REVIEW

published: 05 November 2015

doi: 10.3389/fphar.2015.00262

NLRP3 inflammasome and its

inhibitors: a review
Bo-Zong Shao† , Zhe-Qi Xu† , Bin-Ze Han † , Ding-Feng Su and Chong Liu *

Department of Pharmacology, Second Military Medical University, Shanghai, China

Inflammasomes are newly recognized, vital players in innate immunity. The best
characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in
the complex belongs to the family of nucleotide-binding and oligomerization domain-
like receptors (NLRs) and is also known as “pyrin domain-containing protein 3”.
The NLRP3 inflammasome is associated with onset and progression of various
diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease,
cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-
inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described,
some of which show promise in the clinic. The present review will describe the structure
and mechanisms of activation of the NLRP3 inflammasome, its association with various
auto-immune and auto-inflammatory diseases, and the state of research into NLRP3
Edited by: inflammasome inhibitors.
Wenliang Song,
Bridgeport Hospital and Yale Keywords: NLRP3 inflammasome, inhibitor, autophagy, MCC950, BHB, interferon
University, USA
Reviewed by:
Lydia E. Matesic, INTRODUCTION
University of South Carolina, USA
Xue Liang, The mammalian immune system defends against internal and external threats using innate
University of Pennsylvania, USA immunity and adaptive immunity (Neill et al., 2010). The innate immune response relies on
*Correspondence: pattern-recognition receptors (PRRs) to target pathogenic microbes and other endogenous or
Chong Liu exogenous pathogens. PRRs are expressed mainly in immune and inflammatory cells such as
wanlc2004@aliyun.com monocytes, macrophages, neutrophils, and dendritic cells (DCs) (Schroder and Tschopp, 2010;
† These authors have contributed Fullard and O’Reilly, 2015). They present antigens to the adaptive immune system to generate
equally to this work. long-lasting protection (Alexandre et al., 2014). Pathogen-associated molecular patterns (PAMPs),
which are antigens common to a given group of pathogens (Medzhitov, 2009; Abderrazak et al.,
Specialty section: 2015b), are normally recognized by at least three PRRs: Toll-like receptors (TLRs), C-type lectins
This article was submitted to (CTLs), and Galectins (Bourgeois and Kuchler, 2012; Dzopalic et al., 2012). The innate immune
Inflammation Pharmacology, system is evolutionarily conserved across vertebrates and invertebrates, which means that both
a section of the journal
human and animal studies can provide valuable insights into innate immunity (Dai et al., 2015).
Frontiers in Pharmacology
A newly identified PRR, first described in detail in 2002, is the inflammasome (Martinon
Received: 05 September 2015 et al., 2002; Gentile et al., 2015; Jorgensen and Miao, 2015; Sanders et al., 2015). Numerous
Accepted: 22 October 2015
inflammasomes have been identified, including NLRP1, NLRP2, NLRP3, double-stranded DNA
Published: 05 November 2015
(dsDNA) sensors absent in melanoma 2 (AIM2) and NLRC4 (Ozaki et al., 2015). The best
Citation:
characterized is the NLRP3 inflammasome, so named because the NLRP3 protein in the complex
Shao B-Z, Xu Z-Q, Han B-Z, Su D-F
and Liu C (2015) NLRP3
belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs)
inflammasome and its inhibitors: and is also known as “pyrin domain-containing protein 3” (Inoue and Shinohara, 2013b;
a review. Front. Pharmacol. 6:262. Eigenbrod and Dalpke, 2015). In addition to the NLRP3 protein, the NLRP3 inflammasome
doi: 10.3389/fphar.2015.00262 also contains adapter protein apoptosis-associated speck-like protein (ASC) and procaspase-1

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Shao et al. NLRP3 inflammasome and inhibitors

(Inoue and Shinohara, 2013a; Ito et al., 2015). Interactions among In the first model, extracellular adenosine triphosphate (ATP),
these three proteins tightly regulate inflammasome function in which acts as an NLRP3 agonist, induces K+ efflux through
order to ensure immune activity only when appropriate. a purogenic P2X7-dependent pore consisting of a pannexin-
In the absence of immune activators, an internal interaction 1 hemichannel. This process leads to NLRP3 inflammasome
occurs between the NACHT domain and leucine-rich repeats activation and assembly. Consistent with this model, K+ efflux
(LRRs), suppressing the interaction between NLRP3 and ASC, is a major activator of the NLRP3 inflammasome, while
thus preventing assembly of the inflammasome (Inoue and extracellular ATP and pore-forming toxins are the major triggers
Shinohara, 2013a). In the presence of immune activators such of IL-1β secretion by the inflammasome (Hari et al., 2014;
as PAMPs, danger-associated molecular patterns (DAMPs), other Liu et al., 2014; Ketelut-Carneiro et al., 2015; Schmid-Burgk
exogenous invaders or environmental stress, NLRP3 opens up et al., 2015). Fluxes of intracellular and endoplasmic reticulum
and allows interaction between the pyrin domains (PYDs) in (ER)-related Ca2+ may also activate the NLRP3 inflammasome
NLRP3 and ASC. Subsequently the caspase recruitment domain (Hussen et al., 2012; Zhong et al., 2013b; Shenderov et al., 2014).
(CARD) of ASC binds to the CARD domain on procaspase- In the second model, all known PAMPs and DAMPs, including
1, giving rise to the NLRP3 inflammasome. Formation of the activators mentioned above, trigger the generation of reactive
this complex triggers procaspase-1 self-cleavage, generating oxygen species (ROS), which in turn induce assembly of the
the active caspase-1 p10/p20 tetramer and inducing the NLRP3 inflammasome. For example, damage to NADPH oxidase
conversion of proinflammatory cytokines interleukin (IL)- and other oxidative systems by mitochondrial ROS can activate
1β and IL-18 from their immature “pro” forms to active the inflammasome (van Bruggen et al., 2010; Crane et al., 2014;
forms that are secreted. Formation of the inflammasome Lawlor and Vince, 2014; Rajanbabu et al., 2015).
also triggers a process of inflammation-related cell death In the third model, assembly and activation of the NLRP3
termed pyroptosis (Willingham et al., 2009; Schroder and inflammasome is thought to be triggered by environmental
Tschopp, 2010; Zhong et al., 2013a; Jorgensen and Miao, irritants (such as silica, asbestos, amyloid-β, and alum) which
2015). form crystalline or particulate structures when engulfed by
phagocytes. These aggregates cause lysosomal rupture and release
of lysosomal contents via a mechanism mediated by cathepsin B.
Consistent with this model, crystalline stimuli such as silica are
ACTIVATION OF THE NLRP3
major triggers of IL-1β secretion by the inflammasome.
INFLAMMASOME Other factors can also activate the NLRP3 inflammasome.
These include mitochondrial damage or dysfunction caused by
Models of NLRP3 Inflammasome mitochondrial Ca2+ overload (Iyer et al., 2013; Miao et al., 2014;
Activation Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008;
The NLRP3 inflammasome is present primarily in immune Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction
and inflammatory cells following activation by inflammatory (Cho et al., 2014; Shao et al., 2014; Jabir et al., 2015) and the
stimuli; these cells include macrophages, monocytes, DCs, activity of thioredoxin-interacting protein (TXNIP; Li et al., 2015;
and splenic neutrophils (Guarda et al., 2011b; Zhong et al., Liu et al., 2015).
2013a). Activation of the NLRP3 inflammasome appears to
occur in two steps (Zhong et al., 2013a; Sutterwala et al., The NLRP3 Inflammasome in Disease
2014; Ozaki et al., 2015; Figure 1). The first step involves While the innate immune response to insults can efficiently
a priming or initiating signal in which many PAMPs or protect against disease and death, inappropriate activation
DAMPs are recognized by TLRs, leading to activation of of the NLRP3 inflammasome can contribute to the onset
nuclear factor kappa B (NF-κB)-mediated signaling, which and progression of various diseases, particularly age-related
in turn up-regulates transcription of inflammasome-related diseases such as metabolic disorders and metabolic syndrome
components, including inactive NLRP3, proIL-1β, and proIL- (Franceschi et al., 2000; Goldberg and Dixit, 2015). Increased
18 (Bauernfeind et al., 2009; Franchi et al., 2012, 2014). This production of IL-1β and IL-18 by the NLRP3 inflammasome
priming step is often studied in vitro using lipopolysaccharide contributes to atherosclerotic plaque progression and instability
(LPS; Park et al., 2015). The second step of inflammasome in atherosclerotic patients and animal models (Altaf et al.,
activation is the oligomerization of NLRP3 and subsequent 2015; Patel et al., 2015; Peng et al., 2015). For example,
assembly of NLRP3, ASC, and procaspase-1 into a complex. Patel et al. (2015) showed that genetic ablation of the NLRP3
This triggers the transformation of procaspase-1 to caspase-1, inflammasome suppressor known as the inhibitor of κB kinase
as well as the production and secretion of mature IL-1β and epsilon (IKBKE) enhanced the acute phase response and
IL-18 (Kim et al., 2015; Ozaki et al., 2015; Rabeony et al., down-regulated cholesterol metabolism in cultured macrophages
2015). and hypercholesterolemic mice. Atherosclerosis and other
Three models have been proposed to describe the second step inflammatory diseases were more severe in animals with the
of inflammasome activation, as described in detail by Schroder ablation.
and Tschopp (2010) (shown in Figure 1). Briefly, all models Studies in macrophages and animal models have shown that
assume that NLRP3 does not directly interact with exogenous oxidized low-density lipoprotein and cholesterol crystals trigger
activators, consistent with its ability to sense various pathogens. NLRP3 inflammasome activation (Duewell et al., 2010; Liu et al.,

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Shao et al. NLRP3 inflammasome and inhibitors

FIGURE 1 | Schematic illustration of the NLRP3 inflammasome activation. Upon exposure to pathogen-associated molecular patterns (PAMPs) or
danger-associated molecular patterns (DAMPs), Toll-like receptors (TLRs) are phosphorylated and subsequently activate NF-κB. In the nucleus, NF-κB promotes the
transcription of NLRP3, proIL-1β, and proIL-18, which, after translation, remain in the cytoplasm in inactive forms. Thus, this signal (depicted in red as “Signal 1”) is a
priming event. A subsequent stimulus (shown as “Signal 2” in black) activates the NLRP3 inflammasome by facilitating the oligomerization of inactive NLRP3,
apoptosis-associated speck-like protein (ASC), and procaspase-1. This complex, in turn, catalyzes the conversion of procaspase-1 to caspase-1, which contributes
to the production and secretion of the mature IL-1β and IL-18. Three models have been proposed to describe the second step of inflammasome activation:
(1) Extracellular ATP can induce K+ /potassium efflux through a purogenic P2X7-dependent pore, which, leads to the assembly and activation of the NLRP3
inflammasome. Calcium flux is also involved in this process. (2) PAMPs and DAMPs trigger the generation of ROS that promote the assembly and activation of the
NLRP3 inflammasome. (3) Phagocytosed environmental irritants form intracellular crystalline or particulate structures leading to lysosomal rupture (magenta box) and
release of lysosomal contents like cathepsin B. These induce NLRP3 inflammasome assembly and activation. In addition, other factors and mechanisms have been
implicated in the assembly and activation of the NLRP3 inflammasome, including mitochondrial damage, autophagic dysfunction, and thioredoxin-interacting protein
(TXNIP).

2014). In macrophage and animal models of type II diabetes, including cerebral ischemia/stroke and myocardial ischemia
hyperglycemia, and free fatty acids trigger inflammasome (Sandanger et al., 2013; Marchetti et al., 2014; Hecker et al.,
activation, which harms glucose metabolism and strengthens 2015; Ito et al., 2015). Inflammasome activation appears to
insulin resistance (Honda et al., 2014; Legrand-Poels et al., 2014; contribute to post-ischemic inflammation after stroke. For
Ruscitti et al., 2015). In macrophage and animal models of example, Ito et al. (2015) showed that using ibrutinib to inhibit
uric acid accumulation, monosodium urate crystals activate the Bruton’s tyrosine kinase (BTK), an essential component of the
NLRP3 inflammasome, causing gout (Hari et al., 2014; Wang NLRP3 inflammasome, reduced infarct volume, and neurological
et al., 2014; Cleophas et al., 2015). Taken together, these findings damage in a mouse model of cerebral ischemia/reperfusion
suggest that during the progression of many metabolic diseases, injury. In addition, it is reported by Hecker et al. (2015)
the accumulation of abnormal metabolic products activates that activation of nicotinic acetylcholine receptors containing
the NLRP3 inflammasome. Studies in animal models suggest subunits α7, α9, and/or α10 inhibited ATP-mediated IL-1β
a similar picture in Alzheimer’s disease (Vajjhala et al., 2012; release by human and rat monocytes, helping protect them from
Schnaars et al., 2013; Cho et al., 2014) and obesity induced collateral damage. NLRP3 inflammasome-related proteins are
by a high-fat diet (Haneklaus and O’Neill, 2015; Zhang et al., up-regulated in myocardial fibroblasts following infarction, and
2015). this up-regulation may contribute to infarct size in ischemia-
In macrophages and in animal models, studies have also reperfusion injury (Sandanger et al., 2013). Consistent with this
defined a role for the NLRP3 inflammasome in the initiation idea, inhibiting the NLRP3 inflammasome reduces myocardial
and development of cerebral and myocardial ischemic diseases, injury after ischemia-reperfusion in mice (Marchetti et al., 2014).

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Shao et al. NLRP3 inflammasome and inhibitors

NLRP3 inflammasome activation has also been linked TABLE 1 | Potential mechanisms of several NLRP3 inflammasome
inhibitors.
to various auto-immune and auto-inflammatory diseases.
Work from our laboratory and others has demonstrated that NLRP3 inflammasome inhibitor Potential mechanisms involving NLRP3
NLRP3 inflammasome activation contributes to progression of inflammasome inhibition
multiple sclerosis in humans and experimental autoimmune
Small- MCC950 Blocking apoptosis-associated speck-like
encephalomyelitis (EAE) in animal models (Ming et al., 2002; molecule protein (ASC) oligomerization,
Jha et al., 2010; Lalor et al., 2011; Inoue et al., 2012a,b; inhibitor Inhibiting of canonical and non-canonical
Shao et al., 2014). Severity of multiple sclerosis in patients NLRP3 inflammasome;
correlates closely with levels of IL-1β, IL-18, and caspase-1
(Ming et al., 2002; Jha et al., 2010; Lalor et al., 2011); the BHB Blocking ASC oligomerization,
Inhibiting K+ /potassium efflux;
serum levels of both ILs and of active caspase-1 (p20) are
elevated in mice with EAE (Inoue et al., 2012a,b). Studies
Type I interferon (IFN) and IFN-β Inducting phosporylation of STAT1,
in macrophages and mouse models of colitis have linked transcription factor,
abnormal NLRP3 inflammasome activation with inflammatory Inducting IL-10 production;
bowel disease, including ulcerative colitis and Crohn’s disease
(Cheng et al., 2015; Guo et al., 2015; Sun et al., 2015). Autophagy Resveratrol Inducing autophagy process,
Polymorphism in the NLRP3 gene is linked to colitis severity inducer Suppressing mitochondrial damage;

and progression in patients (Villani et al., 2009; Lewis et al.,

Arglabin Inducing autophagy process,
2011), and gain-of-function mutations in the NLRP3 gene Reducing cholesterol level;
that increase production and secretion of IL-1β and IL-
18 are associated with cryopyrin-associated periodic fever CB2R agonist Inducing autophagy process,
syndrome (CAPS; Bozkurt et al., 2015; Carta et al., 2015; Inhibiting priming step of NLRP3
Zhou et al., 2015). This syndrome comprises several rare inflammasome activation;
hereditary auto-inflammatory diseases in humans and animal
MicroRNA MicroRNA-223 Suppressing NLRP3 protein expression.
models, including familial cold auto-inflammatory syndrome and
Muckle–Wells syndrome. Inhibiting IL-1 using specific blocking
agents effectively reduces systemic inflammation in CAPS
patients (Kuemmerle-Deschner, 2015; Yadlapati and Efthimiou, dependent on the cytoplasmic LPS sensors caspase-4 and caspase-
2015). 5. Krishnan et al. (2015) demonstrated that hypertension in mice
treated with salt and deoxycorticosterone acetate can be reversed
by treating them with MCC950, and this reversal depends on
PHARMACOLOGICAL USE OF NLRP3 the inhibition of inflammasome activation and inflammasome-
INFLAMMASOME INHIBITORS related IL-1β production.
Youm et al. (2015) discovered that the ketone metabolite
The extensive involvement of the NLRP3 inflammasome in β-hydroxybutyrate (BHB), but not acetoacetate or the short-
such a range of diseases makes it a highly desirable drug chain fatty acids butyrate and acetate, reduced IL-1β, and IL-18
target. Fortunately numerous promising inhibitors of NLRP3 production by the NLRP3 inflammasome in human monocytes.
inflammasome activation have been described, several of which Like MCC950, BHB appears to block inflammasome activation
are briefly described below together with their pharmacological by inhibiting NLRP3-induced ASC oligomerization. Their in vivo
mechanisms (shown in Table 1). experiments showed that BHB or a ketogenic diet alleviate
caspase-1 activation and caspase-1-mediated IL-1β production
MCC950 and β-Hydroxybutyrate and secretion, without affecting the activation of NLRC4 or
Two small-molecule inhibitors of the NLRP3 inflammasome AIM2 inflammasomes. BHB inhibits NLRP3 inflammasome
were described in groundbreaking reports in Nature Medicine activation independently of AMP-activated protein kinase,
this year (Coll et al., 2015; Youm et al., 2015). Coll et al. ROS, autophagy, or glycolytic inhibition. These studies raise
(2015) discovered that MCC950, a diarylsulfonylurea-containing interesting questions about interactions among ketone bodies,
compound known to inhibit caspase-1-dependent processing metabolic products, and innate immunity. BHB levels increase
of IL-1β (Perregaux et al., 2001), also inhibits both canonical in response to starvation, caloric restriction, high-intensity
and non-canonical activation of the NLRP3 inflammasome. exercise, or a low-carbohydrate ketogenic diet (Cotter et al.,
MCC950 inhibits secretion of IL-1β and NLRP3-induced ASC 2013). Vital organs such as the heart and brain can exploit
oligomerization in mouse and human macrophages. It reduces BHB as an alternative energy source during exercise or caloric
secretion of IL-1β and IL-18, alleviating the severity of EAE deficiency. Future studies should examine how innate immunity,
and CAPS in mouse models. Coll et al. (2015) further showed particularly the inflammasome, is influenced by ketones and
that MCC950 acts specifically on the NLRP3 inflammasome: other alternative metabolic fuels during periods of energy
it does not inhibit the activation of NLRP1, AIM2, or NLRC4 deficiency (Shido et al., 1989; Johnson et al., 2007; McGettrick
inflammasomes. Baker et al. (2015) have shown that MCC950 and O’Neill, 2013; Mercken et al., 2013; Newman and Verdin,
inhibits LPS-induced production of IL-1β via a mechanism 2014).

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Shao et al. NLRP3 inflammasome and inhibitors

Although both MCC950 and BHB inhibit NLRP3 Type I IFN treatment is not effective for all types of
inflammasome activation, their mechanisms differ in key multiple sclerosis, and the NLRP3 inflammasome may be a
respects. BHB inhibits K+ efflux from macrophages, while key determinant. Inoue et al. (2012b) conducted studies on
MCC950 does not. MCC950 inhibits both canonical and non- mouse primary macrophage cultures as well as EAE mice and
canonical inflammasome activation, while BHB affects only concluded that IFN-β therapy is effective only when the NLRP3
canonical activation. Nevertheless both inhibitors represent a inflammasome contributes directly to the disease process. Their
significant advance toward developing therapies that target IL-1β studies further showed that IFNAR activation could be inhibited
and IL-18 production by the NLRP3 inflammasome in various using the suppressor of cytokine signal 1 (SOCS1), which
diseases (Netea and Joosten, 2015). inhibited Rac1 activation and ROS generation, leading in turn to
inhibition of NLRP3 inflammasome activity and less severe EAE.
Type I Interferon (IFN) and IFN-β These studies highlight the efficacy of type I IFN therapy
In contrast to these newly described, NLRP3-specific and the need for future studies to elucidate the mechanisms
inflammasome inhibitors, type I interferons (IFNs), including of NLRP3 inflammasome inhibition. This work may improve
IFN-α and IFN-β, have been used for some time to inhibit the clinical approaches to treating multiple sclerosis and other auto-
NLRP3 and other inflammasomes in various auto-immune and immune and auto-inflammatory diseases.
auto-inflammatory diseases. These diseases include multiple
sclerosis, systemic-onset juvenile idiopathic arthritis caused Other Kinds of NLRP3 Inflammasome
by gain-of-function NLRP3 mutations, rheumatic diseases and Inhibitors
familial-type Mediterranean fever (Guarda et al., 2011a; Inoue Several additional ways for inhibiting the NLRP3 inflammasome
et al., 2012b; Inoue and Shinohara, 2013b; Malhotra et al., have opened up in recent years. Autophagy, a self-protective
2015; van Kempen et al., 2015). Type I IFNs are produced by catabolic pathway involving lysosomes, has been shown to
specialized immune cells such as macrophages and DCs in inhibit the NLRP3 inflammasome, leading researchers to explore
response to extracellular stimuli such as bacteria and virus as well the usefulness of autophagy-inducing treatments (Shao et al.,
as various environmental irritants (Meylan et al., 2006). These 2014). Chang et al. (2015) showed that the plant polyphenolic
IFNs are recognized by the type I IFN receptor (IFNAR), which compound resveratrol, known to induce autophagy, suppresses
is a member of the TLR family and is composed of the subunits mitochondrial damage in macrophages and thereby inhibits
IFNAR1 and IFNAR2. IFNAR activation involves several NLRP3 inflammasome activation and NLRP3 inflammasome-
proteins, including Janus kinases, tyrosine kinase 2, and several mediated IL-1β secretion and pyroptosis. Abderrazak et al.
kinds of signal transducers and activators of transcriptions (2015a) showed that arglabin inhibits the production and
(STATs). However, how type I IFNs affect NLRP3 inflammasome secretion of IL-1β and IL-18 by the NLRP3 inflammasome in a
and its production of IL-1β and IL-18 remains unclear (Guarda concentration-dependent manner in ApoE−/− mice on a high-
et al., 2011a), despite numerous studies aimed to improve fat diet. The reduced IL production translates to less severe
IFN-based treatments of NLRP3 inflammasome-related diseases. atherosclerosis. Those authors reported that arglabin exerts its
To provide an example of progress in this area, we focus below effects in macrophages by inducing autophagy as well as by
on studies of IFN therapy against multiple sclerosis in patients reducing inflammation and cholesterol levels.
and EAE in mice, since type I IFN therapy has been used as a Cannabinoid receptor 2 (CB2R) is an already demonstrated
first-line or standard treatment of multiple sclerosis for 15 years therapeutic target in inflammation-related diseases (Smoum
(Inoue et al., 2012b). et al., 2015). Work from our own laboratory (Shao et al., 2014) has
Malhotra et al. (2015) classified 97 patients with multiple shown that autophagy induction may help explain why activation
sclerosis into those who responded to IFN-β therapy and of the anti-inflammatory CB2R leads to inhibition of NLRP3
those who did not, based on clinico-radiological criteria at 12 inflammasome priming and activation in mouse BV2 microglia
and 24 months of treatment. They found that expression of stimulated with LPS and ATP as well as in a mouse model of
NLRP3 protein and levels of IL-1β were significantly lower EAE. Such CB2R activation reduces the severity of EAE in mice.
among responsive patients who had relapsing-remitting multiple Thus CB2R agonists similar to the HU-308 used in our work may
sclerosis than among other patients. Guarda et al. (2011a) found become an effective therapy for treating NLRP3 inflammasome-
that IL-1β production by primary monocytes was lower in related diseases by inducing autophagy.
multiple sclerosis patients on IFN-β treatment than in healthy MicroRNAs may provide another route for inhibiting
subjects, supporting the value of IFN-β therapy. Studies in mouse inflammasomes. These endogenous non-coding RNAs are 20–
bone marrow-derived macrophages by Guarda et al. (2011a) 23 nt long and bind to the 3 untranslated region (3
suggest that IFN-β may inhibit IL-1β production through at least UTR) of protein-coding mRNAs to regulate their translation
two mechanisms. In one pathway, phosphorylation of STAT1 (Bartel, 2009; Chen and Sun, 2013). MicroRNA-223 binds to
transcription factor leads to repression of NLRP1 and NLRP3 a conserved site in the 3 UTR of the NLRP3 transcript,
inflammasomes, which in turn inhibits caspase-1-dependent IL- suppressing protein expression and thereby inhibiting NLRP3
1β maturation. In the second pathway, type I IFNs induce IL-10 inflammasome priming and IL-1β production (Bauernfeind
production via a STAT-dependent mechanism, and the IL-10 et al., 2012; Haneklaus et al., 2012; Chen and Sun, 2013).
works in an autocrine fashion to reduce levels of pro-IL-1α and Deficiency in microRNA-223 leads to neutrophilia, spontaneous
pro-IL-1β via a mechanism dependent on STAT3 signaling. lung inflammation, and increased susceptibility to endotoxin

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Shao et al. NLRP3 inflammasome and inhibitors

challenge in mice (Johnnidis et al., 2008; Haneklaus et al., potential inhibitors require further development, such as
2013). Several other microRNAs have been reported to be autophagy-inducing and microRNA agents. This highlights
involved in the activation of the NLRP3 inflammasome, the need for further research into what pathways activate
including microRNA-155, microRNA-377, and microRNA-133a- the NLRP3 inflammasome and can therefore be targeted by
1. Reducing the levels of these factors may be useful for treating appropriate inhibitors. There is still a long way to go toward
inflammasome-related disease (Bandyopadhyay et al., 2013; Chen exploiting NLRP3 inflammasome inhibitors in our fight against
et al., 2015; Wang et al., 2015). diseases.

CONCLUSION AUTHOR CONTRIBUTIONS

The past decade has witnessed tremendous progress in B-ZS and Z-QX were in charge of searching all the relative papers
understanding the structure and activation of the NLRP3 and writing this manuscript. B-ZH was in charge of drawing the
inflammasome, as well as its roles in the initiation and picture. CL gave her valuable and professional suggestions and
progression of various auto-immune and auto-inflammatory guide in organizing and drafting this manuscript. D-FS helped to
diseases, including metabolic disorders, multiple sclerosis, revise the manuscript.
inflammatory bowel syndrome, and CAPS. Several types of
NLRP3 inflammasome inhibitors have been developed and
validated in cell culture studies and animal models of NLRP3 ACKNOWLEDGMENT
inflammasome-related diseases, and type I IFNs have become
well established in the clinic. On the other hand, several This work was supported by a grant from the Shanghai Natural
agents have proven ineffective in clinical settings, and several Science Foundation of China (13ZR1448400).

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Frontiers in Pharmacology | www.frontiersin.org 9 November 2015 | Volume 6 | Article 262