1、ORIGIN AND CONSEQUENCES OFNECROINFLAMMATIONMaysa Sarhan,Walter G.Land,Wulf Tonnus,Christian P.Hugo,and X Andreas LinkermannDivision of Nephrology and Dialysis,Department of Medicine III,Medical University Vienna,Vienna,Austria;INSERM UMR_S 1109,Laboratory of Excellence Transplantex,University of Str
2、asbourg,Strasbourg,France;German Academy of Transplantation Medicine,Munich,Germany;and Division of Nephrology,Department ofInternal Medicine III,University Hospital Carl Gustav Carus at the Technische Universitt Dresden,Dresden,GermanyLSarhan M,Land WG,Tonnus W,Hugo CP,Linkermann A.Origin and Conse
3、quencesof Necroinflammation.Physiol Rev 98:727780,2018.Published February 21,2018;doi:10.1152/physrev.00041.2016.When cells undergo necrotic cell deathin either physiological or pathophysiological settings in vivo,they release highly immuno-genic intracellular molecules and organelles into the inter
4、stitium and thereby represent thestrongest known trigger of the immune system.With our increasing understanding of necrosis as aregulated and genetically determined process(RN,regulated necrosis),necrosis and necroinflamma-tion can be pharmacologically prevented.This review discusses our current kno
5、wledge about signalingpathways of necrotic cell death as the origin of necroinflammation.Multiple pathways of RN such asnecroptosis,ferroptosis,and pyroptosis have been evolutionary conserved most likely because of theirdifferences in immunogenicity.As the consequence of necrosis,however,all necroti
6、c cells releasedamage associated molecular patterns(DAMPs)that have been extensively investigated over the lasttwo decades.Analysis of necroinflammation allows characterizing specific signatures for each partic-ular pathway of cell death.While all RN-pathways share the release of DAMPs in general,mo
7、st of themactively regulate the immune system by the additional expression and/or maturation of either pro-oranti-inflammatory cytokines/chemokines.In addition,DAMPs have been demonstrated to modulatethe process of regeneration.For the purpose of better understanding of necroinflammation,weintroduce
8、 a novel classification of DAMPs in this review to help detect the relative contribution of eachRN-pathway to certain physiological and pathophysiological conditions.I.GENERAL INTRODUCTION727II.REGULATED NECROSIS732III.A CLASSIFICATION OF DAMPs741IV.DAMP-INDUCED INNATE ALLOIMMUNITY745V.DAMP-INDUCED
9、PATHWAYS.751VI.A MODEL FOR THE IMMUNOLOGICAL.755VII.ROLE OF DAMPs IN.756VIII.PERSPECTIVES FOR CANCER AND.758IX.SUMMARY ON ORIGIN AND.759I.GENERAL INTRODUCTIONA.The Concept of NecroinflammationIn this review,we discuss the cell death pathways(Origin)and different classes of DAMPs(Consequences)of necr
10、oin-flammation.We define necroinflammation as the immuneresponse to necrosis in a living organism.Necrosis is exe-cuted as a regulated process through defined signaling path-ways such as necroptosis,ferroptosis,and pyroptosis ormayhappeninanonregulatedfashionastraumaticnecrosis(FIGURE 1).Whenever a
11、cell undergoes necrosis,its intracel-lular content is released as damage associated molecularpatterns(DAMPs).As a consequence of necrosis,DAMPsbindtodifferentmoleculesonvariousothercellsin the interstitium.Here,we provide a classification ofDAMPs which is suggested inTABLE 1.As a mechanisticbasis fo
12、r this classification,we recommend the DAMPsensing as a differentiation criterion.With our increasingunderstanding of the distinct signaling pathways of reg-ulated necrosis,a growing body of evidence suggests thatRN pathways trigger different immune responses.There-fore,a given RN pathway may specif
13、ically fine tune theimmune response for specifc needs to regenerate a giventissue or to fight given microbes more effectively.Differ-ences in necroinflammation may therefore explain whyseveral distinct cell death pathways are conserverd in ourgenome.B.General Introduction to RegulatedNecrosisNecrosi
14、s generally does not occur in an uncontrolled man-ner,at least not in nontraumatic diseases.Instead,it followsgenetically determined signaling pathways.The cell deathPhysiol Rev 98:727780,2018Published February 21,2018;doi:10.1152/physrev.00041.20167270031-9333/18 Copyright 2018 the American Physiol
15、ogical SocietyDownloaded from www.physiology.org/journal/physrev by$individualUser.givenNames$individualUser.surname(132.174.250.220)on July 29,2018.Copyright 2018 American Physiological Society.All rights munity has been addressing the question of uncon-trolled cell death for decades,thereby uncove
16、ring the mo-lecular pathways of regulated necrosis(RN).Many RNpathways have been described,and it is a major task tounravel the overlapping and indistinguishable features ofthese pathways.This problem required some consensus onthe definitions used that have been summarized in theGuidelines of the No
17、menclature Committee on Cell Death,the most current version of which being in line with thisreview(181).Necrosis,defined by plasma membrane rupture(PM-rup-ture),inevitably results in death of a particular cell.At thispoint the cell is dead by definition.As a consequence ofPM-rupture,the intracellula
18、r content gains access to theinterstitial space,to other cells,matrix components etc.Theaccessibility of surveillance immune cells to mitochondria,lysosomes,peroxisomes,and other organelles suggests thatnecrosis per se is a very immunogenic event.Intravital mi-croscopy has visualized the process of
19、necrosis in vivo(384),and DAMPs released during this process were insome cases referred to as cell death associated molecularpatterns(CDAMPs)(330).The amount of DAMPs releasedby a cell is probably much more immunogenic when com-pared with a single molecule on the surface of a living cell,e.g.,the in
20、compatibility of single proteins such as HLA-mismatches and blood group antigens in the setting oftransplantation.It is of interest to realize that the process of regulateddeath takes some time.During this process,cells metab-olize plenty of ATP to drive transcription of hundreds ofmolecules,includi
21、ng pro-and anti-inflammatory cyto-kines.Proteases are very active in some necrotic type celldeath subroutines and process long-lasting cytokines,such as Pro-interleukin(IL)-1?and Pro-IL-18 in case ofpyroptosis.When such cells,often macrophages,finallyundergo pyroptosis,the immunogenicity is not limi
22、ted tothe standard cytosolic arsenal of DAMPs,but containssome additional cytokines that enhance the immunoge-nicity beyond the level of default DAMP release.In con-trast,active transcription of IL-33 during necroptosisstabilizes regulatory T cells in the surrounding microen-vironment and thereby fu
23、nctionally dampens the immuneresponse(540,570).Analyzing these factors for each celldeath subroutine,we will introduce a hierarchy for im-munogenicity of necrotic cell death pathways in this re-view.It is because of the immunogenicity of regulatednecrosis that we should understand these pathways and
24、interfere with them therapeutically as indirect,but puta-tively highly potent immunosuppression.C.General Introduction to DAMPs1.The danger/injury model in immunologyMore than 20 yr ago,in January and April 1994,the dangerhypothesis was first published proposing that a discrimina-tion of the immune
25、system between self and non-self doesnot sufficiently explain immune reponses.Its evolutionarilydetermined driving force was proposed to become alarmedand to react by any form of cell stress and/or tissue damageincluding allograft injury.Two major considerations led todying cellDAMP Ia PRR Necroinfl
26、ammationOriginConsequences NecroptosisPyroptosisFerroptosisTraumatic necrosisDAMP Ib P2x7DAMP II NLRP3DAMP III NKG2D DAMP IV IgM Complement DAMP V UPR DAMP VI GPR91FIGURE 1.Origin and consequences ofnecroinflammation.Necrosis is executed asa regulated process through defined signal-ing pathways such
27、 as necroptosis,ferropto-sis,and pyroptosis or may happen in a non-regulated fashion as traumatic necrosis.Whenever a cell undergoes necrosis,its in-tracellular content is released as damage-associated molecular patterns(DAMPs).Asa consequence of necrosis,DAMPs bind todifferent molecules on various
28、other cells intheinterstitium.ForaclassificationofDAMPs which is suggested in TABLE 1 ofthis review,we recommend the DAMP sens-ing as a means of classifying DAMPs.In thisreview,we will discuss the cell death path-ways(Origin)and different classes of DAMPs(Consequences)of necroinflammation.Wedefine n
29、ecroinflammation as the immune re-sponse to necrosis in a living organism.SARHAN ET AL.728Physiol RevVOL 98APRIL 2018www.prv.orgDownloaded from www.physiology.org/journal/physrev by$individualUser.givenNames$individualUser.surname(132.174.250.220)on July 29,2018.Copyright 2018 American Physiological
30、 Society.All rights reserved.the development of this hypothesis:1)clinical trials withpatients that received a renal allograft led to the conclusionthat allograft injury inevitably resulted in a potent immuneresponse in humans(338),and 2)Polly Matzinger(428)suggested the conclusion that the“self/non
31、-self”theory isinappropriate based on theoretical considerations.Duringthe upcoming decades,further modification of this modelby the two groups led to a more sophisticated outline of thishypothesis.This was triggered in particular by the develop-ments and achievements published in the emerging field
32、 ofinnate immunity.Today,most scientists agree that tissueinjury and metabolic changes in any tissue injury activatethe innate immune system.The response may provide abroad range of protection including killing of invadingpathogens,removing dead cells and cellular debris,but alsobalancing metabolic
33、or psychological irregularities.Impor-tantly,this response is thought to promote regenerative re-pair of destroyed tissues.Finally,when dangerous cellstress/tissue injury is associated with the presence of“non-self”or“altered-self”antigens(or even“self”),this uniquedefense system sends an SOS by ind
34、ucing a supportive im-mune response.How can the danger hypothesis be explained on a molecu-lar level?In the early 2000s,the term damage associatedmolecular patterns(DAMPs)was first used(336,578)Thisallowed the understanding of“danger signals”as definedmolecules.In the 2003 article,Land(336)wrote:“Da
35、m-age-associated molecular patterns(DAMPs)such asheat shock proteins,arising in the stressed allograft,serve as endogenous ligands for and interact with Toll-like receptors(TLRs)on cells of the innate immune sys-tem such as donor-or recipient-derived dendritic cellsand donor-derived vascular cells a
36、nd,by this engage-ment,activate them.”In the 2004 article,Seong andMatzinger(578)wrote:“It is currently thought that im-mune responses are initiated by pathogen-associated mo-lecular patterns or by tissue-derived danger/alarm sig-nals.Many of them might be part of an evolutionarilyancient alert syst
37、em in which the hydrophobic portionsTable 1.Classification of DAMPs involved in inflammation,adaptive immunity,and nociceptionClasses of DAMPs*Categories of Cognate Recognition Receptors/Sensors(Cell Bound,Humoral)Class Ia DAMPs?DAMPs such as HMGB1,HSPs,nucleicacids including mitochondrial and cytos
38、olic DNASensed via binding to“classical”recognition receptors(?PRRs such as TLRs,RLRs,ALRs)on/in innateimmune cells such as phagocytes including DCs,thereby triggering signaling pathwaysClass Ib DAMPs?DAMPs such as CALR and eATPRecognized by“nonclassical”recognition receptorssuch as the scavenger re
39、ceptor CD91 and thepurinergic receptors P2X7 thereby contributing tophagocytes including DCs activationClass II DAMPs?DAMPs(e.g.,eATP,uric acid)operatingas second signals to activate the NLRP3 inflammasomeSensed by NLRP3 receptor to form assembly of theNLRP3 inflammasome contributing to phagocytesin
40、cluding DCs activationClass III DAMPs?DAMPs exposed on stressed cells suchas MICs and ULBPsRecognized by the activating NKG2D receptor,e.g.,on NK cells thereby contributing to NK cellactivationClass IV DAMPs?DAMPs in terms ofneoantigens/neoepitopes(such as NMHC-II,oxidizedphospholipids,actin cytoske
41、leton,etc.)Recognized by binding to preexisting natural IgMantibodies to activate the complement cascadethereby contributing to inflammationClass V DAMPs?dyshomeostasis-associated molecularpatterns(such as accumulation of unfolded proteins inthe ER;intracellular ion perturbations,hypoxia,redoximbala
42、nce;etc.)Sensed by sensors of the UPR(e.g.,PERK)or sensedby NLRP3 receptor thereby contributing toinflammation and DC activationClass VI DAMPs?metabolic DAMPs(such as succinate)Recognized by the“nonclassical”recognition receptorGPR91 thereby promoting inflammationClass VII DAMPs?nociceptor-activatin
43、g DAMPs(such asosmotic challenges,low and high temperature,capsaicin)Sensed by nociceptors such as TRPA1 channels andTRPV1*The attempt to classify DAMPs as depicted in this table is restricted for this article only and with focus on their crucial role in allograft rejection.Class VII DAMPs sensed by
44、 nociceptors have been tentatively included in this table to show that DAMP-induced responses of the innate immunedefense system may exceed the traditional phenomena of inflammation and adaptive immunity.Of course,this approach is debatable and wefreely admit that there are still some deficits in ou
45、r classification waiting for a final resolution.CD,cluster of differentiation;DAMPs,damage-associated molecular patterns;DCs dendritic cells;eATP,extracellular ATP;GPR91,G protein-coupled receptor 91;HMGB1,highmobility group box 1;IgM,immunoglobulin M;MICs,MHC class I chain-related proteins;NK,natur
46、al killer;NKG2D,natural killer group 2member D;NLRP3,NLR family,pyrin domain-containing protein 3;NMHC-II,nonmuscle myosin II-A heavy chain;PERK,the protein kinase R(PKR)-like endoplasmic reticulum kinase;PRRs,pattern recognition receptors;P2X7,purinergic receptor P2X7;RLRs,retinoic acid-induciblege
47、ne(RIG)-I-like receptors;TLR,Toll-like receptor;TRPA1,transient receptor potential cation channel subfamily A member 1;TRPV1,transientreceptor potential vanilloid subtype 1;ULBPs,UL16 binding proteins.NECROINFLAMMATION729Physiol RevVOL 98APRIL 2018www.prv.orgDownloaded from www.physiology.org/journa
48、l/physrev by$individualUser.givenNames$individualUser.surname(132.174.250.220)on July 29,2018.Copyright 2018 American Physiological Society.All rights reserved.of biological molecules act,when exposed,as universaldamage-associated molecular patterns to initiate repair,remodeling and immunity.”In fac
49、t,the very first clue of the existence of such moleculeswas provided by studies published already in 2000/2002 byShi et al.(587)and Shi and Rock(586).These authorsdemonstrated that tumor cell death may provide a triggerfor the stimulation of T cells.Thereafter,in 2003,uric acidwas first ascribed a r
50、ole as a danger signal(585),which waslater broadly accepted as first non-bacterial DAMP(85).2.About DAMPs,PAMPs,and MAMPsAs originally defined,danger signaling DAMPs are endog-enous molecules,that is,encoded by the hosts endogenousgenome.As constitutive DAMPs,they are ad hoc,that is,immediately rele
