Review ArticleNLRP3 inflammasome:From a danger signal sensor to a regulatorynode of oxidative stress and inflammatory diseasesAmna Abderrazaka,b,c,Tatiana Syrovetsd,Dominique Couchiea,b,c,Khadija El Hadria,b,c,Bertrand Frigueta,b,c,Thomas Simmetd,Mustapha Rouisa,b,c,naSorbonne Universits,UPMC Univ Paris 06,UMR 8256,Biological Adaptation and Ageing-IBPS,F-75005 Paris,FrancebCNRS-UMR 8256,F-75005 Paris,FrancecInserm U1164,F-75005 Paris,FrancedInstitute of Pharmacology of Natural Products&Clinical Pharmacology,Ulm University,D-89081 Ulm,Germanya r t i c l e i n f oArticle history:Received 2 December 2014Received in revised form11 January 2015Accepted 12 January 2015Available online 14 January 2015Keywords:NLRP3 inflammasome(PDB id:Q96P20)IL-1(PDB id:P01584,P10749)IL-18(PDB id:Q14116)ObesityCardiovascular diseasesa b s t r a c tIL-1 production is critically regulated by cytosolic molecular complexes,termed inflammasomes.Dif-ferent inflammasome complexes have been described to date.While all inflammasomes recognize certain pathogens,it is the distinctive feature of NLRP3 in-flammasome to be activated by many and diverse stimuli making NLRP3 the most versatile,and im-portantly also the most clinically implicated inflammasome.However,NLRP3 activation has remainedthe most enigmatic.It is not plausible that the intracellular NLRP3 receptor is able to detect all of itsmany and diverse triggers through direct interactions;instead,it is discussed that NLRP3 is responding tocertain generic cellular stress-signals induced by the multitude of molecules that trigger its activation.An ever increasing number of studies link the sensing of cellular stress signals to a direct pathophysiologicalrole of NLRP3 activation in a wide range of autoinflammatory and autoimmune disorders,and thus provide anovel mechanistic rational,on how molecules trigger and support sterile inflammatory diseases.Avast interesthas created to unravel how NLRP3 becomes activated,since mechanistic insight is the prerequisite for aknowledge-based development of therapeutic intervention strategies that specifically target the NLRP3 trig-gered IL-1 production.In this review,we have updated knowledge on NLRP3 inflammasome assembly andactivation and on the pyrin domain in NLRP3 that could represent a drug target to treat sterile inflammatorydiseases.We have reported mutations in NLRP3 that were found to be associated with certain diseases.Inaddition,we have reviewed the functional link between NLRP3 inflammasome,the regulator of cellular redoxstatus Trx/TXNIP complex,endoplasmic reticulum stress and the pathogenesis of diseases such as type 2 dia-betes.Finally,we have provided data on NLRP3 inflammasome,as a critical regulator involved in the patho-genesis of obesity and cardiovascular diseases.&2015 The Authors.Published by Elsevier B.V.This is an open access article under the CC BY-NC-ND license(http:/creativecommons.org/licenses/by-nc-nd/4.0/).Contents lists available at ScienceDirectjournal homepage: Biologyhttp:/dx.doi.org/10.1016/j.redox.2015.01.0082213-2317/&2015 The Authors.Published by Elsevier B.V.This is an open access article under the CC BY-NC-ND license(http:/creativecommons.org/licenses/by-nc-nd/4.0/).Abbreviations:Alum,aluminum hydroxide;ATMs,adipose tissue macrophages;ATP,adenosine triphosphate;ApoE,murin apolipoprotein E;ASC,Apoptosis-associatedSpeck-like protein containing a Caspase-recruitment domain;CARD,caspase recruitment domain;CAPS,cryopyrin-associated periodic syndrome;CAP1,caspase-1;CINCA,chronic infantile neurological cutaneous articular syndrome;CPPD,calcium pyrophosphate dihydrate;CVD,cardiovascular diseases;DAMPs,danger-associated molecularpatterns;DD,death domains;FCAS,familial cold autoinflammatory syndrome;FCU,familial cold urticaria;HFD,high fat Western-type diet;HPFs,hereditary periodic fevers;IAPP,amyloid-containing amylinislet amyloid polypeptide;IL-1,Interleukin-1;IL-1 R1,IL-1 receptor 1;IL-18,interleukin-18;IR,insulin receptor;IRS-1,insulin receptorsubstrate-1;LDL,low density lipoprotein;LDLR,LDL receptor;MDP,muramyl dipeptide;mmLDL,minimally modified low-density lipoprotein;MSU,uric acid crystals;MWS,MuckleWells syndrome;NBD,nucleotide-binding domain;NLRP3,nucleotide-binding domain,leucine-rich-containing family,pyrin domain-containing-3;Nlrp3?/?,Nlrp3-deficient mice3;NLRs,receptors;NOMID,neonatal-onset multisystem inflammatory disease;Nrf2,NF-E2-related 2;LPS,lipopolysaccharide;LRR,leucine-rich-repeatdomain;oxLDL,oxidized LDL;PAMPs,pathogen-associated molecular patterns;PMNL,polymorphonuclear leukocytes;POP,PYD-only proteins;PRRs,pattern-recognitionreceptors;PYD,pyrin domain;RLRs,RIG-1-like helicases;ROS,reactive oxygen species;SMCs,smooth muscle cells;TLRs,toll-like receptors;TNF,tumor necrosis factor;Trx-1,thioredoxin-1;TXNIP,thioredoxin-interacting P;T2DM,type 2 diabetes mellitus;UPR,unfolded protein responsenCorresponding author at:Institute of Biology Paris-Seine(IBPS),Adaptation and Ageing Biology(B2A),UMR-8256/INSERM ERL-1164,Universit Pierre et Marie Curie,Paris 6,7,quai Saint Bernard,Bt A-6me tage-CC 256,75005 Paris,France.E-mail address:mustapha.rouisupmc.fr(M.Rouis).Redox Biology 4(2015)296307ContentsIntroduction.297The pyrin domain in NLRP3 assembly.298The pyrin domain in NLRP3 as a drug target for sterile inflammatory diseases.299Elusive mechanism of NLRP3 activation.299NLRP3 activation by redox-proteins the controversy around TXNIP and potential involvement of another intracellular redox-protein.300Disease-associated mutations in NLRP3.300NLRP3 inflammasome in diabetes and obesity.300Inflammasome in cardiovascular diseases.302References.304IntroductionVertebrates evolved two different systems to recognize andeliminate pathogens:the innate and the adaptive immune sys-tems.The innate immune system is the first one to be activatedand can sense a wide range of pathogenic microbes through alimited number of receptors,called pattern-recognition receptors(PRRs),by recognizing conserved microbial signatures,namedpathogen-associated molecular patterns(PAMPs)1.PRRs areexpressed by many cell types(macrophages,monocytes,neu-trophils,and others),allowing the detection of pathogens to takeplace directly at the site of infection.Once activated,the innateimmune system initiates the inflammatory response by secretingcytokines and chemokines.This leads to the expression of adhe-sion and co-stimulatory molecules able to recruit immune cellsand to stimulate the adaptive immune response.Because of theneed to distinguish between pathogenic and non-pathogenic orcommensal microbes,it has been proposed that the innate im-mune system is activated by the recognition of an antigen,butonly in presence of danger signals released by cells(danger-asso-ciated molecular patterns or DAMPs)2.The NOD-like receptors(NLRs)are a family of PRRs mostlyexpressed in the cytosol and able therefore to detect signs of in-tracellular invaders 3.Some of the NLRs can also sense non-mi-crobial danger signals and form large cytoplasmic complexescalled inflammasomes,responsible for the activation of caspase-1and-5,which ultimately leads to the proteolytic activation of theproinflammatory cytokines interleukin-1(IL-1)and interleukin-18(IL-18)4.Secretion of the key inflammatory cytokine IL-1(and its familymember IL-18)is a consequence of phagocyte activation andpromotes a multitude of metabolic,physiologic,inflammatory,hematologic and immunologic effects.Excessive or prolonged IL-1 generation can cause widespread tissue damage and is a well-documented phenomenon of,and is associated with numerousacute and chronic inflammatory human diseases,many of whichare autoinflammatory or autoimmune pathologies(for detailedreviews see 57).IL-1 production is critically regulated by cy-tosolic molecular complexes,termed inflammasomes 8.Severaldifferent inflammasome complexes have been described to date.All of them specialize in pattern recognition of danger signals,andsubsequently instruct general defense mechanisms of the humanimmune system.While all inflammasomes recognize certain PAMPs or DAMPs,itis the distinctive feature of NLRP3(NLRP3:nucleotide-bindingdomain,leucine-rich-containing family,pyrin domain-containing-3 OR Nod-like receptor protein 3)to be activated by unusuallymany and diverse stimuli making NLRP3 the most versatile,andimportantly also the most clinically implicated inflammasome.Atthe same time NLRP3 activation has remained the most enigmatic.It is not plausible that the intracellular NLRP3 receptor is able todetect all of its many and diverse triggers through direct interac-tions;instead,it is discussed that NLRP3 is responding to certaingeneric cellular stress-signals induced by the multitude of PAMPsand DAMPs that trigger its activation.An ever increasing number of studies link the sensing of cel-lular stress signals to a direct pathophysiological role of NLRP3activation in a wide range of autoinflammatory and autoimmunedisorders,and thus provide a novel mechanistic rational,on howDAMPs trigger and support sterile inflammatory diseases.Severalof these pathologies related to undue NLRP3 activation,like,e.g.gout and pseudogout,obesity,atherosclerosis,Alzheimers diseaseor type 2 diabetes mellitus(T2DM)6,have an immense impacton our society.This has created vast interest to unravel how NLRP3becomes activated,since mechanistic insight is the prerequisite fora knowledge-baseddevelopmentoftherapeuticinterventionstrategies that specifically target the NLRP3 triggeredIL-1production.To this end,many studies have contributed very valuable in-sights.It is known that only stimulated cells activate NLRP3,whichhas a tripartite structure consisting of a pyrin domain(PYD),anucleotide-binding domain(NBD)and a leucine-rich-repeat(LRR)domain 9.Upon activation,NLRP3 associates with the adaptorprotein ASC,which comprises a caspase recruitment domain(CARD)and a pyrin domain,that are held together solely by asemi-flexible linker 10 allowing both domains to engage freelywith ot