 and could be the common NLRP3‑activating
ligand25–27. How Nek7 interacts with NLRP3 and the
mechanisms by which MSU crystals promote the ionic
changes that ultimately engage the NLRP3‑activating cas­
cade are important unanswered questions.
Mediators of the inflammatory response
IL‑1β is a key cytokine in gout
IL‑1β is a cytokine that acts on multiple cell types to elicit
inflammatory responses28. Promotion of vaso­dilatation
by IL‑1β leads to the recruitment of monocytes and

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neutrophils to sites of tissue insults, a response that IL‑1β is mainly produced by innate immune cells and
is crucial in combating infection and restoring tissue signals to target cells by binding to IL‑1 receptor type 1
homeostasis. However, sustained IL‑1β secretion can (IL‑1R1). Once activated, IL‑1R1 and its co‑receptor
result in the production of matrix-degrading enzymes IL‑1 receptor accessory protein (IL‑1RAcP) recruit a
that break down cartilage and bone29. At the systemic signalling complex that shares components with TLR
level, IL‑1β elicits a fever response by acting directly on signalling pathways, leading to the activation of pro-­
the hypothalamic temperature-regulation centre30. inflammatory transcription factors including nuclear
factor‑κB (NF‑κB) as well as p38 c‑Jun N‑terminal
kinase (JNK) (FIG. 2). These transcription factors in turn
Inflamed joint promote the transcriptional upregulation of chemokines
Uric acid and pro-inflammatory mediators that orchestrate the
deposition IL‑1‑mediated inflammatory response.
Although inflammasome activation is the best char­
acterized mechanism leading to IL‑1β maturation in
gout, it should be noted that, in addition to inflammatory
caspases, other proteases can contribute to IL‑1 matura­
tion31. In the absence of the inflammasome, neutrophils
can process pro‑IL‑1β by the activity of neutrophil-­
MSU crystals
derived serine proteases such as proteinase‑3 (PR3,
also known as myeloblastin), neutrophil elastase and
cathepsin G31,32. Other serine proteases can also process
IL‑1β33. Some metallo­proteinases and granzyme A have
also been proposed to trigger the proteolytic activation
of IL‑1β34,35. Whether these pathways function to amplify
Innate immune cells the inflammatory reaction, for example in tissues with
• Macrophages robust neutrophil recruitment, or as back‑up mechanisms
• Monocytes that maintain IL‑1β production in conditions in which
• Neutrophils
inflammasome proteins are absent or inhibited, is unclear.
Although it is now widely accepted that IL‑1β is a
IL-1β
pivotal cytokine in acute gout 15, a role for IL‑1α cannot
IL-1β IL-1R1 IL-1β IL-1RAcP Plasma be ruled out. IL‑1α is released during crystal-induced
membrane
inflammation, and mice with deletion of the Il1b gene
IL-1R-responsive cells are still capable of mounting a neutrophil response36.
• Endothelial cells
• Synoviocytes MyD88 The clinical relevance of IL‑1 is supported by data from
IRAK1/IRAK2/IRAK4 a number of different studies of IL‑1 inhibition37. The clin­
P TRAF6 ical experience with different IL‑1 inhibitors, including
the anti‑IL‑1β monoclocal antibody canakinumab and the
IKKγ synthetic IL‑1 receptor antagonist (IL‑1Ra) anakinra, in
P IKKα IKKβ P the treatment of gout is detailed in a later section.
IκB
P degradation Other contributing cytokines
p65 IκBβ P IL‑8, also known as CXC-chemokine ligand 8, is a
p50
macrophage-­secreted chemokine that acts principally
• Cytokines
• Chemokines on neutrophils. In a study published in 2015, data from
• Cytokines three different cohorts of patients with gout showed that
↑ Inflammatory p65 p50 • Chemokines circulating levels of IL‑8 were increased during the acute
cascades phase of gout and, interestingly, also during the inter­
↑ Neutrophil influx Nucleus critical phase of gout (that is, the interval between flares);
high circulating levels of IL‑8 also predicted concomitant
Figure 2 | IL‑1 signalling links inflammasome activation with inflammatory diabetes mellitus in patients with gout. By contrast, other
cascades. Monosodium urate (MSU) crystals are detected by innate
Nature immune
Reviews cells such
| Rheumatology comorbidities that are commonly seen in gout (such as
as macrophages, monocytes or neutrophils that respond and produce active IL‑1 β. cardiovascular disease and chronic kidney disease) were
IL‑1β signals through the IL‑1 receptor complex, composed of IL‑1 receptor type 1 not significantly associated with high IL‑8 levels38. The
(IL‑1R1) and its cofactor IL‑1 receptor accessory protein (IL‑1RAcP), leading to mechanisms underlying these observations have not yet
recruitment of the adaptor protein MyD88. The expression of IL‑1R1 is widespread, on been elucidated, but suggest that neutrophil recruitment
leukocytes as well as on endothelial and synovial cells. IL‑1R1 expression results in the and neutrophil activation are key inflammatory pathways.
recruitment of effector proteins such as the IL‑1 receptor-associated kinases (IRAKs)
(mostly IRAK4) and TNF receptor-associated factor 6 (TRAF6). This protein recruitment
triggers the IκB kinase (IKK) complex and leads to the phosphorylation and degradation Soluble uric acid
of the NF‑κB inhibitor IκB. Activation of NF‑κB turns on the transcription of cytokines and In gout, it is the formation of MSU crystals that trig­
neutrophil-recruiting chemokines, which will amplify the response and initiate a complex gers acute inflammation, but data show that hyperuri­
inflammatory cascade. caemia can also modulate the inflammatory response.

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Hyperuricaemia in the absence of MSU crystals is able Genetics of gouty inflammation

to skew the leukocyte response towards an inflammatory
pattern through epigenetic modifications such as histone
methylation39. In patients with hyperuricaemia, this effect
was shown by the enhanced production of IL‑1β and
IL‑6, and the concomitant reduction of IL‑1Ra release39.
Dietary factors and the microbiome
Clinical observations indicate that dietary factors have
a major role in gout, and the link between patterns of
food consumption and hyperuricaemia and gout has
long been established40. Moreover, the role of particular
foods in triggering an acute attack has been raised, and
findings from an Internet-based survey suggest that a
purine-rich diet increases the risk of an acute attack of
gout fivefold41. However, which components of food are
responsible and how they can lead to an attack remains
to be determined. As mentioned earlier, long-chain
(C18) FFAs might have a role in priming macrophages
to release IL‑1β upon phagocytosis of MSU crystals18.
The gut microbiome and how this affects inflamma­
tion has been increasingly studied in the past few years.
Using a mouse model of gout, Viera et al. showed that
germ-free mice showed attenuated MSU crystal-induced
inflammation and that this effect was reproduced by anti­
biotic treatment. They also showed that these effects were
mediated by acetate, a short-chain FFA that is released by
gut bacteria. Acetate acts via the macrophage receptor FFA
receptor 2 (also known as GPR43) to modulate inflam­
masome activation and IL‑1β production. Restoring the
normal gut flora in germ-free mice, or the administration
of acetate, restored the inflammatory effects42. The same
group further showed that a high-fibre diet can attenuate
arthritis severity in the same murine model of gout43. In
this study, the increased production of acetate and other
short-chain fatty acids resulting from the high-fibre diet
was proposed to regulate the resolution of inflammation,
possibly by affecting neutrophils43. These studies suggest
that environmental factors such as microbial metabolites
can differentially regulate the cell types and pathways
involved in gouty inflammation. Changes in the micro­
biome in patients with gout have not been extensively
studied; however, in one report, the bacterial flora of
patients with gout was different from that of healthy indi­
viduals and similar to that of patients with type 2 diabetes
mellitus44. These findings need to be reproduced in larger
cohorts before we can draw clear conclusions on how the
microbiome modulates inflammation in gout.
Although interest in using diet to modulate hyper­
uricaemia is high, its overall effect is modest 45. However,
dietary factors might influence gouty inflammation.
Clinical data from a study published in 2016 suggest
that higher dietary consumption of omega‑3 fatty acids
is associated with a lower frequency of acute gout flares46.
Experimentally, omega‑3 fatty acids (eicosapentaenoic
acid and docosahexaenoic acid) can inhibit NLRP3
inflammasome activation via a pathway that involves
β‑arrestin‑2 and the G‑protein coupled receptors FFA
receptor 4 (GPR120) and FFA receptor 1 (GPR40)47.
These findings require confirmation by intervention
trials using omega‑3 fatty acids in patients with gout.
Genetic studies, including genome-wide association
studies (GWAS), have identified dozens of suscepti­
bility loci associated with hyperuricaemia and gout 48.
These loci mostly influence uric acid levels by affecting
pathways such as renal and gut excretion of uric acid.
Although hyperuricaemia might influence oxidative
stress and thereby have some effect on inflammatory path­
ways, whether polymorphisms associated with hyper-
uricaemia and gout directly modulate inflammatory
responses, beyond promoting uric acid crystallization,
remains to be demonstrated.
Two studies demonstrated an association between
gout and functional variants in the gene encoding
caspase recruitment domain-containing protein 8
(CARD8)49,50. CARD8 is a potential negative regulator
of the NLRP3 inflammasome; therefore, it is possible
that these polymorphisms might increase inflammas­
ome activity and thereby contribute to the intensity or
duration of NLRP3 engagement in gouty episodes. In
addition, there is genetic evidence for a role for TLR4
in gout. Employing a candidate-gene approach, two
studies, one performed in a Han Chinese population
and the other in patients of European ancestry, found
an association between the same genetic polymorphism
of the TLR4 gene (rs2149356) and gout 51,52. These poly­
morphisms might affect the priming phase of inflam­
masome engagement or might have a broader effect on
the inflammatory responses in these patients.
Another study linked gout incidence with a poly­
morphism within the PPARGC1B gene, encoding
peroxi-some proliferator-activated receptor γ (PPARγ) co-
­activator 1β53, which increased NLRP3 and IL‑1β expres­
sion. Because PPARγ co-activator 1β functions as a
regulator of PPARγ, a master regulator of metabolism,
this genetic evidence might link metabolic deregulation
with gouty inflammation.
Resolution of inflammation
Monocytes and macrophages are the major cellular
sources of IL‑1, but at the site of inflammation neu­
trophils predominate. The major pro-inflammatory
role of the neutrophil and the mechanisms of interac­
tion between MSU crystals and the neutrophil have
been reviewed elsewhere54. Interestingly, neutrophils
probably also have a major role in the resolution of
acute gout, through the formation of neutrophil extra­
cellular traps (NETs). This process is favoured at high
concentrations of neutrophils in experimental settings
(>10 × 106 cells per ml), and results in the formation of
cellular aggregates that contain cellular debris and DNA,
as well as neutrophil proteases released into the NETs55.
NET formation is dependent on the generation of ROS,
and molecules that regulate necroptosis via the RIPK3
pathway have also been implicated56. In the absence of
RIPK3, NET formation was inhibited completely56. Once
formed, cellular aggregates containing NETs can rapidly
degrade a wide range of pro-inflammatory cytokines
and, in experimental models, the inhibition of NET for­
mation results in severe and persistent gouty inflamma­
tion, whereas joint inflammation spontaneously resolves

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after 3 days when NET formation is not impaired55.
These results show that neutrophils have a dual role in
gouty inflammation: in the initial phase, when inflam­
mation is amplified by recruited neutrophils, and in the
resolution of inflammation (FIG. 3). Currently, no thera­
pies are available that can modulate NET formation or
their activity.
The metabolic regulatory enzyme AMP-activated
kinase (AMPK) contributes to the control of gout by
its modulatory effects on IL‑1β and growth-regulated
α protein (also known as CXCL1) secretion by macro­
phages, and might serve as a sensor that links metabolic
changes to the inflammatory response in gout. AMPK
levels are regulated by multiple factors including exer­
cise and hypoxia, and affect cellular metabolism of
lipids and glucose57. The addition of a pharmaco­logical
AMPK activator inhibited MSU crystal-­m ediated
inflammation both in macrophages and in mice 58.
Moreover, mice deficient for the α‑chain of AMPK had
reduced inflammation compared with wild-type mice.
AMPK levels were also increased by administration
of low-dose colchicine in macrophages treated with
MSU crystals, suggesting that the effects of colchicine
on AMPK might contribute to its ability to inhibit the
secretion of IL‑1β58.
Short-chain FFA
MSU crystals
FFAR2
• XO
• ROS
• Histone
methylation NETosis ROS
Inflammasome
Proteases
Macrophage Neutrophil
TGFβ • IL-1β
• IL-1α Degradation
• IL-8
• IL-6 Pro-inflammatory effects
• TNF
Figure 3 | Checks and balances of gouty inflammation.NatureMultiple regulatory
Reviews pathways
| Rheumatology
influence the acute inflammatory response to monosodium urate (MSU) crystals.
The interaction between macrophages and neutrophils is important in the regulation of
the acute inflammatory response. Modulators of NLRP3 inflammasome activation,
including acetate, omega‑3 fatty acids and antioxidants, can dampen IL‑1β‑release. High
concentrations of neutrophils will also favour the formation of neutrophil extracellular
trap (NET) aggregates and NETosis, which contain proteases capable of degrading
inflammatory cytokines. Finally, the release of transforming growth factor β (TGFβ) by
macrophages also acts as a brake on the inflammatory response. FFA, free fatty acid;
FFAR2, FFA receptor 2 (also known as G-protein coupled receptor 43); ROS, reactive
oxygen species; XO, xanthine oxidase.
Anti-inflammatory cytokines also contribute to the
resolution of the acute inflammatory process. In animal
models, the addition of exogenous transforming growth
factor β1 (TGFβ1) reduced experimental inflammation59;
in patients with gouty arthritis, TGFβ1, IL‑10 and IL‑1Ra
were increased in the synovial fluid and were associated
with the spontaneous resolution of acute gouty arthri­
tis60. Other factors might also contribute to the timely
resolution of inflammation in gout. For example, the pro­
tein annexin A1, a potential inhibitor of phospholipase
A2, decreases inflammation and promotes resolution in
mouse models of gout61.
Comprehensive studies interrogating host and environ-
mental factors influencing inflammation in humans have
shown that seasonal variation in α1‑antitrypsin (AAT)
concentration affects cytokine production in patients
with gout 62. AAT, a member of the serpin superfamily
that inhibits many serine proteases, was found to inhibit
IL‑1β production upon treatment with MSU crystals in
mice63. Circulating levels of AAT are at their highest
in February and their lowest in the summer months. By
contrast, retrospective studies have shown that gout peaks
in the spring and summer 64, when AAT concentration is
at the lowest and IL‑1β production is at the highest. These
findings suggest that AAT is a negative regulator of gouty
inflammation62. Understanding how this seasonally reg­
ulated factor influences inflammation is an exciting new
area of research. In particular, it would be interesting
to understand how AAT influences the duration and
intensity of gouty episodes.
Targeting inflammatory pathways
Treating gout requires two complementary approaches:
one aimed at lowering levels of uric acid and the other
aimed at reducing inflammation. NSAIDs, colchicine and
glucocorticoids are commonly used and are effective in
relieving the pain and inflammation of an acute attack;
however, insights into the biology of inflammation open
the way to new therapeutic strategies (FIG. 4).
Modulators of the NLRP3 inflammasome
As the NLRP3 inflammasome is a key component in
the response to MSU crystals, strategies that impede
its activation or affect its activity could reduce gouty
inflammation. Interestingly, colchicine blocks MSU
crystal-mediated NLRP3 activity in macrophages15,
probably by inhibiting microtubule-driven rearrange­
ment of mitochondria following the engagement of
NLRP3 with MSU crystals65.
Other molecules that target key steps in NLRP3 assem­
bly affect inflammation. β‑Hydroxybutyrate suppresses
inflammasome activation in response to MSU crystals66.
This ketone body is produced in the liver of mammals
during nutrient deprivation. Hence, starvation attenu­
ates caspase‑1 activation and IL‑1β secretion in mouse
models of caloric restriction66. Similarly, a ketogenic diet
protects rats from MSU crystal-mediated gouty flares67.
Mechanistically, β‑hydroxybutyrate has been proposed
to inhibit potassium efflux upstream of NLRP3 and to
directly affect inflammasome assembly 66. However, a
possible effect on priming has also been suggested67.

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Multiple studies in gout highlight the beneficial effects release of IL‑1β in a human cell line70; further studies are
of compounds that inhibit ROS production and decrease required to interrogate possible application of this drug
oxidative stress. Epigallocatechin gallate, a potent anti­ in gout. Xanthine oxidase inhibitors used in patients to
oxidant polyphenol found in green tea, inhibits neutro­ decrease serum urate levels also directly affect mito­
phil infiltration and IL‑1β secretion in a mouse model chondrial ROS production, thereby inhibiting MSU
of MSU crystal-mediated peritonitis68. Morin, a natural crystal-mediated inflammasome activation71.
flavonol, impairs MSU crystal-induced inflammation in Inhibiting ROS production or potassium efflux are
mouse macrophages69.The gastroprotective drug rebami­ rather nonspecific strategies that could have undesirable
pide suppresses the MSU crystal-mediated activation and effects. Identification of more specific NLRP3 inhibi­
tors could, therefore, present more suitable therapeutic
options for gout. For example, MCC950 (also known as
CP‑456,773 or CRID3) has emerged as a potential drug
Potassium of interest. This drug is a diarylsulfonylurea-­containing
Blockers of potassium efflux efflux
compound that was initially identified as an inhibitor
Liver product: of extracellular ATP-mediated maturation of IL‑1β72.
This discovery preceded the initial description of the
β-hydroxybutyrate inflammasome and the identification of NLRP3 as
the main sensor of extracellular ATP signals. Subsequently
K+ it was demonstrated that MCC950 specifically inhib­
its the NLRP3 inflammasome 73. This drug blocks
Antioxidants targeting mitochondrial ROS NLRP3‑induced ASC oligomerization in mouse and
Green tea molecule:
human macrophages without affecting the activation of
ROS
NLRP1, AIM2 or NLRC4 inflammasomes. The effects
Epigallocatechin gallate of several NLRP3 activators, including MSU crystals, were
ROS inhibited by MCC95073,74, indicating that the drug might
ROS directly act on a conserved NLRP3‑activating mechanism;
however, exactly how this drug affects NLRP3 activation
is not yet clear.
NLRP3 inflammasome inhibitors
Plant molecule: Inhibitors of IL‑1β maturation
Colchicine Considerable effort has been made to develop specific
caspase‑1 inhibitors. VX‑765, an orally available pro-
Small molecule: drug, is the best studied of these inhibitors. This drug is
MCC950 rapidly hydrolysed by plasma and liver esterases into a
potent and selective inhibitor of caspase‑175. In a mouse
model of collagen-induced arthritis, VX‑765 ameliorated
IL-1β processing inhibitors the severity and progression of disease76. The caspase‑1
Orally available drug: inhibitor pralnacasan also decreases IL‑1β production
VX-765 Caspase-1
and cartilage damage in mice with streptococcal cell wall
(SCW)-induced arthritis, a model of chronic destructive
Recombinant protein: Pro-IL-1β IL-1β joint inflammation77. However, the effects of caspase‑1
Serine inhibitors in gout have not been explored. Of particular
AAT–Fc proteases
importance will be the specificity of the inhibitor for
caspase‑1, as caspases share a highly conserved catalytic
IL-1β inhibitors
core and off-target inhibition of apoptotic caspases could
cause undesirable consequences.
Antibody:
Canakinumab IL-1β Consistent with the findings indicating that AAT
inhibits inflammation in gout 62, a recombinant human
AAT–Fc fusion protein was found to be effective in a
IL-1R inhibitors mouse model of gouty arthritis63. AAT can modulate
Recombinant protein: inflammation at multiple levels, and whether the effects
observed in the gout model are directly caused by the
Anakinra inhibition of IL‑1β processing is unclear. Nonetheless,
these data indicate that AAT–Fc, and possibly other
serine protease inhibitors, could be of interest for the
treatment of gout attacks.
Figure 4 | Therapeutic targets in gouty inflammation. Pathways leading to IL‑1 signalling
Nature Reviews
can be inhibited at many different steps. Examples of compounds and drugs| Rheumatology
that have
been proposed to affect the various steps are shown. Whereas strategies that target IL‑1 inhibitors
potassium efflux or mitochondrial reactive oxygen species (ROS) production are quite The evidence for the clinical efficacy of IL‑1 inhibition in
unspecific, inhibitors of NLRP3 inflammasome assembly such as colchicine or inhibitors of acute gout has been reviewed elsewhere37. Two IL‑1 inhib­
IL‑1β and IL‑1 receptor (IL‑1R) have already been proven to be effective in gout. itors, canakinumab and anakinra, are currently available

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Table 1 | Available IL‑1 blocking drugs of patients, their use is restricted to patients who have
‘difficult to treat’ disease and their safety with respect to
Drug name Mode of Terminal half Molecular Route of infectious complications needs to be considered when
action life weight administration
they are prescribed.
Anakinra IL‑1 receptor 4–6 hours 17.3 kDa Subcutaneous
antagonist
Conclusions
Canakinumab Human 26 days 145 kDa Subcutaneous
The past 12 years have shown considerable progress in
anti‑IL‑1β our understanding of the mechanisms of inflammation
monoclonal
antibody and the role of innate immune sensors in gout; however,
several questions remain unanswered, with three areas
being of particular interest. Firstly, the detailed specific
for clinical use, but only canakinumab is indicated for mechanism by which NLRP3 is activated upon exposure
acute gout in Europe. The two drugs have different to MSU crystals is still unclear. One emerging possibility
mechanisms of action: canakinumab is a specific inhib­ is that NLRP3 acts as a guardian of cellular integrity by
itor of IL‑1β, and anakinra inhibits the binding of both detecting perturbations triggered when innate immune
IL‑1α and IL‑1β to IL‑1R1. The properties of these drugs cells attempt to engulf large particulates79. This concept
are listed in TABLE 1. would suggest that the size, and possibly the chemical
IL‑1 inhibition can relieve the acute symptoms of nature and shape, of those particulates (including MSU
gout in patients who have not responded to conventional crystals) could affect immune responses. Secondly,
treatments or in whom the use of NSAIDs, colchicine caspase‑1‑independent mechanisms of IL‑1 production,
or glucocorticoidssteroids are contraindicated. Although including which proteases are engaged and what triggers
IL‑1 inhibition is not recommended as a first-line anti-­ their activation, are still poorly understood. In this con­
inflammatory treatment, the results from clinical trials text it would be important to understand at what stage of
of canakinumab and cohort studies of patients who have the response these pathways contribute to the inflamma­
received anakinra as treatment for acute flares showed tory phenotype and what are the cell types orchestrating
a rapid onset of pain relief, with responses observed in this inflammasome-independent response. Finally, the
nearly all treated patients37. Patients who had subsequent mechanisms that initiate gouty attacks in patients who
flares responded equally well when treated again with have persistent MSU crystal deposits are a key area of
canakinumab78 and, in our personal experience, ana­ interest. Whether specific initiating mechanisms contrib­
kinra is also effective when given for recurrent flares. ute to triggering the inflammatory reaction, possibly by
In patients with severe renal and cardiac impairment, acting on priming signalling, or whether a decrease in the
a clinical situation that commonly makes the choice of negative regulation of NLRP3 engagement promotes the
acute therapy difficult, the use of IL‑1 inhibition has inflammatory cascade, remains unclear. A better under­
not been formally assessed in clinical trials; however, no standing of these processes might identify potential spe­
severe adverse effects have been reported in case series37. cific therapeutic strategies that will make the prevention
In the clinical trials involving canakinumab, a significant and management of gout more effective and specific. The
reduction of gout flares was seen for up to 6 months, with study of this old disease has provided us with a greater
canakinumab treatment also reducing gout flares at the understanding of inflammatory pathways; solving the
start of urate-lowering therapy; however, the drug is not remaining questions still bears enormous potential for
registered to reduce gout flares on starting therapy. As new discoveries of pathways and treatments that might
anti‑IL‑1 drugs have not been tested in large numbers have implications in several inflammatory diseases.

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Acknowledgements
The work of F.M.is supported by a grant from the Swiss
National Science Foundation (310030_173152).
Author contributions
Both authors researched data and made a substantial contri-
bution to discussion of the content and writing the article,
and reviewed or edited the manuscript before submission.
Competing interests statement
A.K.S. declares that he has acted as a consultant for
AstraZeneca, Menarini and Novartis. F.M. declares no com-
peting interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

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