HMGB1 and Extracellular Histones Significantly Contribute to Systemic Inflammation and Multiple Organ Failure in Acute Liver Failure

Re iew A icle HMGB1 and Ex acellula His ones Signi ican ly Con ibu e o Sys emic In lamma ion and Mul iple O gan Failu e in Acu e Li e Failu e Runkuan Yang, 1,2,3 Xiaoping Zou, 4 Jy ki Tenhunen, 1,5 and To Inge Tønnessen 3,6 1 Depa men o In ensi e Ca e Medicine, Tampe e Uni e si y Hospi al, Uni e si y o Tampe e, 10 Bio Ka u, 33014 Tampe e, Finland 2 Depa men o C i ical Ca e Medicine, Uni e si y o Pi sbu gh Medical School, 3550 Te ace S ee , Pi sbu gh, PA 15261, USA 3 Depa men o Eme gencies and C i ical Ca e, Oslo Uni e si y Hospi al, P.O. Box 4950 Nydalen, 0424 Oslo, No way 4 Depa men o Gas oen e ology, D um Towe Hospi al, Nanjing Uni e si y Medical School, 321 Zhongshan S ee , Nanjing 210008, China 5 Depa men o Su gical Science, Anes hesiology and In ensi e Ca e Medicine, Uppsala Uni e si y, 751 85 Uppsala, Sweden 6 Ins i u e o Clinical Medicine, Uni e si y o Oslo, Blinde n, 0316 Oslo, No way Co espondence should be add essed o Runkuan Yang; [email p o ec ed] Recei ed 25 No embe 2016; Re ised 27 Feb ua y 2017; Accep ed 8 May 2017; Published 13 June 2017 Academic Edi o : Jose C ispin Copy igh © 2017 Runkuan Yang e al. This is an open access a icle dis ibu ed unde he C ea i e Commons A ibu ion License, which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Acu e li e ailu e (ALF) is he culmina ion o se e e li e cell inju y om a a ie y o causes. ALF occu s when he ex en o hepa ocy e dea h exceeds he hepa ic egene a i e capaci y. ALF has a high mo ali y ha is associa ed wi h mul iple o gan ailu e (MOF) and sepsis; howe e , he unde lying mechanisms a e s ill no clea . Eme ging e idence shows ha ALF pa ien s/ animals ha e high concen a ions o ci cula ing HMGB1, which can con ibu e o mul iple o gan inju ies and media e gu bac e ial ansloca ion (BT). BT igge s/induces sys emic inflamma o y esponses synd ome (SIRS), which can lead o MOF in ALF. Blockade o HMGB1 significan ly dec eases BT and imp o es hepa ocy e egene a ion in expe imen al acu e a al li e inju y. The e o e, HMGB1 seems o be an impo an ac o ha links BT and sys emic inflamma ion in ALF. ALF pa ien s/ animals also ha e high le els o ci cula ing his ones, which migh be he majo media o s o sys emic inflamma ion in pa ien s wi h ALF. Ex acellula his ones kill endo helial cells and elici immunos imula o y effec o induce mul iple o gan inju ies. Neu aliza ion o his ones can a enua e acu e li e , lung, and b ain inju ies. In conclusion, HMGB1 and his ones play a significan ole in inducing sys emic inflamma ion and MOF in ALF. 1. Backg ound Acu e li e ailu e is defined as a clinical synd ome cha - ac e ized by li e inju y wi h e idence o coagulopa hy and any deg ee o al e ed men al s a us in a pa ien wi h- ou p eexis ing li e disease and du a ion o illness less han 26 weeks [1–3]. The e iology a ies wi h geog aphy. Hepa o ophic i uses a e he mos common cause o ALF in de eloping coun ies [4, 5]; d ugs a e he mos common cause o ALF in he indus ialized na ions [4, 6]. The mo - ali y o ALF is as high as 40–50%, and he cause o dea h in ALF includes b ain he nia ion due o aised in ac anial p essu e (35%) and sepsis wi h mul iple o gan ailu e [3]. Li e ansplan a ion is he only he apeu ic in e en ion wi h p o en su i al benefi in pa ien s wi h i e e sible ALF [2]. ALF pa ien s a e p one o in ec ion due o he immunologic de ec and he high-dependency ca e hey equi e [7]. Be ween 39% and 57% o ALF pa ien s expe- ience bac e ial in ec ion [8]. ALF has a high a e o in ec ion wi h g am-nega i e en e ic bac e ia in animal model [9]. G am-nega i e and g am-posi i e bac e ia can elici sepsis [7]. In ec ions and/o he esul ing SIRS a e impo an con ibu ing ac o s ha wo sen hepa ic ence- phalopa hy (HE) [8]. ALF is associa ed wi h MOF and a high incidence o sepsis (35.7%), which con ibu es o 23.1% o he mo ali y [7]; howe e , he unde lying Hindawi Media o s o Inflamma ion Volume 2017, A icle ID 5928078, 6 pages h ps://doi.o g/10.1155/2017/5928078 mechanism is s ill no clea . Ea ly inflamma o y media o s (such as TNF-α, IL-6, and IL-1β) a e ce ainly in ol ed in he pa hogenesis o ALF [10]; howe e , hese ea ly cy o- kines ha e limi ed clinical significance due o he na ow he apeu ic window. In con as , HMGB1 is a la e media- o o le hal sys emic inflamma ion [11], and HMGB1 has a p olonged he apeu ic window as compa ed o hose ea ly inflamma o y cy okines; ci cula ing TNF-αand IL-6 a e ele a ed o 5 days a e he onse o sepsis, and se um HMGB1 le els a e inc eased om day 7 un il a leas day 28 [12]. Eme ging e idences indica e ha HMGB1 is an impo an ac o ha links gu BT and sepsis, and ex a- cellula his ones a e also impo an ac o s ha signifi- can ly con ibu e o MOF in ALF. In his manusc ip , we e iew he cu en unde s anding o HMGB1 and his ones in ALF. 2. The Role o HMGB1 in ALF 2.1. HMGB1 is a Typical Ala min. Endogenous dange - associa ed molecula pa e ns (DAMPs) a e also known as ala mins, which signal cellula damage and ac i a e he inna e immune sys em [13]. Ala mins sha e he ollowing ea u es: (a) apid elease om cells in esponse o in ec ion o issue damage, (b) chemoa ac ion and ac i a ion o an igen-p esen ing cells, and (c) ac i a ion o inna e and adap i e immuni y [14]. HMGB1 is a ypical ala min [14]. 2.2. Passi e Release. HMGB1 can be passi ely eleased by nec o ic/damaged cells o ac i ely sec e ed by immuno- compe en cells [15]. Unde nec o ic condi ion, con en s o he cy osol a e dispe sed in o he ex acellula space due o cellula dis ess o damage [16]. In nec o ic cells, HMGB1 dissocia es om ch oma in and is eleased om cells o igge inflamma ion. Howe e , HMGB1 emains bound o ch oma in and ails o p omo e inflamma ion in cells unde going apop o ic o p og ammed cell dea h, in which cy osolic con en s a e seques e ed and no “seen” by inna e immune cells [16]. 2.3. Ac i e Sec e ion. In esponse o p oinflamma o y s imuli such as LPS, HMGB1 can be ac i ely sec e ed by immuno- compe en cells. This ac i e sec e ion occu s h ough a wo-s ep p ocess. Fi s , HMGB1 is ansloca ed ou o he nucleus o he cy oplasm a e JAK/STAT1- egula ed hype -ace yla ion o lysine esidues loca ed in he A and B box domains [17]. Once in he cy oplasm, HMGB1 is ac i ely sec e ed [17]. The ac i e sec e ion o HMGB1 ollows a nonclassical, esicle-media ed pa hway [18]. 2.4. Redox S a e and Ex acellula Func ions. HMGB1 con- ains h ee conse ed edox-sensi i e cys eines (C23, C45, and C106), and pos ansla ional modifica ion (oxida ion) o hese cys eines de e mines he bioac i i y o ex acellula HMGB1 [19]. The cy okine-s imula ing ac i i y o HMGB1 equi es C23 and C45 o be in a disulfide linkage, while C106 emains in a educed s a e. This disulfide HMGB1 can bind and signal ia TLR4/MD-2 complex o induce cy okine elease in mac ophage [19]. Mo eo e , binding o HMGB1 o TLR4 depends on educed Cys106 [20]. I all h ee cys eines a e in educed o m, his all- hiol HMGB1 has chemo ac ic ac i i y. This o m is p esen unde basal condi ions. Unde inflamma o y condi ions, his all- hiol HMGB1 is eleased and o ms a he e ocomplex wi h he chemokine CXCL12 o in e ac wi h he chemokine ecep o CXCR4 o p omo e cell mig a ion, bu no inflamma o y cy okine sec e ion. The hi d o m o HMGB1 occu s unde a s a e o comple e oxida ion whe ein each cys eine is ully oxidized o a sul onyl o m and is no associa ed wi h any biological unc ion [19]. Hype ace yla ion o HMGB1 shi s i s equilib ium om a p edominan nuclea loca ion owa d a cy osolic and subsequen ex acellula p esence. Hence, pos ansla ional modifica ions o HMGB1 de e mine i s ole in inflamma ion and immuni y [19]. 2.5. ALF Releases HMGB1 as a Signal o Inflamma ion. ALF occu s when he ex en o hepa ocy e dea h exceeds he hepa ic egene a i e capaci y [21], and he mode o he cell dea h ypically ollows one o he wo pa e ns: nec osis o apop osis [21]. In a clinical ial, HMGB1 ep esen s he ci cula ing indica o o nec osis du ing ace aminophen hep- a o oxici y; ull-leng h and caspase-clea ed ke a in-18 a e ci cula ing ma ke s o nec osis and apop osis; hype - ace yla ed HMGB1 is a se um indica o o py op osis and immune cell ac i a ion [22, 23]. Ele a ions in plasma HMGB1 and ke a in-18 can se e as mechanis ic bioma ke s o p o ide ea ly and sensi i e de ec ion o ace aminophen- induced acu e li e inju y a fi s p esen a ion o a hospi al [22]. Inc eased o al and ace yla ed HMGB1 and ull- leng h ke a in-18 a e associa ed wi h wo se p ognosis du ing clinical ace aminophen hepa o oxici y [23]. HMGB1 can be eleased eadily om nec o ic o damaged cells o se e as a signal o inflamma ion [16, 24]. HMGB1 plays an impo an ole in modula ing inflamma o y cascade in ac i a ed mac ophages: HMGB1 s imula es mac ophages o elease TNF-αand IL-6 [20, 25]. HMGB1 is a po en media o o sys emic inflamma ion in sepsis [26]. 2.6. HMGB1 Con ibu es o Mul iple O gan Inju ies. HMGB1 con ibu es o li e inju y in expe imen al ischemia- epe usion [27]. Exogenous HMGB1 injec ion can induce e iden li e inju y in mice [28]. HMGB1 impai s hepa ocy e egene a ion and blockade o HMGB1 imp o es hepa ocy e egene a ion in mice challenged wi h ace aminophen o e - dose [29]. A pa ly humanized an i-HMGB1 monoclonal an ibody a enua es ace aminophen hepa o oxici y and pos inju y inflamma ion in mice [30]. HMGB1 is eleased in o he se um a ea ly s age o D-galac osamine/LPS- induced ALF, and HMGB1 ac s syne gis ically wi h TNF-α o p omo e he inflamma o y li e inju y; his de imen al effec can be e e sed by monoclonal an ibodies agains HMGB1 and TNF-α[31]. Inhibi ion o sphingosine kinase- 1 amelio a es expe imen al ALF by educing high-mobili y g oup box 1 cy oplasmic ansloca ion in li e cells [32]. HMGB1 con ibu es o enal ischemia- epe usion inju y [33], sepsis-induced kidney inju y [34], and se e e acu e panc ea i is- ela ed kidney inju y [35]. HMGB1 also signifi- can ly con ibu es o hemo hagic shock- ela ed acu e lung 2 Media o s o Inflamma ion inju y (ALI) [36], hype oxia-induced ALI [37], and se e e acu e panc ea i is- ela ed ALI [38]. 2.7. HMGB1 Con ibu es o Gu Mucosal Inju y and Media es Gu BT in ALF. Gu mucosal inju y and in es inal BT in ALF is pa icula ly impo an because he in es ine is he bigges ese oi o bac e ia in he body and leakage o bac e ia o mic obial p oduc s, no ably LPS, om he lumen o he gu in o he sys emic ci cula ion, leads o ini ia ion o amplifica- ion o a sys emic inflamma o y esponse synd ome and mul iple o gan dys unc ion synd ome (MODS). The e o e, he leaky gu is hough o be he “mo o ” ha d i es he de elopmen o MODS [39]. The se um HMGB1 concen a ions a e significan ly inc eased in mice challenged wi h ace aminophen o e dose [29, 40]. ALF pa ien s also ha e high concen a ions o ci cu- la ing HMGB1, and he ci cula ing HMGB1 le els a e associ- a ed wi h disease se e i y [41, 42]. The ci cula ing HMGB1 con ibu es o gu mucosal hype pe meabili y and induces e iden BT in expe imen al hemo hagic shock and epe u- sion [43], and exogenous HMGB1 injec ion can induce gu hype pe meabili y and BT in mice [28]. Excep om he ci cula ing HMGB1, bile HMGB1 migh also significan ly con ibu e o in es inal mucosa inju y and induce e iden BT in ALF, because hepa i is E i us- ela ed ALF is associ- a ed wi h significan ly inc eased ci cula ing LPS [44], and LPS injec ion educes 40% o bile flow in a s [45]; adequa e bile is equi ed o main ain gu epi helial igh junc ion and in es inal bac e ial homeos asis [46]; dec eased gu luminal bile olume no only impai s in es inal igh junc ion bu also changes in es inal bac e ial homeos asis o acili a e BT [46, 47]. In addi ion, LPS injec ion ( o no mal animals) ma kedly inc eases bile TNF-αand HMGB1 le els, which can induce gu mucosal hype pe meabili y and e iden BT in mice [45], and his de imen al effec can be e e sed by neu aliza ion o he bile HMGB1 [45]. Expe imen al hepa o oxici y is associa ed wi h high inci- dence o gu de i ed g am-nega i e bac e ial in ec ion [9, 40]. Ace aminophen o e dose can induce e iden gu BT and se e e in es inal mucosal inju y in mice [40], and gu bac e ia can adhe e o he inju ed mucosa, which is necessa y bu no sufficien o induce gu BT [40], because blockade o HMGB1 educes 85% o gu BT, bu i does no dec ease gu mucosal pe meabili y in expe imen al ace aminophen o e dose [40]. This indica es ha BT is media ed (a leas pa ly) by HMGB1 and BT is likely an ac i e “ anscellula ”p ocedu e in which HMGB1 is also needed. 2.8. BT Induces/T igge s Sys emic Inflamma ion, Which Leads o MOF in ALF. Gu BT (o gu -de i ed LPS) induces/ igge s sys emic inflamma ion in c i ical illness [48, 49]. SIRS can lead o MOF in ALF [7]. Sepsis is a ypical example o SIRS igge ed by in ec ion [50]. The e o e, HMGB1 seems o be an impo an ac o ha links BT and SIRS in ALF. 3. The Role o Ex acellula His ones in ALF 3.1. ALF Pa ien s/Animals Ha e High Concen a ions o Ci cula ing His ones. ALF has a la ge numbe o hepa ocy e dea h [21]. The nec o ic issue/ he dying hepa ocy es elease HMGB1 and his ones [50], which can con ibu e o he high concen a ions o ci cula ing his ones in ani- mals challenged wi h concana alin A and ace aminophen o e dose o induce wo diffe en acu e a al li e inju y models [50]. Ci cula ing his ones a e significan ly inc eased in ALF pa ien s and in pa ien s wi h HBV- ela ed acu e-on- ch onic li e ailu e, and he le els o ci cula ing his ones a e co ela ed wi h disease se e i y and mo ali y [51, 52]. ALF pa ien s also ha e ele a ed plasma his one-associa ed DNA le els [53]. DAMPs ac i a e inna e immune cells in he li e and he ci cula ion, subsequen ly leading o issue inflamma ion and SIRS [53, 54]. 3.2. Ex acellula His ones Con ibu e o Mul iple O gan Inju ies in ALF. His ones a e impo an s uc u al elemen s o nuclea ch oma in and egula e gene ansc ip ion [54]; howe e , ex acellula his ones a e cell oxic o hos cells [50, 54] and elici immunos imula o y effec ha can induce mul iple o gan inju ies [50, 53–55]. Ci cula ing his ones exace ba e inflamma ion in mice wi h ALF [56]. The se a (con aining high le els o his ones) om ALF pa ien s can induce L02 cell (hepa ocy e) dea h and s imula e U937 cells (monocy es) o elease inflamma o y cy okines; hese de i- men al effec s can be abolished by non-an icoagulan hepa in ha can bind his ones, sugges ing ha ci cula ing his ones migh be he majo media o s o sys emic inflamma ion and cellula inju y in pa ien s wi h ALF [51]. The ci cula ing angiopoie in-2 le els, a ma ke o issue endo helial dys unc- ion and leakage, a e ma kedly inc eased in ALF pa ien s [53], and his migh be due o he oxici y o ex acellula his- ones in ALF pa ien s. Ex acellula his ones con ibu e o acu e a al li e inju y ia TLR 2 and TLR4 ecep o s, and neu aliza ion o his ones can amelio a e a al li e inju y in mice [50]. The le els o ci cula ing his ones a e significan ly highe a e li e ischemia/ epe usion, he endogenous his ones unc ion as ala mins in s e ile inflamma o y li e inju y h ough oll-like ecep o 9, and neu aliza ion o his one significan ly p o ec s agains inju y [57]. Ex acellu- la his ones can induce mic o ascula endo helial inju y, and he TLR2/4-media ed inflamma ion leads o acu e ubu- la nec osis in expe imen al acu e kidney inju y [58, 59]. Ex acellula his ones can inju e endo helial cells o cause mic o ascula h ombosis and hemo hage in expe imen al acu e lung inju y [60]. His ones also con ibu e o expe i- men al acu e b ain inju y, and neu aliza ion o his ones can educe he in a c size [61]. His one H4 and inc eased ci cula ing neu ophil ex acellula aps (NETs) can ac i a e pla ele s; his may cause mic o ascula h ombosis in sepsis [50, 55, 59, 62]. HMGB1 may induce he same biological esponse [63]. Ex acellula his ones kill endo helial cells and a e one o he majo media o s o dea h in sepsis [55]. 4. Conclusions HMGB1 and ex acellula his ones play a significan ole in inducing sys emic inflamma ion and MOF in ALF; neu ali- za ion o HMGB1 and his ones may p esen a no el he apy o ea ALF. 3Media o s o Inflamma ion A g aphical abs ac is p o ided as he Supplemen a y ma e ial a ailable online a h ps://doi.o g/10.1155/2017/ 5928078. Abb e ia ions ALF: Acu e li e ailu e MOF: Mul iple o gan ailu e SIRS: Sys emic inflamma o y esponse synd ome BT: Bac e ial ansloca ion HMGB1: High mobili y g oup box 1 NETs: Neu ophil ex acellula aps DAMP: Damage-associa ed molecula pa e n TLR: Toll-like ecep o APAP: Ace aminophen MODS: Mul iple o gan dys unc ion synd ome MD-2: Myeloid diffe en ia ion ac o 2 LPS: Lipopolysaccha ide D-GalN: D-galac osamine Sphk1: Sphingosine kinase 1. Con lic s o In e es The au ho s decla e ha hey ha e no compe ing in e es s. Au ho s’Con ibu ions Runkuan Yang designed and d a ed he manusc ip . Xiaoping Zou ca ied ou he li e a u e sea ch and d a ed he manusc ip . To Inge Tønnessen d a ed and e ised he manusc ip . Acknowledgmen s This in es iga ion was pa ly suppo ed by Sig id Juselius Funding in Finland and Sou h-Eas e n No way Regional Heal h Au ho i y, G an no. 2013121. Re e ences [1] J. Polson and W. M. Lee, “Ame ican associa ion o he s udy o li e disease. 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