Annu. Rev. Physiol. 2019肺细胞死亡：细胞凋亡 - 坏死性凋亡轴.pdf

PH81CH17_LeeARI16 November 201813:53Annual Review of PhysiologyCell Death in the Lung:TheApoptosisNecroptosis AxisMaor Sauler,Isabel S.Bazan,and Patty J.LeeDepartment of Medicine,Yale School of Medicine,New Haven,Connecticut 06520,USA;email:patty.leeyale.eduAnnu.Rev.Physiol.2019.81:17.117.28The Annual Review of Physiology is online atphysiol.annualreviews.orghttps:/doi.org/10.1146/annurev-physiol-020518-114320Copyright c?2019 by Annual Reviews.All rights reservedKeywordsapoptosis,necroptosis,idiopathic pulmonary fibrosis,chronic obstructivepulmonary disease,asthma,pulmonary arterial hypertension,acuterespiratory distress syndromeAbstractRegulatedcelldeathisamajormechanismtoeliminatedamaged,infected,orsuperfluous cells.Previously,apoptosis was thought to be the only regulatedcelldeathmechanism;however,newmodalitiesofcaspase-independentreg-ulated cell death have been identified,including necroptosis,pyroptosis,andautophagic cell death.As an understanding of the cellular mechanisms thatmediate regulated cell death continues to grow,there is increasing evidencethat these pathways are implicated in the pathogenesis of many pulmonarydisorders.Thisreviewsummarizesourunderstandingofregulatedcelldeathas it pertains to the pathogenesis of chronic obstructive pulmonary disease,asthma,idiopathic pulmonary fibrosis,acute respiratory distress syndrome,and pulmonary arterial hypertension.17.1Review in Advance first posted on November 28,2018.(Changes may still occur before final publication.)Annu.Rev.Physiol.2019.81.Downloaded from www.annualreviews.org Access provided by University of Winnipeg on 11/30/18.For personal use only.PH81CH17_LeeARI16 November 201813:53INTRODUCTIONThe health and survival of multicellular organisms rely on the ability to eliminate damaged,infected,or superfluous cells.Therefore,multicellular organisms possess genetically encodedmechanisms via which cells can undergo regulated cell death(RCD).RCD occurs as part ofnormal physiologic programming,including organ development and epithelial renewal.It alsooccurs in cells that cannot mitigate stressors that threaten tissue homeostasis,e.g.,cells infectedby intracellular pathogens or cells encumbered by DNA damage,oxidative stress,and misfoldedproteins.Initially,investigatorsheldthebeliefthattherewereonlytwoformsofcelldeath,apoptosisandnecrosis.Apoptosis is a metabolically active process in which cell death occurs with characteristicmorphologicfeatures thatinclude cell membraneshrinkage,nuclear chromatincondensation,nu-clear fragmentation,and plasma membrane blebbing.In contrast,necrosis occurs when cells dieaccidentally from extreme or rapid injury,resulting in the dissolution of the plasma membrane,cellular swelling,and the release of intracellular contents that promote inflammation(13).Whilethese morphologic features remain relevant to understanding RCD,this dichotomous character-ization of cell death has been elaborated,and now the term RCD encompasses multiple forms ofactive cell death with morphologic features that resemble apoptosis or necrosis(4).Dysregulated RCD has been implicated in human disease.Excessive RCD causes tissue in-jury and destruction,whereas a failure of RCD is implicated in mutagenesis,impaired immunity,and autoimmune disease(5).Nowhere is the regulation of cell death more important than in thelung,an organ required to maintain a delicately thin network of epithelial-endothelial interfacesto allow for effective exchange of CO2for O2,all while exposed to environmental stressors such aspathogensandaerosolizedtoxins.Inthisreview,wesummarizethecurrentmolecularunderstand-ing of RCD and focus on the role of RCD in five lung diseases:chronic obstructive pulmonarydisease(COPD),asthma,idiopathic pulmonary fibrosis(IPF),acute respiratory distress syndrome(ARDS),and pulmonary arterial hypertension(PAH).APOPTOSISApoptosis is mediated by two signaling cascades:the intrinsic and extrinsic apoptosis pathways.Intrinsic apoptosis commonly occurs due to a disruption of cellular homeostasis(Figure 1),and extrinsic apoptosis occurs as a consequence of extracellular signaling via death receptors(Figure 2).While intrinsic and extrinsic apoptosis have unique initiating steps,both culmi-nate in the activation of a set of cysteine proteases called caspases(6).Initiator caspases(e.g.,caspase8or9)beginaseriesofproteolyticstepsthatleadtoactivationofexecutionercaspases(e.g.,caspase 3 or 7)(1).Executioner caspases cleave thousands of substrates and are responsible for theenzymatic degradation of organelles,DNA fragmentation,and characteristic phosphatidylserineexposure.Inhumanlungtissue,apoptosishasbeencommonlyassessedby:ultrastructuralanalysesof cellular morphology via electron microscopy;measuring DNA fragmentation histologically byterminal dUTP nick end labeling(TUNEL);flow cytometry of isolated cells for assessment ofphosphatidylserine exposure and cell viability with annexin V and propidium iodide,respectively;and immunohistochemistry of proteins involved in apoptosis(7,8).Mitochondrial outer membrane permeabilization(MOMP)commits cells to undergoing in-trinsicapoptosis(Figure 1).MOMPleadstothereleaseofproapoptoticfactorsintothecytoplasmfrom the mitochondrial intermembrane space,including cytochrome c and second mitochondria-derived activator of caspase(SMAC).Cytochrome c binds apoptotic protease activating factor1(APAF1)which activates caspase 9,and SMAC neutralizes cytoplasmic inhibitors of apoptosis17.2SaulerBazanLeeReview in Advance first posted on November 28,2018.(Changes may still occur before final publication.)Annu.Rev.Physiol.2019.81.Downloaded from www.annualreviews.org Access provided by University of Winnipeg on 11/30/18.For personal use only.PH81CH17_LeeARI16 November 201813:53BIMBADNOXABIDPUMASMACIAPCytochrome CAPAF1Caspase 9ApoptosisBAK BAKBCL2MCL1BCL-xLFigure 1Intrinsic apoptosis.The step that commits cells to undergoing apoptosis is permeabilization of themitochondrial outer membrane(MOMP).MOMP occurs when B-cell lymphoma 2(BCL2)-associated Xapoptosis regulator(BAX)and BCL2 antagonist/killer 1(BAK)form outer mitochondrial membrane pores.This process is promoted by BH3-only proteins,including BCL2-associated death promoter(BAD),p53-upregulated binding component(PUMA),BCL2-like 11(BIM),phorbol-12-myristate-13-acetate-induced protein(NOXA),and BH3-interacting domain death agonist(BID);and antagonized byantiapoptotic BCL2 proteins,including BCL2,B-cell lymphoma extra large(BCL-xL),and myeloidleukemia cell differentiation protein(MCL1).MOMP causes the release of cytochrome c and secondmitochondriaderived activator of caspase(SMAC).Cytochrome c binds apoptotic protease activatingfactor 1(APAF1)and initiator caspase 9 to form the apoptosome,where caspase 9 is activated.SMACneutralizes the cytoplasmic proteins maintained by cells to restrain caspase activation(inhibitor of apoptosisproteins,IAPs).proteins(IAPs)thatrestraincaspaseactivation,e.g.,X-linkedinhibitorofapoptosisprotein(XIAP)and survivin.Inhibition of caspases,either genetically or pharmacologically(e.g.,Z-VAD-fmk),will only delay cell death,as intact mitochondria are necessary for cellular survival.Classically,MOMP was considered an all or nothing response;however,sublethal MOMP activation existsand is often associated with genomic instability(9).MOMP is regulated by the B-cell lymphoma 2(BCL2)family of proteins,which shares upto four BCL2 homologous domains(BH1BH4)(4).Three categories of BCL2 proteins are in-volved in intrinsic apoptosis:(a)MOMP effectors that form pores across the outer mitochondrialmembrane in response to apoptotic stimuli,including BCL2-associated X apoptosis regulator(BAX)and BCL2 antagonist/killer 1(BAK);(b)proteins with only a BH3 motif(BH3-only)thatpromote apoptosis by binding and neutralizing prosurvival BCL2 proteins,including BCL2-associated death promoter(BAD),p53-upregulated binding component(PUMA),BCL2like11(BIM),phorbol-12-myristate-13-acetate-induced protein(NOXA),and BH3-interacting domaindeath agonist(BID);and(c)BCL2 apoptosis inhibitors,including BCL2,B-cell lymphoma extrawww.annualreviews.orgCell Death in the Lung17.3Review in Advance first posted on November 28,2018.(Changes may still occur before final publication.)Annu.Rev.Physiol.2019.81.Downloaded from www.annualreviews.org Access provided by University of Winnipeg on 11/30/18.For personal use only.PH81CH17_LeeARI16 November 201813:53TRADDFasFasFasLUApoptosisDISCRIPK1TRADDRIPK1TNFR1TNFR1CYLDComplex ITNF-FADDCaspase 8cFLIPNF-BIAPLUBACComplex IIFADDCaspase 8cFLIPFigure 2Extrinsic apoptosis.Ligand binding to Fas results in the formation of the death-inducing signaling complex(DISC),composed of Fas-associated death domain(FADD),cellular FLICE-inhibitory protein(cFLIP),andcaspase 8.Upon activation,cleavage of caspase 8 leads to cleavage of executioner caspases and apoptosis.Theconsequences of TNF receptor 1(TNFR1)activation depends on posttranslational modifications of anotherprotein recruited to Complex 1,receptor-interacting protein kinase 1(RIPK1).Upon TNFR1-associateddeath domain(TRADD)-dependent recruitment,RIPK1 can be ubiquitinated by inhibitor of apoptosisproteins(IAPs)and linear ubiquitination chain assembly complex(LUBAC).Ubiquitinated RIPK1(U)promotes inflammation and cell survival by activating protein kinase signaling and IB kinase(IKK)-dependent NF-B activation.If IAPs are absent or inhibited,RIPK1 is deubiquitinated bycylindromatosis(CYLD).Consequently,RIPK1 forms a complex with FADD and caspase 8 in the cytosol(Complex II).Similar to signaling by Fas,this complex is also regulated by cFLIP proteins and can lead tocaspase 8 activation and apoptosis.large(BCL-xL),and induced myeloid leukemia cell differentiation protein(MCL1).Pharmaco-logic BH3 mimetics have been developed to antagonize prosurvival BCL2 proteins and are cur-rently in use for treatment of chronic lymphocytic leukemia or under investigation for treatmentof other malignancies.Direct activators of BAX have also been developed(10).In the lung,intrinsic apoptosis can occur as a consequence of growth factor withdrawal,ox-idative stress,endoplasmic reticular(ER)stress,and DNA damage.Growth factors,cytokines,and other extracellular ligands can activate tyrosine kinase receptors and G proteincoupled re-ceptors to upregulate prosurvival signaling cascades.For example,protein kinase B(AKT)isactivated by the phosphorylation of phosphoinositide 3-kinase(PI3K)and negatively regulated byphosphatase and tensin homolog(PTEN)(11).Phosphorylated AKT directly inhibits BAD andcaspase 9.AKT also inhibits transcription factors that upregulate proapoptotic BCL2 proteins,including the forkhead family of transcription factors(FOXO)and yes-associated protein(YAP).AKT also activates transcription factors that upregulate antiapoptotic BCL2 proteins,includingcAMP response element-binding protein(CREB)and nuclear factor kappa B(NF-B)(11,12).Othersignalingpathwaysthatcanpromotecellularsurvivalincludeextracellularregulatedkinases(ERK1/2),Januskinases(JAKs)/signaltransducer,andactivatoroftranscriptionproteins(STATs)17.4SaulerBazanLeeReview in Advance first posted on November 28,2018.(Changes may still occur before final publication.)Annu.Rev.Physiol.2019.81.Downloaded from www.annualreviews.org Access provided by University of Winnipeg on 11/30/18.For personal use only.PH81CH17_LeeARI16 November 201813:53(13).In addition to growth factor withdrawal,there is a special type of apoptosis called anoikisin which the loss of integrin-dependent anchorage to the extracellular matrix triggers caspaseactivation(4,14).Oxidative stress is an important cause of intrinsic apoptosis.Although reactive oxygen species(ROS)are important for cell signaling,excessive levels lead to macromolecular damage and celldeath.In the lung,oxidative stress occurs as a consequence of inhaled toxins such as cigarettesmoke,ROS generation by inflammatory cells,and mitochondrial metabolism(15).Oxidativestress can decrease mitochondrial membrane potential,promoting MOMP.Oxidative stress alsoleads to activation of p38 mitogenactivated protein kinase(p38)and c-Jun N-terminal kinase(JNK)via apoptosis signalregulating kinase 1(ASK1).Both JNK and p38 can function as pro-or antiapoptotic mediators,depending on the context.In the lung,JNK activation from oxidativestress promotes apoptosis by facilitating cytochrome c release,activating BH3-only proteins,andinhibiting BCL2.Oxidative stress also contributes to ER stress and DNA damage.ER stress is a consequence of excess protein misfolding,often due to oxidative stress,viral in-fection,orgeneticmutations.InresponsetoERstress,cellsactivatetheunfoldedproteinresponse(UPR),a protective mechanism to facilitate protein folding that includes upregulation of proteinchaperones,inhibition of mRNA translation,and promotion of the transport of misfolded ERproteins into the cytosol for ubiquitination and degradation(16).However,if ER stress is suffi-ciently severe or prolonged,the UPR leads to the degradation of prosurvival mRNAs,activationof JNK,upregulation of BH3-only proteins,and lowers mitochondrial membrane potential viathe efflux of Ca2+from the ER to the mitochondria.DNA damage is also an important cause of intrinsic apoptosis.In response to DNA dam-age,various kinases phosphorylate and stabilize p53.The consequences of p53 stabilization arecontext specific and include DNA repair and cellular senescence.However,if DNA damage issufficiently severe,p53 can mediate intrinsic apoptosis through the direct interaction with pro-apoptotic proteins such as PUMA and NOXA,and transcriptional upregulation of proapoptoticproteins including BIM,BAX,and APAF1.Extrinsic apoptosis is triggered by the activation of death receptors.The best character-ized death receptor is the Fas cell-surface death receptor,which can be activated by solubleor membrane-bound Fas ligand(FasL).In the lung,Fas is expressed by alveolar and bronchialepithelial cells,Clara cells,macrophages,and myofibroblasts.FasL is expressed on epithelial cells,neutrophils,monocytes,eosinophils,cytotoxicTcells,andplatelets(17).Otherwell-studieddeathreceptors include the tumor necrosis factor(TNF)receptor superfamily 10(TRAILR14)andTNF receptor 1(TNFR1),activated by TRAIL and TNF-,respectively(1,2).Following ligandactivation of Fas or TRAILR,a conformational change in the cytosolic tail of the receptor leadsto the recruitment of Fas-associated death domain(FADD)and procaspase 8.Here,activationof caspase 8 is regulated by cellular FLICE-inhibitory proteins(cFLIPs).Short cFLIP isomers(cFLIPs)competitively inhibit caspase 8 activation,whereas long cFLIP isomers(cFLIPL)pro-mote caspase 8 activation(4)(Figure 2).The response to caspase 8 varies across cell types.Insome cells,such as mature lymphocytes,activation of caspase 8 directly leads to proteolytic acti-vation of executioner caspases and cell death in a mitochondrion-independent manner.In othercell types,the presence of IAPs antagonizes direct activation of ap