British JOURNAL of ANAESTHESIA, 117 (6): 693–707 (2016)

doi: 10.1093/bja/aew376
Review Article

R E V I EW AR TI C L E

The inflammasome as a target for pain therapy

H. Zhang1,†, F. Li1,†, W.-W. Li2, C. Stary2, J. D. Clark2, S. Xu1,* and X. Xiong3,*
1
Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong,
PR China, 2Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of
Medicine, Stanford, CA, USA and 3Department of Neurosurgery, Renmin Hospital of Wuhan University,
Wuhan, Hubei, PR China
†
Co-first author.
*Corresponding author. E-mail: shiyuanxu355@163.com, xiaoxingxiong@whu.edu.cn

Abstract
The interleukin-1 family of cytokines are potent inducers of inflammation and pain. Proteolytic activation of this family of
cytokines is under the control of several innate immune receptors that coordinate to form large multiprotein signalling plat-
forms, termed inflammasomes. Recent evidence suggests that a wide range of inflammatory diseases, cancers, and meta-
bolic and autoimmune disorders, in which pain is a common complaint, may be coordinated by inflammasomes. Activation
of inflammasomes results in cleavage of caspase-1, which subsequently induces downstream initiation of several potent
pro-inflammatory cascades. Therefore, it has been proposed that targeting inflammasome activity may be a novel and effec-
tive therapeutic strategy for these pain-related diseases. The purpose of this narrative review article is to provide the reader
with an overview of the activation and regulation of inflammasomes and to investigate the potential therapeutic role of
inflammasome inhibition in the treatment of diseases characterized by pain, including the following: complex regional pain
syndrome, gout, rheumatoid arthritis, inflammatory pain, neuropathic pain, chronic prostatitis, chronic pelvic pain syn-
drome, and fibromyalgia. We conclude that the role of the inflammasome in pain-associated diseases is likely to be inflam-
masome subtype and disease specific. The currently available evidence suggests that disease-specific targeting of the
assembly and activity of the inflammasome complex may be a novel therapeutic opportunity for the treatment of refractory
pain in many settings.

Key words: caspase 1; inflammasomes; inflammation; interleukins; NOD-like receptor; pain

The interleukin-1 (IL-1) family of cytokines is composed of 11
isoforms, all of which share the characteristic of their ability to
induce inflammation. The principal species, IL-1b, possesses
strong pro-inflammatory effects on a variety of cells, and its
aberrant production contributes to acute and chronic inflamma-
tion and pain.1 2 Notably, increased IL-1 activity is associated
with autoimmune disorders, such as rheumatoid arthritis (RA),
inflammatory bowel disease, multiple sclerosis (MS), and
Alzheimer’s disease (AD), 1–4 which are all conditions in which
pain is a common complaint. The pain-inducing mechanisms of
IL-1b include the direct activation of neuronal activity in the
peripheral and central nervous system, and IL-1b acts as a
mediator that stimulates the production of additional algogenic
substances.2 5–8 Blocking the IL-1b signalling pathways has
proved to be highly effective in reducing inflammatory pain
sensitization in animal models 2 6 8–10 and patients.2 11 12
However, the mechanisms underlying the aberrant upregula-
tion of IL-1b were largely unknown before the recent discovery
of the inflammasome by Martinon and colleagues. 13
Inflammasomes are multiprotein complexes that coordinate
to activate caspase-1, an IL-1-converting enzyme.13–16 Cleavage
of the inactive IL-1b and IL-18 precursors (pro-IL-1b and pro-IL-
18) with caspase-1 is a prerequisite for activation. Like IL-1b,
caspase-1 is synthesized as an inactive 45 kDa enzyme,

V
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pro-caspase-1, which also requires inflammasome activity for
cleavage. Given that IL-1b plays a well-established role in
inflammation and pain and that inflammasomes are able to
sense a wide range of danger signals, such as pathogen-associ-
ated molecular patterns (PAMPs) and damage-associated molec-
ular patterns (DAMPs) to control IL-1 production,17
inflammasomes may play a central role in supporting pain in a
diverse range of conditions. Predictably, this discovery has pro-
moted research investigating the potential targeting of inflam-
masomes both to control inflammation and to reduce the
associated pain. This type of approach may be particularly
important in diseases where inflammasome dysfunction has
been shown to play a central role. 1 18–20
In this review, we present a narrative overview of the current
understanding of inflammasome activation and regulation. We
then address the question of whether inflammasomes may be a
potential target for pain therapy in pain-associated disease by
reviewing current literature on the role of inflammasomes in
various pain-related disease states.
This was accomplished by an electronic database search of
PubMed and Google Scholar with several key terms. These terms
included the following: ‘inflammasome, inflammation, NLRP,
NALP, cytokines, IL-1, IL-18, immune, purinergic receptors,
immunoglobulin, pain, hyperalgesia, inflammatory pain, neuro-
pathic pain, complex regional pain syndrome, gout, migraine,
chronic prostatitis, chronic pelvic pain syndrome, fibromyalgia,
autoimmune disorder, arthritis, multiple sclerosis, Alzheimer’s
disease, cancer, pathogen associated molecular patterns, dam-
age associated molecular patterns, and toll like receptors’. In
addition, articles relevant to our discussion were retrieved from
the reference list of other online articles on each subtopic.
Articles in a language other than English and conference
abstracts were excluded from further consideration. In the end,
150 articles closely related to the aims set forth for this review
were selected and used.
The following questions were addressed in constructing the
review. What is our current understanding of inflammasome
activation and regulation? What roles does the inflammasome
play in pain-associated diseases? Are inflammasomes potential
targets for pain-associated diseases?
Inflammasome composition and subtypes
A summary of inflammasome structure and activation is pre-
sented in Fig. 1 and Table 1.//// The multiprotein inflammasome
complex contains a nucleotide-binding oligomerization domain
(NOD)-like receptor (NLR), an adaptor protein apoptosis-
associated speck-like protein (ASC, which contains a caspase-
activating recruitment domain), and pro-caspase-1, pro-caspase
5, or both. NLRs contain the following three domains: a
nucleotide-binding domain (NBD), which mediates adenosine
triphosphate (ATP)-dependent self-oligomerization;38 a

NALP1/NLRP1 NALP3/NLRP3 NLRC4/IPAF AIM2

Inflammasome Inflammasome Inflammasome Inflammasome
NACHT

NACHT

NACHT

HIN200
LRRs

LRRs

LRRs
FIIND

CARD

CARD
PYD

PYD

PYD

PYD

PYD

PYD
CARD

CARD

CARD

CARD

CARD

CARD

CARD

CARD

CARD
P20
P10
P20

P20

P20

P20
P10

P10

P10

P10

ASC PYD CARD CARDINAL FIIND CARD Pro-Caspase CARD P20 P10

Fig 1 Schematic diagram illustrating the composition of inflammasomes. The activation and formation of inflammasome complexes is mediated through several
protein domains. NLRs are characterized by the combined presence of a NACHT domain and LRRs. Most NLRs also contain either a CARD or a PYD motif in their
amino terminus. AIM2 is composed of an amino-terminal PYD and a carboxy-terminal DNA-binding HIN200 domain. Murine NALP1 lacks the amino-terminal
PYD motif found in human NALP1 and is autocatalytically cleaved in its central FII domain. CARD, caspase activation and recruitment domain (orange rectan-
gles); Caspase domain, p20 and p10 as the large and small subunits, respectively (pink and red rounded rectangles); FIIND, function-to-find domain (blue rectan-
gles), which is involved in NALP1 inflammasome activation through auto-proteolysis; HIN: haematopoietic, interferon-inducible, nuclear localization domain
(light blue rounded rectangles); LRRs, leucine-rich repeats (white elongated ovals); NACHT, nucleotide-binding and oligomerization domain (light blue and grey
rounded rectangles); NLR, NOD-like receptor; PYD, pyrin domain (green rectangles). NLRP1/NALP1, leucine-rich repeat and pyrin domain containing protein 1;
NLRP3/ NALP3, leucine-rich repeat and pyrin domain containing protein 3; IPAF/NLRC4, NLR family CARD domain-containing protein 4; ATP, adenosine triphos-
phate; AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein; CARDINAL, the card containing protein; dsDNA, double-stranded DNA.

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Table 1 Known types of inflammasomes and their activators. NLRP1/NALP1, leucine-rich repeat and pyrin domain containing protein 1;
NLRP3/NALP3, leucine-rich repeat and pyrin domain containing protein 3; IPAF/NLRC4, NLR family CARD domain-containing protein 4;
ATP, adenosine triphosphate; AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein; CARDINAL, the card containing
protein; dsDNA, double-stranded DNA
Inflammasome Components
NLRP1/NALP1 NLRP1, ASC, caspase-1, caspase-5
NLRP3/NALP3 NLRP3, ASC, CARDINAL, caspase-1
IPAF/NLRC4 NLRC4, caspase-1
AIM2 AIM2, ASC, caspase-1
C-terminal leucine-rich repeat (LRR) serving as a recognition
domain for other receptors (such as Toll-like receptors, TLRs) or
microbial ligands; and a variable N-terminal interaction domain
responsible for homotypic protein–protein interactions. This N-
terminal domain can consist of a caspase recruitment domain
(CARD), a pyrin domain (PYD), acidic transactivating domains
(ADs), or baculovirus inhibitor repeats (BIRs). 21 39 There seems
to be very limited information on how the structure of an
inflammasome is related to its activity. The molecular mecha-
nism of inflammasome assembly was only recently elucidated
and specifically requires PYD oligomerization. 40 We now know
that inflammasome oligomerization requires the following two
signals: a priming signal that results in the transcription of pro-
IL-1b and pro-IL-18; and a second signal that promotes indirect
activation of the inflammasome, such as ion or membrane per-
turbations, reactive oxygen species, or extracellular ATP. 41
Inflammasome oligomerization leads to the cleavage and acti-
vation of caspase-1, which subsequently promotes the process-
ing and secretion of IL-1b and IL-18.
To date, at least three major inflammasomes have been
described, and they are defined by the NLR protein they contain:
the NLRP1/NALP1 (leucine-rich repeat and pyrin domain-con-
taining protein 1) inflammasome; the NLRP3/NALP3 inflamma-
some (leucine-rich repeat and pyrin domain-containing protein
3); and the IPAF/NLRC4 inflammasome (NLR family CARD
domain-containing protein 4). These three NLR inflammasomes
have two common features: an NBD for self-oligomerization; 38
and a C-terminus LRR for ligand recognition of other receptors
(e.g. TLR) or microbial ligands. Additional inflammasome sub-
types continue to be identified, including most recently the
AIM2 (absent in melanoma 2)-containing subtype and an NALP2
subtype.22–24 42 43
The NALP1 inflammasome, the first molecular platform
identified, is relatively widely expressed in cells and tissues of
the immune system and in non-haematopoeitic tissues. 44
NALP1 directly binds to ASC via its PYD and to caspase-1/
caspase-5 via its CARD domain. A two-step process of activation
was proposed, involving mediation by microbial ligands/bacte-
rial toxins, followed by binding of a ribonucleoside triphosphate
(rNTP) to the nucleotide-binding domain of NALP1.21 25 26
The NALP3 inflammasome, the most studied inflamma-
some, contains NALP3, the CARD-containing protein CARDINAL
(part of the NLRP3 inflammasome complex in humans), ASC,
and caspase-1.27 The NALP3 inflammasome can be activated by
diverse ligands and stimuli. This can include exogenous micro-
bial components (RNA and muramyl dipeptide) or endogenous
activating signals, such as cholesterol, monosodium urate
(MSU) crystals,28 ATP,29 low intracellular Kþ,30 aluminum
hydroxide (alum),31 deposition of amyloid polypeptide,32 and
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The inflammasome and pain | 695
Activators References
Lethal toxin, muramyl dipeptide 21 25 26
Muramyl dipeptide, ATP, b-amyloid, 27–33
uric acid crystal, alum, low K þ etc.
Flagellin, T3SS, T4SS 28 29 34–36
dsDNA 22–24 37
high extracellular glucose. 33 The NALP3 inflammasome isoform
shows a restricted tissue distribution, with expression mainly in
non-keratinizing epithelia in the oropharynx, oesophagus, ecto-
cervix, in the urothelial layer in the bladder,44 in myeloid and
endothelial cells, and in B cells. 45
The NLRC4 inflammasome, the only member of the NLRC
family, contains an amino-terminal CARD, a central NBD
domain, and C-terminal LRRs.34–36 NLRC4 associates with pro-
caspase-1 with its CARD domain, without the need for an adap-
tor protein. However, interaction with ASC is required for IL-1b
secretion. Oligomerization of NLRC4 is triggered by cytosolic
flagellin from a variety of bacteria. 28 29 NLRC4 is expressed pre-
dominantly in haematopoietic tissues.34–36
AIM2 is perhaps the best known non-NLR capable of forming
an inflammasome.22 23 24 37 In contrast to the NLRs, this pyrin
and HIN domain (PYHIN)-family protein binds directly to its
ligands, cytosolic double-stranded DNA (dsDNA), and associates
with ASC through their PYD to form a caspase-1-activating
inflammasome, leading to IL-1b secretion.22 23 24AIM2 has been
found to be expressed in the cytosol in skin and neural tissues. 46
Inflammasomes and pain-associated diseases
Inflammatory pain states
Inflammatory hyperalgesia is a complex process that depends
on the sensitization of nociceptive neurons, triggered by pro-
inflammatory mediators such as IL-1b, resulting in a heightened
sensitivity to pain.1 14 47 Using a carrageenan-induced acute
inflammatory pain model, Cunha and colleagues48 demon-
strated that the peripheral activation of caspase-1 was impli-
cated in the induction of acute inflammatory pain by promoting
the maturation of IL-1b. This finding was confirmed and
extended by Lopes and colleagues.49 In their experiments, wild-
type, NALP3 double knockout (NALP3—/—), NLRC4—/—, and ASC—/—
mice were subjected to plantar injection of carrageenan or
vehicle. Mechanical and thermal nociceptive changes were
measured before and 1, 3, and 5 h after injection, and ratios of
pre-caspase-1/caspase-1 and pre-IL-1b/IL-1b in the plantar skin
were determined 5 h after the injection. The results indicated
that mice deficient in NLRC4 or ASC, but not in NALP3, pre-
sented reduced mechanical and thermal acute inflammatory
hyperalgesia induced by carrageenan. 49 The reduced hyperalge-
sia was accompanied by significant reductions in the relative
ratios of mature to pro-IL-1b (p17) and pro-caspase-1 (p20) at the
inflammatory site compared with wild-type mice. The authors
concluded that the assembly of these components was respon-
sible for the carrageenan-induced acute inflammatory pain
state.49 However, it remains unknown how carrageenan
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Table 2 Summary of studies investigating inflammasomes in pain
Pain condition studied Animal model/patient
Inflammatory pain Carrageenan-induced
state inflammatory pain
model.
Wild-type, NLRC4—/—, ASC—
/—
, and NALP3—/—
mice
Inflammatory pain Acute intracranial inflam-
state matory pain model (rat)
Neuropathic pain Spared nerve injury neuro- Excluded NALP3
pathic pain model.
Wild-type, NALP3—/— mice
Neuropathic pain Sciatic nerve chronic con-
striction injury-induced
neuropathic pain model
(rat)
Neuropathic pain Spinal nerve ligation model Only know cas-
(rat)
Complex regional pain Distal tibia fracture with
syndrome cast immobilization (rat)
696
Inflammasome Activator Inhibitor Evidence/proposed function of inflammasome in References
targeted pain
|
Zhang et Al.
NLRC4 excluded Carrageenan NLRC4- or ASC- but not NALP3-deficient mice Lopes and colleagues 49
NALP3 exhibited reduced mechanical and thermal
hyperalgesia induced by carrageenan
NALP3 Low Kþ Inflammatory soup induced nuclear–cytoplasmic Chen and colleagues 50
shuttling of NALP3, activated caspase-1, and
mature IL-1b in small- to medium-sized C-type
neurons in the trigeminal ganglion, and pain
behaviour; treatment with the caspase-1
inhibitor Ac-YVAD-CMK diminished these
effects
SNI-elicited pain behaviours do not require Curto-Reyes and
NALP3 expression; intrathecal lipopolysac- colleagues65
charide injection increases apoptosis-associ-
ated speck-like protein, caspase-1, and IL-1b
expression in both wild-type and NALP3 —/—
mice
NALP1 Aspirin-trig- Chronic constriction injury activated NALP1 Li and colleagues61
gered-15-epi- inflammasome in spinal astrocytes and neu-
lipoxin-A4 rons, leading to an increased production of IL-
(ATL) 1b and neuropathic pain-like behaviour.
Repeated intrathecal injection with ATL mark-
edly attenuated the chronic constriction injury-
induced thermal hyperalgesia and sig-
nificantly inhibited NALP1 inflammasome acti-
vation, caspase-1 cleavage, and IL-1b
maturation
Pannexin-1 (panx1) Nerve injury increased panx1 expression in dor- Zhang and colleagues 87
pase-1 sal root ganglia, and panx1 knockdown
reduces caspase-1 release and hyperalgesia
NALP1 Substance P Substance P released from peripheral nerve ter- Li and colleagues99
minal innervated in the fractured hindlimb,
which in turn, via NK1 receptors in keratino-
cytes, stimulated the production of NALP1
inflammasome components, generation of IL-
1b and IL-18, and nociceptive sensitization;
LY303870, an NK1 receptor antagonist, blocked
the upregulation of activated NALP1 inflam-
masome components, the production of cyto-
kines, and nociception sensitization in the rat
complex regional pain syndrome model
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Table 2. Continued
Pain condition studied Animal model/patient Inflammasome Activator Inhibitor Evidence/proposed function of inflammasome in References
targeted pain

Complex regional pain Distal tibia fracture with NALP1 Substance P and cal- Both calcitonin gene-related peptide and Shi and colleagues 100
syndrome cast immobilization citonin gene- substance P upregulate NALP1 inflammasome
(mouse) related peptide and IL-1b production in a time- and dose-
dependent manner in vitro and in vivo
Gout Crystal-induced murine NALP3 Monosodium urate Monosodium urate engages NALP3 inflamma- Martinon and
peritoneal model of acute some activation, resulting in the production of colleagues35
gout active IL-1b and IL-18. Macrophages from mice
deficient in various components of the inflam-
masome, such as casepase-1
Wild-type, CASPASE-1—/—, ASC and NALP3 are defective in crystal-induced
MyD88—/—, ASC—/— IL-1b activation. Moreover, an impaired neu-
NALP3—/— mice trophil influx is found in an in vivo model of
Human primary monocyte crystal-induced peritonitis in inflammasome-
and THP1 cells deficient mice or mice deficient in the IL-1b
receptor (IL-1R). Provides solid evidence for
MSU-mediated inflammation in an inflamma-
some-dependent manner in gout
Gout Monosodium urate-induced NALP3 Monosodium urate Monosodium urate induces neutrophil influx in Armaral and
murine peritoneal model crystals, 5-lipoxy- NALP3/ASC/caspase-1/IL-1b/IL-1R1-dependent colleagues114
of acute gout genase-derived manners. Inhibition of leukotriene B 4 pre-
leukotriene B4 vented the neutrophil influx, IL-1b production,
and hyperalgesia
Gout Subcutaneous air-pouch NALP3 Monosodium urate Monosodium urate crystal-induced inflamma- Hoffman and
model of gout (mice) crystals tory responses were comparably attenuated in colleagues116
NALP3—/— mice and murine LRR domain-deleted or NALP3 knockout mice
bone marrow and bone marrow-derived macrophages
macrophages
Rheumatoid arthritis Spontaneous arthritis NALP3 ATP, migraine, crys- A20 A20 as a negative regulator of NALP3 (but not Vande Walle and
model (A20myel-KO mice) talline (silica) NLRC4 and AIM2) inflammasome activation colleagues125
NALP3—/— mice and IL-1b production. Arthritis pathology relies
crucially on the NALP3 inflammasome–IL-1b

The inflammasome and pain

axis. The P2X7 purinergic receptor, an ATP-
gated ion channel, is an important cell surface
inducer of key
Rheumatoid arthritis Rheumatoid arthritis NALP3 Polyinosinic-polycy- Patients with active rheumatoid arthritis have Choulaki and
patients tidylic acid, lipo- increased expression of NALP3 and NALP3- colleagues126
polysaccharide mediated IL-1b secretion in whole blood cells
upon stimulation via TLR3 and TLR4
Adjuvant Arthritis Adjuvant arthritis model NALP1 Adjuvant Carboxy NALP1 inflammasome was activated in arthritic Zhu and colleagues 128
(rats) amidotrazole synovia, which might be a novel therapeutic
target for rheumatoid arthritis. Carboxy ami-
dotrazole may have therapeutic value
(decreased the arthritis index, improved radio-

|
logical and histological changes) in rheuma-

697
toid arthritis by inhibiting the activation of
NALP1 inflammasome and nuclear factor-jB
and by decreasing pro-inflammatory cytokines

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Table 2. Continued
Pain condition studied Animal model/patient Inflammasome Activator Inhibitor Evidence/proposed function of inflammasome in References
targeted pain

Chronic polyarthritis DNase II-deficiency model AIM2 Self-DNA Arthritis-prone (DNASE2—/—) mice lacking AIM2 Jakobs and
of polyarthritis (mice) displayed strongly decreased signs of joint colleagues129
inflammation and associated histopathologi-
cal findings. This was paralleled by a reduction
of caspase-1 activation and pro-inflammatory
cytokine production in diseased joints
Chronic prostatitis and Carrageenan-induced NALP1 Carrageenan Increased concentrations of NALP1 (not NALP3), Chen and
chronic pelvic pain chronic prostatitis and caspase-1, and IL-1b in the cytoplasm of pros- colleagues135Qi and
syndrome chronic pelvic pain model tate glandular epithelium; treatment with colleagues137
(rats) chlorogenic acid altered the expression pat-
tern of NALP1 and reduced caspase-1 and IL-1b
expression and pain behaviour
Fibromyalgia Fibromyalgia patients and NALP3 Coenzyme Q10 Activation of NALP3 inflammasome and mito- Cordero and
coenzyme Q10 deficiency chondrial dysfunction were observed in FM colleagues141
mouse model patients and the corresponding animal model;
coenzyme Q10 deficiency resulted in NALP3
inflammasome activation and marked hyper-
algesia in mice. In a placebo-controlled trial,
coenzyme Q10 in fibromyalgia patients reduced
NALP3 inflammasome activation
Fibromyalgia Fibromyalgia patients and NALP3 Adenosine Impairment in AMPK activation provoked hyper- Bullón and
NALP3—/— transgenic monophos- algesia associated with marked NALP3 inflam- colleagues142
mice phate-acti- masome activation and IL-1b and IL-18
vated protein production, which can be rescued by increas-
kinase (AMPK) ing AMPK phosphoralation via metformin
modulation treatment, caloric restriction diet, or NALP3
knockout. Deficient AMPK activation and over-
activation of NALP3 inflammasome were
observed in blood cells from patients with
fibromyalgia

initiates oligomerization of the NOD-like receptor in the NLRC4
inflammasome.
Although the NALP3 inflammasome does not appear to con-
tribute to carrageenan-induced inflammatory pain, it may play
a role in other inflammatory pain states, as reported by Chen
and colleagues.50 The NALP3 inflammasome has been impli-
cated in acute intracranial inflammatory pain caused by dural
inflammation,50 as occurs during infection or injury to the cen-
tral nervous system (CNS). Dural inflammation, induced by infu-
sion of a mixture of inflammatory mediators (histamine,
serotonin, bradykinin, and prostaglandin E2, pH 5.5) caused a
dose- and time-dependent induction of nuclear–cytoplasmic
shuttling of NALP3, activated caspase-1, and mature IL-1b pro-
teins in small- to medium-sized C-type neurons in the trigemi-
nal ganglion, withnociceptive sensitization. 50 Application of a
selective caspase-1 inhibitor, Ac-YVAD-CMK, diminished these
effects. A low intracellular Kþ concentration was proposed as a
mechanism responsible for the NALP3 inflammasome activa-
tion. Collectively, these studies suggest that specific targeting of
inflammasome subtypes may be an effective strategy for
decreasing inflammatory pain states.
Neuropathic pain
Approximately 3–4.5% of the global population is afflicted with
neuropathic pain,51 a pain state involving damage or disease
affecting the somatosensory nervous system, which is severely
disruptive to quality of life.20 52 Although neuropathic pain is a
complicated condition, IL-1b activation has been widely regarded
as an important contributory mechanism. 53 54 Enhanced IL-1b
expression was observed in damaged nerves, dorsal root ganglia,
and spinal nerves in animals and patients with neuropathic
pain.55–57 Ineterleukin-1b was shown to be an active participant
in the pathogenesis of neuropathic pain, stimulating a secondary
injury cascade.1 53 58 However, the mechanisms underlying IL-1b
production in neuropathic pain have not been clearly described,
particularly in the CNS. Previous research has shown that the
NALP1 inflammasome participates in CNS disorders and is
mainly present in neurons56 59 and astrocytes.60
Based on this information, Li and colleagues 61 recently
examined the role of the NALP1 inflammasome in neuropathic
pain using the widely accepted sciatic nerve chronic constric-
tion injury (CCI) model. After CCI surgery, inflammasome plat-
forms consisting of NALP1, caspase-1, and ASC were detected in
spinal astrocytes and neurons, particularly in the superficial
laminae of the spinal dorsal horn, resulting in increased produc-
tion of mature IL-1b in the ipsilateral spinal cord and neuro-
pathic pain-like behaviour. 61 Another group also demonstrated
the anti-NALP1 effect on the inhibition of IL-1b maturation in a
spinal nerve ligation induced neuropathic pain model. 62
Treatment with intrathecal caspase-1 inhibitor Ac-YVAD-CMK
significantly reduced the CCI-induced IL-1b formation and the
pain behaviour, suggesting that formation of the NALP1 inflam-
masome platform is central to CCI-induced neuropathic pain.
This finding was supported by experiments with aspirin-
triggered-15-epi-lipoxin A4 (ATL). ATL is an endogenous anti-
inflammatory lipid capable of reducing IL-1b concentrations,
thereby relieving neuropathic pain behaviours. 63 64 The investi-
gators evaluated whether the NALP1 inflammasome plays a role
in ATL-induced analgesia in the CCI model by observing the
effects of repeated intrathecal injection of ATL on CCI-induced
thermal hyperalgesia. In addition to attenuating CCI-induced
thermal hyperalgesia, repeated intrathecal injection of ATL
inhibited NALP1 inflammasome activation, caspase-1 cleavage,
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and IL-1b maturation.61 The authors concluded that the NALP1
inflammasome was central to the development of neuropathic
pain, and the analgesic effect of ATL was associated with sup-
pressing NALP1 inflammasome activation. A recent study indi-
cated that the NALP3 inflammasome does not regulate
neuropathic pain in the mice spared nerve injury model. 65
Several key questions remain unanswered in the literature.
For example, how does the NALP1 inflammasome become acti-
vated after CCI in specific cell types, such as astrocytes or neu-
rons? What signals are responsible for NALP1 activation?
Finally, the observation that IL-1b expression is altered in the
brainstem, hippocampus, thalamus, and prefrontal cortex after
sciatic nerve injury66 or spinal nerve ligation67 suggests that
future studies should be directed at understanding inflamma-
some activation in higher CNS regions.
Central neuropathic pain is encountered in chronic neurode-
generative diseases, such as AD and MS, and in post-trauma
states, such as spinal cord injury and traumatic brain injury. 1
Consistent with a role for inflammasomes in neuroinflammation,
elevated production of IL-1b has been identified in injured CNS
tissues after spinal cord injury or traumatic brain injury, 68 and in
the brain tissues in patients with MS69 and AD.70 71 Notably,
NALP1 inflammasome activation was observed in both microglia
and astrocytes after spinal cord injury 51 or traumatic brain
injury.56 NALP3 inflammasome activation in microglial cells exa-
cerbated AD72 and experimental autoimmune encephalomyelitis,
an animal model of MS. 73 Further experiments are required to
address how the central activation of inflammasomes leads to
pain, for instance by supporting the activity of pro-nociceptive
circuits or reducing the activity of inhibitory neurons.
It is well established that several danger signals can induce
NALP inflammasome activation, among them ATP and the P2X
receptors (P2XRs), such as P2X4R and P2X7R, key players in IL-1
processing and release.74 P2X7-induced IL-1b release through
activation of the NALP1 or NALP3 inflammasome has been dem-
onstrated extensively in immune cells 75 76 and spinal neurons.77
More recently, P2X4 and P2X7 receptors were shown to be
expressed on dorsal root ganglion neurons, spinal microglia,
and neurons.78–81 Activation of P2X7R controls the release of
pro-inflammatory cytokines (such as IL-1b, IL-6, and tumour
necrosis factor-a) involved in nerve-injury-induced pain behav-
iours and hyperexcitability of dorsal horn neurons and glial
cells.82–84 Suppression of the function or expression of these
purinergic receptors, for example by using small interfering
RNA or blocking P2X7R activity, strongly suppresses neuro-
pathic pain.85 86 Finally, inflammasome activation may be asso-
ciated with increased expression of pannexin 1 (Panx1), a gap
junction protein. Nerve injury increased expression of Panx1 in
dorsal root ganglia, and Panx1 knockdown reduced caspase-1
release and hyperalgesia. 87 Panx1 has recently been proposed to
be the cell membrane pore induced by P2X7R activation, and
this in turn may activate the NALP1 inflammasome in astro-
cytes and neurons. 88 89 Thus, targeting purinergic signalling
may reduce pain in part by reducing inflammasome activation.
Complex regional pain syndrome
Complex regional pain syndrome (CRPS) is a chronic postinjury
pain condition commonly affecting a single limb. 90 Pain is a
hallmark feature of this syndrome, and pain-related disability
in the setting of CRPS is very common. Unfortunately, the mech-
anisms supporting these changes remain highly enigmatic, and
available clinical treatments are limited in efficacy. 90–93 A tibial
fracture model was described that exhibits the principal
 700 | Zhang et Al.
stigmata of CRPS type I (without associated nerve injury),
including chronic oedema, allodynia, epidermal thickening, and
periarticular osteoporosis. 94 95 In this model, the investigators
observed that activation of the innate system of immunity in
skin initiates a cascade of changes supporting a sustained pain
response.96 In relation to IL-1b, Li and colleagues 7 95 demon-
strated that tibial fracture induces keratinocyte activation, pro-
liferation, and overexpression of IL-1b and other inflammatory
cytokines, which in turn contribute to hindlimb nociceptive and
vascular CRPS-like changes. Importantly, continuous infusion of
the IL-1 receptor antagonist IL-1ra (anakinra) reduced fracture-
induced nociceptive sensitization in the rat fracture model. 7 In
situ hybridization and immunostaining demonstrated that epi-
dermal keratinocytes were the main source of IL-1b.7 95 Clinical
studies have demonstrated elevated IL-1b concentrations in the
skin of CRPS patients.97 Thus, peripheral IL-1b production con-
trolled by the NALP1 inflammasome may support pain in the
CRPS model.
During neurogenic inflammation, peripheral afferent and
efferent neurons induce a rapid release of neural mediators
independent of those produced by immune cells. 98 Indeed, Li
and colleagues99 demonstrated tibial fracture-induced sub-
stance P (SP) release from peripheral nerve terminals that in
turn stimulated the production of NALP1 via the NK1 receptor in
keratinocytes, activation of caspase-1, enhanced IL-1b produc-
tion, and nociceptive sensitization. The neurocutaneous
immune regulation of the NALP1 inflammasome in keratino-
cytes was recently confirmed by Shi and colleagues, 100 who
observed that both calcitonin gene-related peptide and SP upre-
gulated NALP1 inflammasome and IL-1 production in a time-
and dose-dependent manner in vitro and in vivo. Collectively,
these studies demonstrate that the nervous system and innate
immune system interact, through inflammasome activation, to
form an integrated early host response to injury.
It is noteworthy that the inflammasome is not only an
innate responder to pathogenic and danger signals, but can also
affect adaptive autoimmunity. 101–103 Growing evidence high-
lights the role of inflammasome-dependent cytokines in shap-
ing the adaptive immune response, as exemplified by the
capacity of IL-1b to support T-helper 17 responses or by the find-
ing that IL-18 evokes antigen-independent interferon-c secre-
tion by memory CD8þ T cells.102 I.V. immunoglobulin treatment
protected neurons in experimental stroke models by a mecha-
nism involving suppression of NALP1 and NALP3 inflamma-
some activity.104 Several reports have linked various
polymorphisms in different components of inflammasome-
forming NLRs, including NALP1 and NALP3, to autoimmunity.105
Interestingly, autoimmunity has been suggested as one of the
pathophysiological mechanisms that might underlie CRPS,
because of the compelling evidence that CRPS is associated with
an autoantibody-mediated autoimmune process in some
patients106 and in the CRPS animal model. 107 Moreover, anti-
CD20 (B cell) treatment reduces IL-1 production and nociceptive
responses in a laboratory model of CRPS. 107 Examination and
characterization of the interactive pathways between the
inflammasome and adaptive immunity leading to CRPS may
provide insight into the pathophysiology and optimal treatment
of CRPS.
Gout
Gout is a relatively common inflammatory arthritis, character-
ized by intense pain in the affected joints, and can greatly
impact patient quality of life. It is typically known to occur in
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middle-aged men, yet is increasing in incidence in the elderly
population. 108 Although the initiation and development of gout
is not fully understood, the precipitation of MSU crystals in
joints appears to be a key factor in induction of gout-associated
inflammation.109 Accumulating evidence indicates that orches-
tration of the MSU-induced inflammatory response is depend-
ent on IL-1b. In an animal model of gout, wild-type mice
pretreated with the IL-1 inhibitor rilonacept demonstrated atte-
nuated inflammation after MSU injection into the ankle joint.110
111
Correspondingly, mice deficient in IL-1 receptor failed to
develop gout-like symptoms fully after MSU injection. 110 111 The
recent finding of NALP3 inflammasome in sensing MSU deposi-
tion and subsequent activation of the downstream innate
immune response further demonstrates a role of IL-1b in gout
pathogenesis and hyperalgesia.35
Monocytes, macrophages, and neutrophils are key cells
implicated in the pathogenesis of gout. For instance, macro-
phages initiate the inflammatory response to MSU crystals and
produce inflammatory cytokines and chemokines that induce
migration of blood monocytes to amplify the inflammatory
response further. 110 Neutrophil influx into the synovium and
joint fluid is the pathological hallmark of acute gout. 112 113 It is
clear that NALP3 is expressed in all these cell types, with the
capability to activate an inflammasome-mediated response. In
an MSU-induced murine peritoneal model of acute gout,
Martinon and colleagues 35 observed that macrophages from
mice deficient in various key components of the NALP3 inflam-
masome, including caspase-1, ASC, and NALP3, failed to pro-
duce active IL-1b in response to MSU. Moreover, animals
deficient in NALP3 inflammasome components exhibited
impaired neutrophil influx after i.p. MSU injection. These find-
ings have been confirmed by other laboratories. 114–116 However,
how MSU crystal deposition induces neutrophil influx was not
addressed. Recently, Amaral and colleagues 114 investigated the
sequence of events leading to neutrophil influx in a murine
model of gout induced by joint injection of MSU crystals.
Injection of MSU into joints can also induce leucocyte recruit-
ment in a NALP3/ASC/caspase-1/IL-1b/IL-1R1-dependent man-
ner. Neutrophil influx, dependent on CXCR2 chemokine and
CXCR2 ligand production, was driven by NALP3 inflammasome-
derived IL-1b production. Inhibition of 5-lipoxygenase-derived
leukotriene B4 prevented neutrophil influx, IL-1b production,
and hyperalgesia, but this could not be attributed to a direct
neutrophil-recruiting ability of leukotriene B 4. Neutrophil influx
in gouty inflammation might also be driven by mast cells. 117
Mast cells are able to release IL-1b by activation of the NALP3
inflammasome. 118 Taken together, these results suggest that
the NALP3 inflammasome controls CXCR2 ligand production,
neutrophil influx, and the subsequent pathological hallmark of
an acute gout attack and hyperalgesia. Notably, block of 5-lip-
oxygenase or leukotriene B4 was shown to prevent IL-1b produc-
tion, neutrophil migration, and functional joint impairment.117
Current strategies for targeting IL-1b have proved successful
for alleviating the symptoms of gout in clinical studies, suggest-
ing that targeting this and other components of the pathway
may have an important role in gout treatment. 119–124 Interleukin-
1 inhibitors currently in clinical trials include ana- kinra (IL-1
receptor antagonist), rilonacept (IL-1 Trap, a soluble decoy
receptor), and canakinumab (anti-IL-1b monoclonal anti- body).
Anakinra has been shown to be efficacious for combating acute
gout pain and inflammation, 119 whereas rilonacept has been
revealed to be efficacious in reducing the risk of recurrent
attacks.121 123 124 Canakinumab was found to be efficacious both
in inhibiting pain and inflammation in acute attacks, and for

reducing the risk of recurrent attacks. 120 122 All three IL-1 inhibi-
tors are generally well tolerated.
Rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic autoinflammatory dis-
ease that affects 1–2% of the world’s population and is charac-
terized by chronic pain, warmth, and swelling. 125
Inflammasomes have been linked to RA. For example, enhanced
NALP3 inflammasome activity appears to contribute to the
pathology of RA. 125 126 Patients with active RA have increased
expression of NALP3 and associated IL-1b secretion in whole
blood cells upon stimulation via TLR3 and TLR4 (CFA mice, a
model of RA, had analgesic responses to a TLR4 antagonist). 127
In these patients, IL-1b secretion seems to be predominately
driven by caspase-1 and caspase-8. Targeting NALP3 or down-
stream caspases may be of benefit in suppressing IL-1b produc-
tion in RA.126 Other investigators demonstrated that A20, an RA
susceptibility gene, puts a break in NALP3 and reduces inflam-
masome activation.125 Likewise, excessive NALP3 inflamma-
some activation drives arthritis in A20 knockout mice,
suggesting that A20 mutant mice might be a suitable preclinical
model for validating the effectiveness of experimental therapies
for RA-targeting inflammasomes, IL-1 signalling, or both. 125
Interestingly, in adjuvant arthritic rats, a model of RA, Zhu and
colleagues128 demonstrated NALP1 but not NALP3 inflamma-
some activation in the synovium. The discrepancies may be
because arthritis is a complex disease that may be caused by
different combinations of genetic and environmental triggers.
An additional target may be the AIM2 inflammasome. Arthritis-
prone mice lacking AIM2 displayed strongly decreased signs of
joint inflammation and associated histopathological findings.
This was paralleled by a reduction of caspase-1 activation and
pro-inflammatory cytokine production in diseased joints. 129 In
contrast, systemic signs of inflammation were not dependent
on AIM2. These data suggest a tissue-specific role for the AIM2
inflammasome as a sensor for tissue damage. Ultimately, these
studies suggest that targeting inflammasome activity may
prove beneficial in the clinical treatment of RA.
Blocking of IL-1 has been evaluated in the treatment of RA in
clinical trials. The efficacy of anakinra in patients with RA, alone
or in association with methotrexate, was evaluated in several
controlled studies, all of which demonstrated a significant
reduction in disease severity and pain, an improvement in the
quality of life, and reduction of joint damage and bone ero-
sions.130 131 The treatment is well tolerated; opportunistic infec-
tions are rare compared with those seen with anti-tumour
necrosis factor-a agents. Like anakinra, the anti-IL-1b
monoclonal antibody canakinumab reduces disease severity in
RA patients, including those unresponsive to anti-tumour
necrosis factor-a therapies.132 Unlike anakinra, the long-term
preservation of joint function with canakinumab remains
unstudied.133 These findings seem to be promising and support
the development of a new IL-1b-targeted therapy for more com-
mon inflammatory diseases.
Chronic prostatitis and chronic pelvic pain syndrome
The aetiology, pathogenesis, and optimal treatment of non-
bacterial chronic prostatitis and chronic pelvic pain syndrome
(CP/CPPS) have long been investigated but remain largely
unknown. Chronic prostatitis and chronic pelvic pain syndrome
is a highly prevalent condition, with detrimental effects on the
quality of life.134 The finding of NALP1 in prostate tissue and
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The inflammasome and pain | 701
NALP3 in bladder urothelium provides a new platform to study
innate immunity in CP/CPPS.44 Recently, Chen and colleagues135
evaluated NALP1 and NALP3 inflammasome pathways in the
development of CP/CPPS. The rat CP/CPPS model that mimics
National Insitutes of Health category IIIA prostatitis (i.e. the
most common type of prostatitis) was created by injection of
carrageenan into each prostatic lobe. Tactile hyperalgesia, local
prostate inflammation status, and inflammasome concen-
trations were determined, and it was observed that rats with
CP/CPPS exhibited scrotal static tactile allodynia, increased con-
centrations of NALP1 (but not NALP3), and downstream inflam-
masome proteins such as caspase-1 in the cytoplasm of
glandular epithelium. Application of chlorogenic acid altered
the distribution pattern of NALP1 from glandular epithelium into
the interstitial region and induced an increase in total NALP1 in
the prostate, while reducing caspase-1, IL-1b, and hyperalgesia.
Although elevated concentrations of NALP1 in the interstitial
region may be have been the result of clearance of carrageenan by
migrating cells (i.e. macrophages or lympho- cytes), IL-1b has
previously been shown to be a reliable indicator of CP/CPPS in
clinical studies.136 To investigate inflammasome mediation of
CP/CPPS further, Qi and colleagues137 recently established a new
animal model using prostate extract with alum. As several
reports demonstrate induction of inflamma- some activation by
alum in a NALP3-dependent manner,21 this model may help to
elucidate both the complex aetiology of CP/ CPPS and the role that
inflammasomes are likely to play in the modulation of pain in
CP/CPPS.
Fibromyalgia
Fibromyalgia (FM) represents a prevalent chronic pain syn-
drome characterized by generalized hyperalgesia associated
with a wide spectrum of symptoms, such as fatigue and joint
stiffness.138 Fibromyalgia affects 2–4% of the population, mostly
women. Diagnosis and treatment of FM can be difficult, as both
the aetiology and the pathogenesis of FM remain largely
unclear. Oxidative stress, mitochondrial dysfunction, bioener-
getic alterations, and inflammation have all been proposed as
contributing to the symptomatology of FM. 139 140 Cordero and
colleagues141 recently investigated the role of coenzyme Q 10
deficiency and mitochondrial dysfunction in inflammasome
activation in blood cells from patients with FM, and coenzyme
Q10 deficiency animal models. They observed that mitochon-
drial dysfunction was accompanied by the activation of NALP3
and caspase-1 and by increased concentrations of IL-1b and IL-
18 in cells from patients with FM and from an animal model of
FM. Coenzyme Q10 deficiency induced by p-aminobenzoate
treatment resulted in NALP3 inflammasome activation in blood
mononuclear cells that occurred with marked hyperalgesia in
mice. A placebo-controlled trial of coenzyme Q 10 in FM patients
resulted in reduced NALP3 inflammasome activation and
decreased IL-1b and IL-18 serum concentrations, suggesting
that NALP3 inflammasome-mediated pathogenesis of FM is
likely to be regulated by coenzyme Q 10 activation of the NALP3
inflammasome.
The contribution of the NALP3 inflammasome to pain in FM
is supported by a recent observation from Bullón and
colleagues,142 who demonstrated that adenosine
monophosphate-activated protein kinase (AMPK) phosphora-
tion modulated pain by activation of the NALP3 inflammasome.
Deficient AMPK activation and overactivation of the NALP3
inflammasome axis were also observed in blood cells from
patients with FM.129 In addition, metformin treatment, which
 702 | Zhang et Al.

increased AMPK activation, restored all biochemical alterations
in blood cells and significantly improved clinical symptoms,
such as pain, fatigue, depression, disturbed sleep, and tender
points, in FM patients. 142 A recent report regarding mutation in
cytochrome b gene of mitochondrial DNA in FM patients with
NALP3 inflammasome activation also supports this hypothe-
sis.143 Alternatively, elevated substance P concentrations in
patients with FM have been the focus of therapeutic trials. 144 145
It has been shown that substance P enhances the activation of
AMPK in vitro,146 and substance P controls NALP1 inflamma-
some activation after fracture.99 Finally, an inflammasome–
microglial activation mechanism was also proposed in FM. 147
Collectively, these studies suggest that inhibition of NALP3
inflammasome activity by coenzyme Q 10 and AMPK activators
may be a potentially effective therapy for the specific and non-
specific pain states associated with FM.
Conclusions and future perspectives
The discovery of inflammasomes has provided a new avenue
for investigating the molecular mechanisms underlying innate
immune system activation in infectious, autoinflammatory,
metabolic, and neurodegenerative diseases. As these diseases
are commonly associated with pain, modulators of innate
immunity may provide effective pain relief. Although our
understanding of the role of inflammasomes in pain is in the
early stages, a review of the currently available literature sug-
gests that collectively, dysregulation in inflammasome activity
plays a central role in inflammatory pain, neuropathic pain,
CRPS, gout, rheumatoid arthritis, fibromyalgia, and CP/CPPS.
Therefore, we conclude from this review of the literature that
targeting inflammasomes in these specific pain-associated dis-
ease states may indeed prove to be a novel approach to the con-
trol of pain.
It is also clear from this review that different inflammasome
subtypes are recruited and modulate pain in different diseases
(Fig. 2). In general IL-1b can act directly or indirectly as an inter-
mediate inflammatory mediator serving to upregulate down-
stream cytokines and directly activate nociceptive neurons. 1 7 8
10
Targeting inflammasome subtypes in specific diseases may
more efficiently modulate activation of IL-1 and IL-18 and there-
fore more effectively inhibit downstream cytokine cascades
compared with traditional therapies aimed at countering the
effect of individual cytokines. Furthermore, the IL-1 inhibitors
anakinra, rilonacept, and canacinumab targeting IL-1 are not
specific to NALP inflammasome activity and cause general
immune suppression. 148 A therapeutic approach involving the
targeting of inflammasome subtypes in specific diseases may be
superior to the currently used antibody-based therapies, by
avoiding universal suppression of IL-1 activation by other
inflammasome-forming NLRs. Unfortunately, no specific inhibi-
tor is available clinically; although both endogenous and syn-
thetic inflammasome inhibitors have been described, this
would be a big obstacle for taming the inflammasome via tar-
geted manipulation of the inflammasome complex using a spe-
cific inhibitor. However, two potent and specific inhibitors of
NALP3 were described recently, thus constituting promising
candidates for clinical testing. 149 Other questions also remain.
For example, although many NALPs have been demonstrated to
modulate caspase-1 activity in animal pain models and in vitro,
the precise physiological mechanisms of inflammasome activa-
tion in patients with pain remain obscure. Delineating these
mechanisms would therefore permit more specific anti-
inflammasome therapies for specific pain states. Moreover,
although four inflammasome subtypes had been identified to
play a role in pain (i.e. NLRP1, NLRP3, NLRC4, and AIM2),150 up to
eight inflammasome subtypes have so far been described. 43
Future investigations delineating the specific role of these other

Gout, RA, FM, Acute Carrageenan

Neuropathic pain, Chronic
intracranial inflammation, induced acute
CRPS polyarthritis
CP/CPPS inflammatory pain

MSU
Alum ATP and P2XRs
LPS Pannexin Carrageenan Self- DNA
Low intracellular [K+] SP, CGRP
AMPK
CoQ10 deficiency

NALP3 NALP1 NLRC4 AIM2

inflammasome inflammasome inflammasome inflammasome

PAIN

Fig 2 Schematic overview of proposed inflammasome activation mechanisms in pain. The different inflammasomes are recruited and impl icated in the pain in
response to a variety of triggers. DAMPs, MSU, alum, low intracellular Kþ concentration, AMPK, and coenzyme Q10 (CoQ10) deficiency are thought to activate the
NALP3 inflammasome, contributing to pain in gout, FM, acute intracranial inflammation, and CP/CPPS, respectively; Purinergic signalling and P2XRs, pannexin,
SP, and calcitonin gene-related peptide are thought to activate the NALP1 inflammasome, contributing to neuropathic pain, CRPS, and adjuvant arthriti c pain,
respectively. The NLRC4 inflammasome activation contributes to pain in a model of (carrageenan-induced) acute inflammation. The AIM2 inflammasome activa-
tion triggered by endogenous DNA drives chronic polyarthritis.

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subtypes in modulating pain may also aid in developing tar-
geted therapies. An additional exciting frontier may be to
exploit apparent differences in inflammasome subtypes
between diseases to achieve tissue specificity when designing
pharmaceutical therapies. Continued research into the mecha-
nisms of inflammasome activation in specific pain-associated
diseases will be likely to aid in developing precision medicines
for the treatment of diseases in which pain secondary to inflam-
mation is a known component.
Authors’ contributions
Study design/planning and writing the paper: H.Z., F.L., W.-W.L.,
S.X., X.X.
Study conduct: H.Z., F.L.
Revising paper: H.Z., F.L., W.-W.L., C.S., J.D.C., S.X., X.X.
Declaration of interest
None declared.
Funding
Guangdong Natural Science Foundation, PR China
(2015A030313258 to H.Z.); American Heart Association (14FTF-
19970029 to C.S.); National Institutes of Health (NS072143,
GM079126 to J.D.C.); and National Natural Science Foundation of
China, Beijing, PR China (81571147 to X.X. and 81501082 to F.L.).
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