1、Received:31 January 2021Revised:17 June 2021Accepted:21 June 2021Published online:29 July 2021DOI:10.1002/ctm2.492REVIEWPyroptosis,metabolism,and tumor immunemicroenvironmentTiantian Du1,#Jie Gao1,#Peilong Li1,#Yunshan Wang1Qiuchen Qi1Xiaoyan Liu1Juan Li1Chuanxin Wang1,2,3Lutao Du1,2,31Department of
2、 Clinical Laboratory,TheSecond Hospital,Cheeloo College ofMedicine,Shandong University,Jinan,Shandong,China2Shandong Engineering and TechnologyResearch Center for Tumor MarkerDetection,Jinan,Shandong,China3Shandong Provincial Clinical MedicineResearch Center for Clinical Laboratory,Jinan,Shandong,Ch
3、inaCorrespondenceLutaoDu,ChuanxinWang,andJuanLi,DepartmentofClinicalLaboratory,TheSecondHospital,CheelooCollegeofMedicine,ShandongUniversity,247BeiyuanStreet,Jinan250033,Shandong,China.Email:;Graphical Abstract1.Gasderminsareexecutorsofpyroptosis,whichcauseinflammatorycelldeath,accompanied with vari
4、ous inflammatory mediators.2.Pyroptosisplaysadualroleintumormicroenvironment,includinganti-tumorand pro-tumor effects.3.Pyroptosis can be used as a new target to fight against the tumor.Clin.Transl.Med.2021;11: January 2021Revised:17 June 2021Accepted:21 June 2021Published online:29 July 2021DOI:10.
5、1002/ctm2.492REVIEWPyroptosis,metabolism,and tumor immunemicroenvironmentTiantian Du1,#Jie Gao1,#Peilong Li1,#Yunshan Wang1Qiuchen Qi1Xiaoyan Liu1Juan Li1Chuanxin Wang1,2,3Lutao Du1,2,31Department of Clinical Laboratory,TheSecond Hospital,Cheeloo College ofMedicine,Shandong University,Jinan,Shandong
6、,China2Shandong Engineering and TechnologyResearch Center for Tumor MarkerDetection,Jinan,Shandong,China3Shandong Provincial Clinical MedicineResearch Center for Clinical Laboratory,Jinan,Shandong,ChinaCorrespondenceLutaoDu,ChuanxinWang,andJuanLi,DepartmentofClinicalLaboratory,TheSecondHospital,Chee
7、looCollegeofMedicine,ShandongUniversity,247BeiyuanStreet,Jinan250033,Shandong,China.Email:;AbstractIn response to a wide range of stimulations,host cells activate pyroptosis,a kindof inflammatory cell death which is provoked by the cytosolic sensing of dan-ger signals and pathogen infection.In manip
8、ulating the cleavage of gasdermins(GSDMs),researchers have found that GSDM proteins serve as the real execu-tors and the deterministic players in fate decisions of pyroptotic cells.Whetherinflammatorycharacteristicsinducedbypyroptosiscouldcausedamagethehostor improve immune activity is largely depen
9、dent on the context,timing,andresponse degree.Here,we systematically review current points involved in reg-ulatory mechanisms and the multidimensional roles of pyroptosis in severalmetabolic diseases and the tumor microenvironment.Targeting pyroptosis mayreveal potential therapeutic avenues.KEYWORDS
10、gasdermin,metabolism,pyroptosis,tumor immunity,tumor microenvironmentAbbreviations:AKT,protein kinase B;ANSD,auditory neuropath spectrum disorder;ASC,apoptosis-associated speck-like protein containing aCARD;ATP,adenosine triphosphate;CAR,chimeric antigen receptor;CatG,Cathepsin G;CCA,extrahepatic ch
11、olangiocarcinoma;cGAS,cyclicGMP-AMP synthase;CRC,colorectal cancer;CRS,cytokine-release syndrome;CT,C-terminal;DAC,decitabine;DAG,diacylglycerol;DAMPs,damage-associated molecular patterns;DCs,dendritic cells;DHA,docosahexaenoic acid;DN,diabetic nephropathy;dsDNA,double-stranded DNA;ECs,endothelial c
12、ells;ELANE,neutrophil elastase;ER,endoplasmic reticulum;ERK,extracellular signal-regulated kinase;ESCRT,endosomal sortingcomplexes required for transport;GGA,geranylgeranoic acid;GSDMD,gasdemin D;GSDME,gasdemin E;GSDMs,gsdermins;GZMA,granzyme A;GZMB,granzyme B;Hcy,Homocysteine;HER2,human epidermal g
13、rowth factor receptor 2;HFD,high-fat diet;HG,high-glucose;HMGB1,high-mobility group box 1;HUVECs,human umbilical vein endothelial cells;ICD,inflammatory cell death;ICI,immune checkpoint inhibitor;IFN-,interferon-gamma;IRF2,IFN regulatory transcription factor-2;JNK,c-Jun N-terminal kinase;LOF,loss-of
14、-function;LPC,lysophosphatidylcholine;LPS,lipopolysaccharide;LUAD,lung adenocarcinoma;MDMs,monocyte-derived macrophages;MLZE,melanoma-derived leucine zipperextranuclear factor;mtDNA,mitochondrial DNA;NaB,sodium butyrate;NAFLD,non-alcoholic fatty liver disease;NFATc1,nuclear factor of activatedTcells
15、,cytoplasmic 1;NF-B,nuclear factor kappa B;NK,natural killer;NT,N-terminal domain;OA,oleic acid;ox-LDL,oxidized low-densitylipoprotein;P2 7R,P2 7 receptor;PA,palmitic acid;PD-L1,programmed death-ligand 1;PGE2,prostaglandin E2;PRRs,pattern recognitionreceptors;RIPK1,receptor-interacting serine/threon
16、ine protein kinase 1;ROS,reactive oxygen species;S1P,sphingosine-1-phosphate;S1PR2,S1Preceptor 2;SGNs,spiral ganglion neurons;SIRT1,Sirtuin1;SM,sphingomyelin;SMSs,sphingomyelin synthases;SSc,systemic sclerosis;STAT3,signaltransducer and activator of transcription 3;T1D,T2D,Type 1 and 2 diabetes;T3SS
17、,type-3 secretion system;TcdB,Clostridium difficile(C.difficile)toxin B;TET2,tet methylcytosine dioxygenase;TILs,tumor-infiltrating lymphocytes;TLR4,toll-like receptor 4;TMAO,trimethylamine N-oxide;TME,tumor microenvironment;TNF-,tumor necrosis factor alpha;UQCRC1,ubiquinol cytochrome c reductase co
18、re protein I;VSMCs,vascular smoothmuscle cells;YAP,yes-associated proteinThis is an open access article under the terms of the Creative Commons Attribution License,which permits use,distribution and reproduction in any medium,provided theoriginal work is properly cited.2021 The Authors.Clinical and
19、Translational Medicine published by John Wiley&Sons Australia,Ltd on behalf of Shanghai Institute of Clinical BioinformaticsClin.Transl.Med.2021;11: of 29https:/doi.org/10.1002/ctm2.4922 of 29DU et al.#Theseauthorscontributedequallytothiswork.FundinginformationtheNationalNaturalScienceFounda-tionofC
20、hina,Grant/AwardNumbers:81972007,81873977,81874040,82002228,81902882;theNationalKeyResearchandDevelopmentProgramofChina,Grant/AwardNumber:2018YFC0114700;theNaturalScienceFoundationofShan-dongProvince,Grant/AwardNum-bers:ZR2019PH074,ZR2019BH066,ZR201910250056;TaishanScholarPro-gramofShandongProvince;
21、theKeyResearchandDevelopmentProgramofShandongProvince,Grant/AwardNumbers:2019GHZ003,2018YFJH0505,2019GSF108091,2019GSF1082181INTRODUCTIONIn 1992,the initial phenomenon of pyroptosis was first dis-covered;this is a novel type of suicide in macrophagesinfected by Shigella flexneri,a type of gram-negat
22、ive bac-terial pathogen.1Then,in 2001,pro-inflammatory pro-grammed cell death termed“pyroptosis”was defined,which distinguishes it from apoptosis.2However,themolecular mechanism of pyroptosis is still not clear;caspase-1 was considered the critical player for a long timeuntil the cleavage of GSDMD w
23、as found.3Since then,pyroptosis has been characterized by GSDM-mediatedmembrane pore-formation and cytokine release.Surpris-ingly,pyroptosis does not always lead to lytic cell death;in some contexts,there is a damage impair systemnamed endosomal sorting complexes required for trans-port(ESCRT),which
24、 could eliminate the pores of gasder-mins(GSDMs)and protect the plasma membrane fromrupture.4Therepairsystemdevelopsanewunderstandingfor the mechanism of pyroptosis.5With further researchinto inflammatory cell death(ICD),pyroptosis was shownto be a two-sided sword in different contexts.On theone han
25、d,moderate pyroptosis facilitates cells to main-tain homeostasis,improve immune activity,and effec-tively clear damage and pathogens to protect the host,69which benefits antitumor immunotherapy and nanodrugresearches.6,10On the other hand,excessive inflamma-tion caused by pyroptosis is unfavorable t
26、o the host andmay aggravate disease development,especially tumor pro-gression,which releases various inflammatory factors andforms an inflammatory immune microenvironment11,12(Table 1).2THE MECHANISM OF THEPYROPTOSIS PATHWAYCell death is a complex and important regulatory net-work,which involves the
27、 immune system.53The pyrop-tosis pathway is linked to both the innate immunesystem and the adaptive immune system,which con-tains varieties of molecules.54Generally,gasdemin fam-ily members are core among the pyroptosis pathway,which can be cleaved and activated by inflammatorycaspases(caspase-1,cas
28、pase-4,caspase-5,caspase-11),apoptosis-related caspases(caspase-3,caspase-6,caspase-8),and granzymes,especially granzyme A(GZMA)andgranzyme B(GZMB).3,6,36,42,45,50,5558Then,large amountsof cytokines and alarmins are released from the formedpores which exert effects on the downstream pathway.7,59Anot
29、her important player is the inflammasome,althoughthis is not the essential member in the pyroptosispathway.7,59,60Except for the above major components,there are also a lot of regulators working on each node ofthe pathway.7,49,59(Figure 1)2.1The initiation of pyroptosis:Inflammasomes,caspases,and ot
30、herenzymes2.1.1Inflammasomes and caspase-1The inflammasomes are large multiprotein complexeswhich usually consist of pattern recognition receptors(PRRs),inflammatory caspases(caspase-1)and sometimesDU et al.3 of 29TABLE 1Major events in the history of pyroptosisTimeEventsRefs.1986Arthur Friedlander
31、showed that anthrax lethal toxin(LT)induced robust cell death with rapid release ofcellular contents in primary mouse macrophages131989ICE(interleukin-1-converting enzyme,caspase-1)was first discovered as a pre-aspartate-specific proteaseby cleaving pro-interleukin-1 beta(IL-1)14ICE was identified a
32、s unique cysteine protease to process the IL-1 precursor into mature IL-1.15,161992Shigella flexneri infection induced suicide in mouse macrophages,and it was regarded as programmed celldeath(apoptosis)11996ICE was activated during Shigella flexneri infection by directly binding with IpaB.171998Gene
33、tic mutations of DFNA5(GSDME)linked to non-syndromic hearing impairment182000Gasdermin(Gsdm,Gsdma1)was first named.And,it was the first report that its expression was restrictedto both upper gastrointestinal(GI)tract and skin.192001The term“pyroptosis”(from the Greek roots pyro,relating to fire or f
34、ever,and ptosis(tosis)to denote afalling,)was first proposed to describe pro-inflammatory programmed cell death(Salmonella-induceddeath).22001MLZE(GSDMC)as a novel gene was first isolated whose expression in accordance with metastatic abilityof melanoma cells.202002The term“inflammasome”was first pu
35、t forward to replace caspase-activating complex,which can activateinflammatory caspases and process pro-IL-1.212004GSDML(GSDMB)was identified as homologous gene cluster of GSDM(GSDMA)gene.22Gsdm-related genes were first designate as Gsdm2 and Gsdm3(Gsdma 1,Gsdma 2,Gsdma 3).Moreover,Gsdm3 played role
36、s during the catagen to telogen transition at the end of hair follicle morphogenesisand the formation of hair follicle-associated sebaceous glands.23DFNA5L(GSDMDC1,GSDMD)gene was identified,together with GSDM(GSDMA),GSDML(GSDMB),MLZE(GSDMC),DFNA5 and their mammalian orthologs,all were found to const
37、itute the DFNA5 DC(GSDMDC)family.242006DFNB59 was found as the first human gene implicated in non-syndromic deafness due to a neuronaldefect.252007Pejvakin(PJVK)(encoded by Dfnb59)is essential for outer hair cell function.262009GSDMB was associated with asthma and autoimmune disease.272010GSDMD was
38、first identified as a substrate of inflammatory caspase-1 by enzymatic N-terminal enrichmentmethod with mass spectrometry-based proteomics.282012Gsdma3 mutation was associated with hair follicle keratinocytes and skin keratinocytes.292012Caspase-11-dependent macrophage death(pyroptotic cell)is detri
39、mental to the host in the absence ofcaspase-1 during S.typhimurium infection.302014Caspase-4 and caspase-5 act as direct sensors of cytosolic LPS.312015GSDMD was cleaved by inflammatory caspase1/4/5/11 and as the real executioner of pyroptosis.3,32,332015Pejvakin is essential for antioxidant activit
40、y of peroxisomes in hair cells and primary auditory neurons toprotect the auditory system against noise-induced oxidative stress.342016Liposome-leakage and pore-forming activities of the gasdermin-N domain(GSDMD,GSDMA3 andGSDMA)are required for pyroptosis.The crystal structure of GSDMA3 was identifi
41、ed.352017GSDME was found as a substrate of caspase 3 to trigger pyroptosis under chemotherapy drugs treatment.362018Necrosulfonamide was identified as a direct chemical inhibitor of gasdermin D.37GSDMD plays an essential function in the generation of neutrophil extracellular traps and NETosis.38,39E
42、LANE could mediate GSDMD cleavage and induce lytic cell death in neutrophil.40Cryo-EM structure of the GSDMA3 membrane pore was found.41Caspase-8 was indicated to induce cleavage of GSDMD to activate pyroptosis during Yersinia infection.422019Caspase-8 cleave GSDMD to promote lytic cell death during
43、 extrinsic apoptosis which could becounteracted by caspase-3.43(Continues)4 of 29DU et al.TABLE 1(Continued)TimeEventsRefs.Cathepsin G(CatG)could cleave GSDMD to induce pyroptosis in neutrophils and monocytes.442020GSDME-triggered pyroptosis activated antitumor immunity.GZMB was found to directly cl
44、eave GSDME at the same site as caspase-3 and then activate pyroptosis.6GZMA could cleave GSDMB to induce pyroptosis in target cells.45GSDMC could be specifically cleaved by caspase-8 with macrophage-derived TNF treatment,which wasswitched by PD-L1.46BRAFi+MEKi treatment could promote cleavage of GSD
45、ME to regulate the tumor immunemicroenvironment.47Succination blocked pyroptosis by inactivating GSDMD.48FDA-approved disulfiram identified as GSDMD inhibitors.49Caspase-6 was involved in pyroptosis in host defense against influenza A virus(IAV)infection.50Substrate-targeting mechanism was identifie
46、d during recognition of GSDMD by inflammatory caspases.512021Cryo-electron microscopy structures of the pore and the prepore of GSDMD was reported.GSDMD pore mediated preferential release of mature IL-1 by electrostatic filtering.52an adaptor protein,like apoptosis-associated speck-likeprotein conta
47、ining a CARD(ASC).6062Pyroptosis medi-ated by the inflammasomes is commonly categorizedas the canonical caspase-1-dependent inflammasomepathway.62Generally,as sensors to various dangers,thePRRs(NLRP1,NLRP3,NLRC4,NLRP6,NLRP7,NLRP9b,NLRP12,pyrin,and AIM2)first recognize a variety ofstimulates,then act
48、ivate pro-caspase-1 cleavage and ASCrecruitment to assemble inflammasomes.6365Activatedcaspase-1 can cleave pyroptosis executor gasdemin D(GSDMD)proteins(Asp275 site)to free the N-terminal(NT)domain and generate nonselective pores on the cellmembrane.3,55,66,67At the same time,caspase-1 cleavesand a
49、ctivates the precursors of IL-1 and IL-18 to becomemature IL-1 and IL-18.The latter together with othercellular contents then is released from the pores,leadingto cell pyroptosis.55,60,68In the case of NLRP3,the mostcommon PRRs can be activated by a wide range of factors,including viruses,bacterial toxins,fungi,parasite,nucleicacids,crystalline substrates,some drugs,silica particles,long-chain saturated fatty acids,reactive oxygen species(ROS)and various endogenous damage signals.6972Notably,there is a two-step procedure for NLRP3 inflam-masome activation,including the priming step by variou