Molecula Mechanisms

7/28/2019 Molecula Mechanisms

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Nosocomial infections

Ths a inctions that occu

duing tatmnt in a hospital

o a halthca svic unit and

a sconday to th patints

oiginal condition. Nosocomial

stms om th Gk wod

nosokomion maning

hospital (nosos, disas;

komo, to tak ca o). This

typ o inction is also known

as a hospital-acquid

inction.

Anaphylatoxin

Th po-inlammatoy

complmnt-activation

agmnts C3a, C4a and

C5a a also known as

anaphylatoxins. Thy mdiat

inlammatoy sponssthough cll activation and

induc cts such as

chmotaxis and histamin

las.

Neutrophil extracellular

traps

(NeTs). A st o xtacllula

ibs poducd by activatd

nutophils to nsna

invading micooganisms.

NeTs nhanc nutophil

killing o xtacllula

pathogns whil minimizing

damag to host clls.

Inrs lls f pptsis in lyphyts nnriti lls (DCs) frthr ntrit t th sp-prssin f in rspnss ring spsis (riwin ref. 4). In itin t sing rk rs inll nrs, th pptsis f lyphyts n DCsntrits t inprlysis thrgh th in-spprssi ffts f pptti lls. Hwr, iffrnttyps f in ll ri iffrnt pptti signlsring spsis. In ntrst t lyphyts n DCs, thpptsis f rphgs n ntrphils ss t nfft r n rs ring spsis7,8. Whrsth inrs pptsis f lyphyts n DCs rsltsin sr inspprssin, whih pls th ptintt risk fnosocomial inctions, rs ntrphilpptsis inrss th ystnr g s ythir pr-infltry tiity. Rnt t inittht T-ll-it spprssin f th rly inntin rspns is rqir t iniiz g tth hst n xiiz th hst fn rspns9.

Thr is nw in tht spsis is nitintht ffts nt nly th in syst t ls thr

ilgil systs, sh s th gltin systn th tni nrs syst (ANS)1012. In thisRiw, w sri th intrply twn nrllyhst-prtti hniss tht, thrgh plifitinr spprssin ring spsis, n instrntsf hr. W isss th hniss tht initit ys-rgltin f th infltry rspns n srith rl f spifi infltry itrs tht t sntrl hs t nnt th ris pnnts f thisrspns. In itin, w sri th pthgni rlsf th plsti ss (th gltin, firinlysisn plnt systs) n th rntly rgnizintrtins tht r twn th, s wll s nwinsights rgring th infln f th ANS n thinfltry rspns. T illstrt th plxity fth infltry rspns in spsis, w highlight thltiirtinl intrtins twn th ris sys-ts tht ntrit t spsis pthgnsis in plxinfltry ntwrk.

Initiation of the inflammatory response

In lls xprss st f rptrs knwn s pttrn-rgnitin rptrs (PRRs) tht rpily initit hstfn rspnss ftr ttin f tiss g riril inftin. Th prsn f iril inf-tin is tt y rgnizing nsr pthgn-ssit llr pttrns (PAmPs) tht r xprss

y th ining n inns irrgniss. Byntrst, in rgnitin f g tiss isit y intrlllr prtins r itrs tht rrls fr ying lls. Ths prtins r knwn slrins n, tgthr with PAmPs, r rfrr t sg-ssit llr pttrns (DAmPs)13. Tll-lik rptrs (TLRs), whih r sfily f PRRs,h rg s ril rptrs fr th rgnitin fDAmPs n inititin f th infltry rspns.

Dring spsis, thr is fll-lwn, systi ti-tin f in rspnss t th rls f ry highlls f DAmPs fr ining irrgniss n/rg hst tiss, whih ls t th rstiltin

f in lls. As rslt, spsis is pni y rkly iln ytkin rspns (knwn s ytkin str), whih nrts rspnss tht rnrlly nfiil fr fighting inftins int xssi,ging infltin.

TLR4-it rgnitin f lipplyshri(LPS), wll-hrtriz PAmP tht is fn in thtr rn f Gr-ngti tri, is thghtt n iprtnt triggr f th infltry rspnsin spsis14,15. TLR4 frs rptr plx with CD14n mD2, th lttr f whih ls hs n iprtnt rlin th rgnitin f LPS16,17. In itin t LPS, ri-s ngns ligns fr TLR4 h n sri,inling high-ility grp x 1 prtin (HmGB1),whih is n iprtnt itr ring th lt phs fspsis (s ltr)18. In th pst, hwr, stis f TLR4h n prlti wing t LPS ntintin inrinnt prtins, whih ight liit th infrti

l f s stis.It hs n pstlt tht rsstlk rs twn

TLR4 n th plnt syst, th f whih r

inl in th inititin f th infltry rspns inspsis19,20. mst strikingly, th plnt anaphylatoxinC5 ngtily rglts TLR4-it rspnss19.Th xtnt f th rgltry fft f plnt nTLR4-it ytkin prtin rrlts with thll f plnt-titin prts n, in trn, thytkins tht r in y TLR4 titin prg-lt xprssin f th plnt nphyltxin rp-trs C5ARn C3AR20,21. Th fining tht titinf TLR4 in pltlts initits th frtin fnutophilxtacllula taps t nsnr tri in th sltrfrthr nstrts th intrit intrply twninnt inity n th ltting syst in spsis22.

owing t its prinnt rl in th inititin f thinfltry rspns, TLR4 is ptntil thrptitrgt fr spsis. In rnt sty, ntiy-itlk f TLR4 n mD2 prtt ginst ply-iril spsis23(TABLe 1). Hwr, th rtlity fspti i tht xprss ysfntinl tnt TLR4prtin ws nt signifintly iffrnt fr tht f wil-typ i with spsis24. In hn spsis, linil trilstht lk TLR4 i nt shw nfiil ffts25, ps-sily s trgting TLR4 ight nly n fftitrtnt fr spsis s y Gr-ngti tri rLPS, whrs th inin f Gr-psiti n fnglspsis is inrsing.

S, th rly phs f spsis, whih is s y th

xssi titin f th hst pthgn-rgnitinsyst y lrg-sl tiss g n/r sr inf-tin, ls t sr ysrgltin f ris y sys-ts s rslt f th pr-infltry nirnnt.

Harmful central hubs in sepsis

Th isry tht infltry itrs ntnly ining irrgniss r inl in thpthgnsis f spsis hs pn p nw nfr th instigtin f pthlgil hniss finfltin. mny iffrnt itrs h nlink t th pthlgy f spsis, s f whih n nsir t ntrl hs in th infltry

R E V I E W S

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Tautomerase activity

Th ability to catalys thtautomization (switching om

on isomic om to anoth)

od-dopachom and

l-dopachom mthyl st

into thi cosponding indol

divats. This action was

usd by aly li oms o

synthtic pathways.

Macophag migation-

inhibitoy acto (MIf) has bn

shown to hav tautomas

activity; this volutionaily

consvd catalytic unction

is sponsibl o its

po-inlammatoy cts.

ntwrk(fIG. 1). Althgh thy iffr in trs f thirsr, kintis f rls n th stg f spsis ringwhih thy print, ths ntrl hs ll hplitrpi ffts n nnt ris pthwys f thin rspns.

C5a. As prt f th innt in rspns, th pl-nt syst is tit ring th rly stgs f spsis,whih gnrts lrg nts f th nphyltxin C5.At high nntrtins, C5 hs nrs hrflffts (riw in ref. 26; s ltr). Aringly, C5ts s ntrl itr in spsis y lting thrsysts inling th gltin s, TLR4-it rspnss n th rls f ytkins, shs rphg igrtin-inhiitry ftr (mIF) nHmGB1 (refS 10,19,2729).

MIF. mIF, whih ws n f th first ytkins t isr, hs pitl rl in rglting systin ll infltry rspnss (riw in ref. 30).Btril n- n xtxins, n pr-infltryitrs sh s tr-nrsis ftr (TNF),IFN n C5 r strng inrs f mIF srtin

y lkyts28,30. unlik thr ytkins, mIF is n-stittily xprss y lkyts n str intrl-llrly30. Aftr its srtin, mIF fntins s lssilpr-infltry ytkin n prts innt npti in rspnss y titing rphgsn T lls30. Intrstingly, th pr-infltrytiitis f mIF r it y its tautomas activity,whih is n y in ntining n ltin-rily nsr tlyti sit31. In itin t itingits wn pr-infltry ffts, mIF ls ins nplifis th prtin f thr pr-infltryytkins n prglts th xprssin f TLR4 yphgyts30. At high nntrtins, mIF prnts th

p53-pnnt pptsis f tit rphgs,whih rslts in sstin infltry rspnss30.Hwr, th xt hniss y whih mIF xrtsits ilgil ffts in th ntxt f infltin rnt ntirly lr. Althgh mIF tits intrlllrsignlling pthwys ftr its nytsis (whih is ntypil f ytkin tin)30, th CD74 rptrplx hs ls n sri t fntin s mIFrptr, fr whih signls r trns thrghCD44(ref. 32).

mIF is niq ng ytkins in tht it links thin syst with th nrin syst. In rspnst strss, mIF is srt y th hypthls, thntrir pititry gln n th rnl glns30,33.Iprtntly, mIF ntgnizs n rris th nti-infltry ffts f ngns stris30, whihight h nsqns fr th wll-stlish sf rtistris s thrpy fr spsis. engnsrtistris in th rls f mIF fr inlls, n s th inhiitry fft f mIF n th tinf rtistris is ngti-fk lp30,34,35.exssi prtin f mIF is hrfl in th tphs f spsis n pls lls f mIF rrlt with

spsis srity36. Ntrliztin f mIF r trgtingf its ttrs tiity ttnt th infl-try rspns n ipr sril in xprintlspsis36,37. In itin, this trtnt pprh lsrkly ipr sril n whn strt ftrth nst f iss, whih inits tht mIF is prising thrpti trgt36,37(TABLe 1).

HMGB1. HmGB1 ws riginlly sri s trnsriptin ftr38. Aftr its rfinitin s pr-infltry ytkin39, HmGB1 th fsf lrg nr f stis. HmGB1 is xprss ylst ll ll typs, xpt ths lking nls

Table 1 | Potential therapeutic targets in sepsis

Sste Prpse ecas Taret Reereces

Pattern- recognitionsystem

Inhibition of PRRs to dampen the inflammatoryresponse

TLR4 blockade 23

RAGE blockade 49

Pro-inflammatorymediators

Blockade of central hubs of the inflammatoryresponse to reverse established sepsis

MIF blockade or inhibition of its tautomerase activity 36,37

HMGB1 blockade 44,50

IL-17A blockade 52

Complement system Neutralization of the harmful effects of C5a;formation of the MAC not affected

C5a neutralization 58

Dual C5AR and C5L2 blockade 29

Coagulation system Induction of anticoagulant andanti-inflammatory effects

Administration of activated protein C 74

Selective PAR1 and PAR2 activation 83

Autonomic nervoussystem

Activation of the cholinergic anti-inflammatorypathway and/or suppression of the adrenergicpro-inflammatory pathway to restorehomeostasis

Parasympathetic branch:

Pharmacological stimulation of7nAChR on immune cells

Vagus-nerve stimulation42

104

Sympathetic branch:

Pharmacological modulation of- andb-adrenergicreceptor pathways on leukocytes

12, 108

7nAChR, 7-nicotinic acetylcholine receptor; C5AR, C5a receptor; C5L2, C5a-like receptor 2; HMGB1, high-mobility group box 1 protein; IL-17A, interleukin-17A;MAC, membrane-attack complex; MIF, macrophage migration-inhibitory factor; PAR1, protease-activated receptor 1; PRR, pattern-recognition receptor; RAGE,receptor for advanced glycation end-products; TLR4, Toll-like receptor 4.

R E V I E W S

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Cholinergic

anti-inflammatory pathway

This pathway in-tunscytokin poduction duing

inlammation in a highly

gulatd and lxiv

mann. Intaction o

actylcholin with th

7-nicotinic actylcholin

cpto (7nAChr) xpssd

by macophags sults

in th suppssion o

po-inlammatoy cytokin

poduction. Th main

componnt o this pathway is

th vagus nv o th

paasympathtic banch o th

autonomic nvous systm.

(sh s rythryts), n th in srs f HmGB1in infltin r rphgs, nyts n n-trphils40,41. HmGB1 n srt y in llsftr its tyltin in th nls n ssqnt trns-ltin t th ytpls, r it n rls frnrti lls40. Th ti srtin f HmGB1 is rg-lt y nlr ftr-B (NF-B) titin, prlythrgh nn-trnsriptinl hniss, lthghhw this rs is nt wll nrst42. Intrigingly,lthgh pptti lls r nt sr f xtrl-

llr HmGB1 (ref. 43), thy s rphgs trls HmGB1 ring spsis44. extrlllr HmGB1spifilly intrts with PRRs, inling th rptrfr n glytin n-prts (RAGe), TLR2n TLR4. HmGB1-in signlling hs plitrpiffts n in lls, prting infltin nth ptntilly hrfl isrptin f pithlil rri-rs18,40,45. In itin t th titin f PRRs, HmGB1inrss th pr-infltry tiity f ytkins(sh s IL-1b) thrgh ining t ths itrs,whih spprts th i tht HmGB1 ight nt tslly s pr-infltry itr, t ight lsfntin s rrir r DAmP46,47.

Althgh HmGB1 is rls systilly ringspsis, pls lls nt nssrily rrlt with t- r sril40. In ntrst t thr spsis-ssitytkins, th pk f HmGB1 rls rs ringltr stgs f th iss, n th lls f HmGB1 nt lwys rs in ptints wh h rrfr spsis39,48. Pthgn-ri lls n pr-infltry stili (sh s TNF, IL-1b n IFN)in th srtin f HmGB1 ring infltin40.Intrtin twn C5 n its thr rptr, C5-likrptr 2 (C5L2), ls triggrs th rls f HmGB1in spsis29. Intrstingly, HmGB1 srtin is nr thinfln f th ANS42. Atitin f th cholingic anti-inlammatoy pathway spprsss HmGB1 srtin yrphgs in spsis n iprs sril42.

owing t th plitrpi ffts f HmGB1 n thinfltry rspns n its lt rls in spsis, tr-gting HmGB1 ight prising thrpti strtgy.In xprintl sttings, th irt lk f HmGB1r inhiitin f RAGe ipr sril in ndotoxamian xprintl spsis39,44,49,50(TABLe 1). Siilr t th

trgting f mIF, ntrliztin f HmGB1 prntlthlity whn trtnt rr ftr th nst f spsisn it rrs th lpnt f lti-rgn filr44,50(TABLe 1). Hwr, th plxity f th nrlyinghniss f HmGB1 fntin prls th s fHmGB1 lk in linil trils t this pint.

IL17A. Th rnt isry f th IL-17 ytkinfily, th rs f whih h rg s ipr-tnt itrs f in rgltin, hs grtlyipr r nrstning f th intrply twninnt n pti in rspnss (riwin ref. 51). IL-17A, th first sri r fth IL-17 fily, is pr-infltry ytkintht is inly pr y T

H17 lls51. IL-17A is

ls srt y ris thr typs f in ll,inling ntrphils, CD8+ T lls, ntrl killr lls,thr T

H-ll ssts n T lls51. In rif, IL-17A

is inl in iting pr-infltry rspnssy triggring th prtin f ny thr ytkins(sh s IL-1b, IL-6 n TNF) n pris rsstlktwn lyphyts n phgyts51.

It hs rntly n shwn tht inrs IL-17Alls h rs ffts ring xprintl sp-sis 52. Ntrliztin f IL-17A rkly iprsril, n whn th trtnt ws inistrs lt s 12 hrs ftr th inititin f xprin-

tl spsis52(TABLe 1). Th prtti ffts f IL-17Alk wr ssit with rk ttntinf tri n rkly rs pls llsf pr-infltry ytkins52. In grnt withths t, th in vitro prtin f pr-infltryitrs y rphgs in rspns t LPS wssignifintly inrs in th prsn f rinntIL-17A52. Hwr, it is nt yt knwn whthr llsf IL-17A r inrs in ptints with spsis, r r-ing whih phs f spsis th ntrliztin f IL-17Awl nfiil in th linil stting. Bsth prtin f IL-17 is iprtnt fr irting thin rspns ginst s spifi inftins, th

|

Innateimmune response

Adaptiveimmune response

Autonomicnervous system

Endocrine system Coagulation

Production ofpro-inflammatorycytokines and chemokines

Adrenergicpathway

Cholinergicpathway Cholinergic

pathway

MIF

IL-17AHMGB1

C5a

TLR4

Figure 1 | Cetra bs te aatr respse sepss. During sepsis,

the complement anaphylatoxin C5a is generated following the activation of the

complement system and by the C5-convertase activity of thrombin of the

coagulation cascade. C5a triggers the release of pro-inflammatory mediators,including macrophage migration-inhibitory factor (MIF) and high-mobility group

box 1 protein (HMGB1), and it activates the coagulation cascade by inducing

tissue-factor expression (not shown). HMGB1 is a pleiotropic cytokine that binds to

Toll-like receptor 4 (TLR4) and acts as an endogenous alarmin to increase the release

of pro-inflammatory mediators. TLR4-mediated responses, in turn, are negatively

regulated by C5a. Similar to HMGB1, large amounts of MIF are released during

sepsis, which promotes a pro-inflammatory response by amplifying cytokine

secretion through the upregulation of TLR4 expression. MIF, which is produced by

the pituitary gland as well as by leukocytes, inhibits the anti-inflammatory effects of

endogenous glucocorticoids of the endocrine system, which, in turn, induce MIF

secretion. HMGB1 links the immune response with the autonomic nervous system,

which regulates the release of HMGB1 and other cytokines during sepsis.

Interleukin-17A (IL-17A), which is an important regulator of inflammation at the

interface between innate and adaptive immunity, orchestrates responses of both

innate and adaptive immune cells.

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Endotoxaemia

This is causd by th psnc

o ndotoxins, which a

divd om Gam-ngativ

bactia, in th blood. It sults

in systmic activation o th

inlammatoy spons, th

dvlopmnt o shock and

multi-ogan ailu and dath.

Modls o ndotoxamia a

usd in xpimntal sttings

to induc systmic

inlammation, but thy do not

ncssaily mimic human

spsis.

Septic cardiomyopathy

Th dcasd myocadial

unction that occus duing

spsis-associatd multi-ogan

ailu. Hypothss concning

th atiology o this dcasd

unction includ impaimnt

o mitochondial unction,

dysunction o th

b-adnocptoG-potinadnylat cyclas systm,

calcium-channl blockad

by dict and indict

cadiodpssant actos and

contactil impaimnt by

activatd lukocyts.

lk f IL-17A nr rtin nitins ights r hr thn g. Thrfr, it rins t trin whthr IL-17A is sfl trgt frthrpti intrntin in spsis.

Dysregulation of plasmatic cascades

Complementopathy. Th plnt syst n tit thrgh thr iffrnt pthwys, whih n-

rg n th gnrtin f th nphyltxins C3 nC5, C4 n th rn-ttk plx (mAC;ls knwn s C5C9). In linil stis f spsis,inrs nntrtins f C3, C4 n C5 in thpls h n link t pr t n sr-

il53,54. Intrstingly, C3 ight h nti-infltryprprtis in itin t ting s pr-infltrynphyltxin55. mi with C3AR fiiny wr rssptil t ntxin shk, whih ws pniy n inrs in th nntrtin f pr-infltryytkins in th pls. Bining f C3 t C3AR ntriggr th srtin f nti-infltry hrns yth pititry gln56, whih ight nt fr th nti-

infltry prprtis f C3.Nw isris ntin t inrs r nrstn-

ing f th nrs hrfl ffts f xssi C5prtin ring spsis. Th ffts f C5 ntritt inprlysis57, lti-rgn filr58, th pptsisf thyyts59 n rnl llry lls60, n il-ns in th gltin syst61(fIG. 2). In itin, C5

is inl in th lpnt fsptic cadiomyopathy62.Drs prssr in th lft ntril f th hrt hsn sr fllwing spsis, pni y f-ti ntrtility f riyyts; th f ths fftswr rrs y inistrtin f C5-spifi lk-ing ntiy62. Frthrr, whn rinnt C5 ws t islt rt riyyts in vitro, ntrtilysfntin ws in62, whih inits tht xssignrtin f C5 ring spsis ss riypthy.

Rnt stis rrrt n iprtnt rl fr C5in spsis n init tht it xrts its hrfl fftsin plx nnr29. In itin t C5AR, C5 nin spifilly t sn rptr, C5L2, th fntinf whih ws nknwn ntil rntly. It ws riginllyhypthsiz tht C5L2 fntins s y rptrfr C5, pting with C5AR fr ining f C563,lthgh nwr in inits tht C5L2 is fn-tinl rptr29,64. In hn spsis, th xprssin fC5L2 ws wnrglt n th srf f ntrphilsring spti shk65. Th xtnt f this wnrgltinrrlt with th lpnt f lti-rgn filr,

whih inits tht C5L2 ntrits t th pthgn-sis f spsis65. Thr is nw in tht C5AR nC5L2 prtily nhn th infltry rspnsring spsis, lthgh h rptr ight h sp-ifi n istint fntinl rls29. Fr xpl, C5-in rls f mIF pns n C5AR signlling,whrs C5L2 its th C5-pnnt rls f

|

C5L2 C5a C5AR

Tissue-factor expression Production of pro-inflammatory cytokines(MIF, HMGB1)

Neutrophildysfunction

Increasedapoptosis

Septiccardiomyopathy

Hypercoagulability

DIC SIRS

Defectiveclearanceof bacteria

Lethalbacteraemia

Immuno-deficiency

Immuno-suppression

Adrenergicinsufficiency

Septicshock

Heartfailure

Figure 2 | C5a s a cetra eatr te aatr respse sepss. During the early stages of sepsis, the

complement system is systemically activated, generating large amounts of the anaphylatoxin C5a. C5a, which is a central

molecule in the immunopathogenesis of sepsis, exerts its effects through interactions with its two receptors, C5a receptor

(C5AR) and C5a-like receptor 2 (C5L2). The expression of these receptors is upregulated during sepsis, and their

interactions with C5a contribute synergistically to harmful events in sepsis. The numerous effects of C5a include

activation of the coagulation cascade by the induction of tissue-factor expression, which can result in disseminated

intravascular coagulation (DIC). Furthermore, C5a triggers the release of pro-inflammatory cytokines, including

macrophage migration-inhibitory factor (MIF) and high-mobility group box 1 protein (HMGB1), which contribute to the

systemic inflammatory response syndrome (SIRS). In the later stages of sepsis, C5a is also responsible for sepsis-induced

neutrophil dysfunction, leading to the shut down of intracellular signalling (immune paralysis) and increased susceptibility

to secondary infections. C5a-induced apoptosis of thymocytes further aggravates immunosuppression, whereas the

apoptosis of adrenal medullary cells results in insufficiency of the adrenergic system, eventually leading to septic shock.

Recently, C5a and C5AR were also shown to be directly involved in the development of septic cardiomyopathy.

R E V I E W S



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Disseminated intravascular

coagulation

(DIC). Also known as

consumptiv coagulopathy,

this is a pathological pocss

in which th blood bgins to

coagulat thoughout th

nti body. Duing this

pocss, platlts and

coagulation actos a

dpltd, sulting in a

paadoxical situation in which

th is a high isk o

simultanous atal thombosis

and lag-scal hamohag.

DIC otn occus in citically ill

patints with ovwhlming

inction, ulminant spsis o

malignancy.

Thrombin

Thombin (also known as

activatd facto II) is th

cntal sin potas thatconvts solubl ibinogn into

insolubl stands o ibin. It

also catalyss many oth

coagulation-latd actions.

Tissue factor

A po-coagulant acto that

stimulats thombus omation

ollowing contact with blood by

acclating th action o th

coagulation actos facto VIIa

and facto Xa. It can also b

xpssd on th suac o

activatd ndothlial clls.

Activated protein C

A physiological anticoagulant.

Th activatd om dgads

facto Va and facto VIIIa o

th coagulation cascad.

Th potin-C pathway has

anti-thombotic activity,

as wll as anti-inlammatoy

and anti-apoptotic unctions.

Administation o human

combinant activatd

potin C o th tatmnt

o spsis might block

dysgulatd coagulation,

inhibit po-inlammatoy

pathways and psv

ogan unction.

Thrombomodulin

An intgal mmban potin

that is xpssd on th

suac o ndothlial clls. It

unctions as a co-acto in

thombin-inducd activation o

potin C in th anticoagulant

pathway by oming

complxs with thombin.

Thombomodulinthombin

complxs also stimulat

ibinolysis by claving

thombin-activatabl

ibinolysis inhibito (TAfI)

into its activ om.

HmGB1 fr phgyts28,29.Iprtntly, lkf ithr rptr prtts ginst lthlity in r-t frs f spsis, t nly th inhiitin f th C5rptrs pris prttin in sr spsis29.

Althgh inhiitrs f thr plnt ftrs(sh s C1 inhiitr r sll rinnt -plnt rptr 1) h h liit nfiil fftsin th lini66,67, C5 ight prising trgt frphrtil intrntin in spsis. Th ntgf this strtgy is tht th inhiitin f th hrflffts f C5 s nt intrfr with th ssly fth mAC, whih is ssntil fr fn ginst iningirrgniss68. Crrntly, l lk f C5ARn C5L2, rthr thn lk f C5 ln, ss t n nrging strtgy fr linil trils29(TABLe 1).Hwr, s plnt titin is n rly nt inspsis, th ilility f rlil n snsiti sitst t ssss th xtnt f plnt titin in ptint will ssntil fr sssfl intrntinirt t th plnt s.

Coagulopathy. In th linil stting f spsis, ys-rgltin f th gltin s (BOX 1) rsltsin jr plitins69. Th xtnt f titin fth gltin s ring spsis n rng frn insignifint ll t th rrn fdissminatdintavascula coagulation (DIC). In th initil phs fDIC, thombin titin rslts in intr- n xtrs-lr firin frtin ( prss knwn s hyprg-lility), fllw y th nsptin f gltinftrs n pltlt ysfntin (knwn s hypg-lility)70. In th lt phs f DIC, irslr firinpsitin is ftn ssit with th lpntf lti-rgn filr wing t prtrtins in thirirltin70. As DIC lps, infltinn gltin intrt in iirtinl nnr71.Atit thrin n prt th titin f

ris pr-infltry pthwys inling th

prtin f pr-infltry ytkins (sh sTNF, IL-1b n IL-6) n th gnrtin f C5 nytkins, in trn, n stilt gltin10,7274.Tissu acto, whih is ntrl ll in th initi-tin f DIC, is xprss y tit nthlil llsn y lls tht r nt nrlly xps t lflw, sh s s-nthlil lls n firlsts,n ls y irlting in lls75. In spsis, thpr-infltry nirnnt ss nnlrlls t prglt th xprssin f tiss ftr nthir ll srf, ling t th systi titinf gltin76.

Anthr nsqn f DIC is th inhiitin ffirinlysis. In itin t nthlil-ll ysfn-tin ring spsis, whih ls rs s rslt fth pr-infltry nirnnt, inrs l-ls f plsingn-titr inhiitr 1 (PAI1) nthrin-titl firinlysis inhiitr (TAFI) lt ipir rl f firin77. Als, th nsptin f

ris ftrs tht nrlly rglt th gnrtinf thrin, sh s ntithrin III, prtin C n

tiss-ftr pthwy inhiitr (TFPI), ntrits tth lpnt f DIC78.

Rinnt activatd potin C is rrntly th nlyppr rg fr th trtnt f spsis tht trgtsth infltry rspns74(TABLe 1). Prtin C, whihis rgltr f th gltin s, is tit ythrin n t thombomodulin n y nthlilprtin C rptr (ePCR) n nthlil-ll -rns79. Aftr issitin fr ePCR, tit pr-tin C ins t its -ftr, prtin S, whih thn rsltsin th intitin f ltting ftrs v n vIII 79. Initin t its ntiglnt tiity, tit prtin Chs prfn nti-pptti n nti-infltryprprtis. It rkly rss th pptsis fnthlil lls n lyphyts n xrts pr-firinlyti ffts y inhiiting PAI1 (refS 74,80). Thnti-infltry ffts f tit prtin C r

Box 1 | Coagulation

The coagulation cascade is initiated by the exposure of coagulation factors in the blood to subendothelial proteins

following damage to the blood-vessel endothelium. In primary haemostasis, circulating platelets bind to collagen

through their cell-surface glycoprotein Ia/IIa receptors to form a haemostatic plug at the site of injury. The adhesion of

platelets is stabilized by large, multimeric von-Willebrand-factor proteins, which form links between platelets,

glycoproteins and collagen fibrils. Simultaneously, the action of a complex cascade of coagulation factors (a group of

serine proteases that are activated in a sequential manner) results in the formation of fibrin strands, which further

strengthen the platelet plug (secondary haemostasis). Traditionally, the coagulation cascade has been described as two

pathways: the contact-dependent (intrinsic) activation pathway and the tissue-factor (extrinsic) pathway, the latter

being the main pathway for the initiation of blood coagulation. These two pathways converge on the activation of

thrombin, which converts fibrinogen to fibrin and ultimately results in the formation of a fibrin-crosslinked clot. The

contemporary description of physiological haemostasis in vivo does not divide coagulation into cellular and plasmatic

components or different activation pathways, but instead describes that coagulation involves three phases121. First, the

initiation phase is characterized by the exposure of tissue factor after endothelial damage, resulting in the activation of

thrombin. Second, thrombin augments coagulation by fully activating platelets and increasing platelet adhesion during

the amplification phase. Third, large amounts of thrombin are generated on the surface of activated platelets, resulting in

the stabilization of the blood clot in the propagation phase121.

Eventually, blood clots are organized (which involves the laying down of collagen and the formation of vascular

channels) or absorbed by fibrin degradation (a process known as fibrinolysis). The main protease of the fibrinolysis

cascade is plasmin, which is activated by tissue plasminogen activator, urokinase-like plasminogen activator, thrombin

and fibrin itself. Under normal conditions, the balance between the coagulation and fibrinolysis systems, which is

maintained by various regulatory mechanisms, prevents intravascular coagulation.

R E V I E W S

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it y ePCR n th lg f prts-titrptr 1 (PAR1), whih hs ntrl rl in linkinggltin n infltin8183(TABLe 1).

Th prtin-C pthwy is prtilrly ssptilt inhiitin y infltry rspnss in spsis-ssit DIC71. In itin t rs in th llf prtin C, th wnrgltin, shing n l-g f thrlin n ePCR r th in ssf ysfntin f th prtin-C pthwy84. HmGB1inhiits th prtin-C pthwy y intrfring with ththrinthrlin plx n it ls pr-ts gltin y stilting tiss-ftr xprs-sin n inhiiting tiss plsingn titr (TPA), srin prts n th srf f nthlil lls thttits plsin f th firinlysis s85.

Th inistrtin f tit prtin C in spsisspprsss pr-infltry ytkin prtinn rss th hsin f phgyts t injrnthli thrgh ePCR- n PAR1-pnntsignlling74,86. Hwr, th ntiglnt tiity ftit prtin C ight xrt ling -

plitins in ptints wh slly h prisltting syst74. Ftr linil trils shl sssswhthr fr f tit prtin C tht s nth ntiglnt ffts87 will ipr linil ffi-y (tht is, rs spsis rtlity) n sfty (thtis, rs th inin f ling plitins) inhns with spsis.

Linking complement and coagulation. Tritinlly,th plnt n gltin systs r sris sprt ss. As snnts f nnstrl pthwy, th r prtlyti ss tht rps f srin prtss with n strtrlhrtristis n siilr titing stili71,88. Thrltinship is nt liit t th ihil siilrityin thir srin prtss, hwr, s ths tw pthwysr ls link y ny tl nntins tht fr plx ntwrk(fIG. 3).

Dring spsis, th tit gltin pthwyprispss t thrsis n DIC, whih frthrggrt th xssi infltry rspns nplnt titin71. A wll-knwn intrtintwn th plnt n gltin systs isth titin f th lssil plnt pthwy ygltin Ftr XII, whih n tit th pl-nt pnnt C1 (ref. 89). mr rntly, it hs nshwn tht thrin n fntin s C5 nrtsin C3-inpnnt nnr10. This rsstlk is pr-tilrly intrsting, nt nly s thrin n

C5 r ntrl ftrs in thir rspti ss, tls s this inits tht C5 n th mAC n gnrt in th sn f pstr plnttitin. Siilr t thrin, kllikrin n plsinirtly l C3 n its titin frgnts90,91. Inn inirt ngti-fk lp, thrin-titTAFI intits C3 n C592.

|

Coagulation Complement Fibrinolysis

FXIIa

FXa

FVa

FVIIIa

Prothrombin

Thrombin

Activatedprotein Cprotein S

Tissue factor

C4BP

MAC

TAF1

Fibrinogen

C4b C3

C3aC5

C5a C5b

Classical:C1 and C4

Lectin:MASP2

Alternative:C3b

TPA, UPA

PAI1,PAI2 Plasminogen

Plasmin

Fibrin

Fibrin-degradationproducts

Figure 3 | Crss-ta betwee te cpeet, caat a brss sstes. The complement system,

the coagulation cascade and the fibrinolysis cascade communicate through many direct and bidirectional interactions(indicated by red arrows). Activated clotting Factor XII (FXIIa) can activate the classical complement pathway through

cleavage of the complement component C1. Similarly, thrombin, kallikrein (not shown) and plasmin directly cleave

complement component C3, as well as its activation fragments. Moreover, thrombin can cleave C5 into C5a, which

occurs independently of C3 and therefore represents a bypass of the three traditional complement-activation

pathways (that is, the classical, lectin and alternative pathways). Thrombin-activatable fibrinolysis inhibitor (TAFI)

inactivates C3a and C5a in a negative-feedback loop. The complement system also amplifies coagulation through the

C5a-mediated induction of expression of tissue factor and plasminogen-activator inhibitor 1 (PAI1) by leukocytes,

the latter of which inhibits fibrinolysis. In addition, mannan-binding lectin serine protease 2 (MASP2) of the lectin

complement-activation pathway triggers coagulation by converting prothrombin to thrombin. C4b-binding protein

(C4BP) of the complement pathway inhibits protein S, which is a co-factor for the activated protein-C pathway of

coagulation inhibition, which indicates that the inhibition of anticoagulant mechanisms further augments the

pro-coagulant activities of complement. MAC, membrane-attack complex (C5bC9); TPA, tissue plasminogen activator;

UPA, urokinase-like plasminogen activator.

R E V I E W S

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Catecholamines

Tyosin-divd mdiatos

that a poducd mainly by

th adnal mdulla and by th

postganglionic ibs o thsympathtic nvous systm.

rcntly, it has bn ound

that immun clls a also a

souc o catcholamins. Th

most abundant catcholamins

a th biognic amins

adnalin, noadnalin and

dopamin, which unction as

nuotansmitts in th

sympathtic banch o th

autonomic nvous systm

though intaction with

adngic cptos xpssd

by numous cll and tissu

typs.

Th plnt syst plifis gltin yifitin f phsphlipi rns (whih is

rqir fr th inititin f gltin thrgh tis-s ftr), y titing pltlts n y ining thxprssin f tiss ftr n PAI1 y lkyts71,93,94.Aringly, lk f C5 ring xprintl spsisrkly lirt th ffts f DIC61. In itin,nnn-ining ltin srin prts 2 (mASP2), pr-ts tht is hrtristi f th ltin pthwy f -plnt titin, n tit gltin y lingprthrin int ti thrin95. Th pr-glnttiitis f plnt r inrs whn ntig-lnt hniss r inhiit; fr xpl, th frtinf plx twn C4-ining prtin n prtin Srslts in rs in th ilility f prtin S t ts -ftr fr th nti glnt prtin-C pthwy96.In itin, srl inirt inflns f th pl-nt syst n gltin tht r it thrghthr pr-infltry ftrs (sh s TNF, IL-6 nHmGB1) h n nt.

In sry, th plnt, gltin n firin-lysis systs r tightly nnt thrgh ltiplirt intrtins f srin prtss, whih tgthrk p pls srin-prts ntwrk. In th st-ting f spsis, rsstlk twn th plnt ngltin pthwys is f prtilr iprtn, s thirnntrll titin is n ssntil ntritr t thpthgnsis f th iss.

The autonomic nervous systemRnt ns in th fil f nrinlgy hshwn tht th nrs syst n th in systnit ring infltin. Th in pthwysinl in this rsstlk r th hypthlipititryrnl xis n th ANS11,97,98(BOX 2). In lls nls synthsiz n rls nrtrnsittrs n xprssrptrs fr ths itrs11,12,99. S, ths nri-trs fntin s th ihil lngg f th nrnrinin ntwrk, whih llws th y tpt rpily t hngs f intrnl n xtrnl nirn-nts. Aringly, mnfr n Try h sggsttht sr spsis is nrnrin isrr100.

The parasympathetic ANS. Signlling f th gs nry nggnt f hlinrgi rptrs xprss y

phgyts hs n iprtnt rgltry rl in infl-tin101. Atitin f

7-nitini tylhlin rp-

trs (7nAChRs), ithr y gs-nr stiltin r

y7nAChR gnists, rss intrlllr ytkin

synthsis y rphgs n pns th infl-try rspns42,101(fIG. 4). In thr wrs, infltinis nr nrnl ntrl y th ANS, whih n rflx-ily lt th infltry rspns y inhiitingth prtin f pr-infltry ytkins. Thisnpt hs thrfr n tr th infltryrflx11. Th ffrnt r f th infltry rflx isth hlinrgi nti-infltry pthwy102, whih is rst rgltr f ytkin prtin.

Rnt stis h shwn tht th rnh f thgs nr tht innr ts th spln is ril frth spprssin f ytkin synthsis in spsis103. Thspln is n iprtnt sr f TNF ring spsisn splnty signifintly rss systi nhpti lls f TNF in spti i102,103. In itin,irt hlinrgi ltin f in lls thttrnsit thrgh th spln ntrits t th rgltinf infltin t istnt sits. In xprintl spsis,titin f th hlinrgi nti-infltry pthwyinhiit th prtin f pr-infltry itrs(inling HmGB1 n TNF) n rkly inrssril, n whn rri t s lt s 24 hrs ftrth nst f iss42,104.

The sympathetic ANS. Th in trnsittrs f thsypthti rnh f th ANS r catcholamins, whiht thrgh ining t rnrgi rptrs. Th rlyphs f spsis is hrtriz y high nntrtinsf irlting thlins, whih st th initilinfltry rspns. Ltr in spti shk, th pr-tin n rls f ngns thlins n insffiint fr intining qiliri f thrislr syst (s init y th n fr t-hlin inistrtin ring spti shk). Thpltin f ngns thlin srs ight s y th pptsis f rnl llry lls60.

Box 2 | The autonomic nervous system

The autonomic nervous system (ANS) is part of the peripheral nervous system. It has three components: the parasympathetic

branch, the sympathetic branch and the enteric nervous system. The ANS maintains homeostasis in the body by controlling vital

functions that include heart rate, respiration rate, digestion, perspiration and body temperature. Traditionally, the sympathetic

and parasympathetic branches of the ANS were thought to be endogenous neuronal antagonists. Therefore, the classical

terminology referred to adrenergic responses (sympathetic) as fight or flight and to cholinergic responses (parasympathetic)

as rest and digest responses. However, it is now clear that the relationship between these pathways is more complex.

Signal transmission in the parasympathetic branch of the ANS is mediated by acetylcholine and its receptors, which areabundantly expressed by many cell types122. The main peripheral component of the parasympathetic branch of the ANS

is the vagus nerve.

The sympathetic branch of the ANS consists of sympathetic neurons and the adrenal medulla. Catecholamines, which

are the main mediators of the sympathetic branch, mediate pleiotropic effects by interacting with adrenergic receptors

that are ubiquitously expressed by nearly all tissue and cell types122. The activation of adrenergic receptors triggers an

intricate intracellular signalling network that has yet to be fully understood.

The enteric nervous system, which controls the gastrointestinal system, is also considered to be part of the ANS. Anatomically,

the enteric nervous system consists of a large number of neurons that are embedded in the lining of the gastrointestinal tract.

Although the enteric nervous system can operate autonomously, it communicates closely with the central nervous system, and

is associated with a considerable amount of sympathetic and parasympathetic innervation.

R E V I E W S

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10747&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10747&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


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Kupffer cells

Th sidnt macophags o

th liv, which a divd

om blood monocyts. Thy

phagocytos pathognic

paticls and micooganisms

that hav ntd th liv

sinusoids.

Th nitnt ysfntinl rnrgi ltinf hrt n l ssls ring spti shk initstht ipirnt f rnrgi rgltin ntrits tri-irltry filr105.

It ws riginlly thght tht th synthsis f t-hlins ws rri t nly y th nrnl lls fth sypthti rnh f th ANS, t it hs nw nshwn tht lkyts r ls n nnt sr fthlins12,99. Lkyts ls xprss rnrgirptrs, whih inits tht thlins ight

h trin n/r prrin ffts n inlls12,99. Th titin f rnrgi rptrs nin lls triggrs istint n finly tn ytkinrspnss thrgh NF-B-pnnt hniss12,99.

Dring spsis, thlins xrt in-ltry ffts thrgh - n b-rnrgi rptrstht r xprss y in lls106108. Stiltin fths rptrs ltrs lyphyt trffiking, slrprfsin n ll prlifrtin n pptsis, thryffting th fntinl rspnss f lkyts109111.Th rspns f ntrphils n rphgs inprtilr nrlis rnrgi rgltin y th-lins, s th rls f pr-infltry ytkins

y ths lls is tightly rglt y-rnrgi rp-trs12,111. Cthlins ight ls ntrit t thltris ffts f spsis thrgh irt stiltinf tril grwth in th gstrintstinl syst,whih ight ntrit t tri thrgh thtrnsltin f ntri tri int th lyphti nl prtnts112.

In sry, titin f th rnrgi pthwysf th sypthti rnh f th ANS ring th rlyphs f spsis prts pr-infltry rspnss nggrts rs nts, lthgh th hniss thtnrli ths ffts h yt t lt in til.

The enteric nervous system. Spsis n r s rsltf infltin in th inl ity (knwn s pri-tnitis) tht rslts fr th isrptin f rrirs thtprtt th stril prtnt f th inl ityfr pthgns in th intstinl ln. It ws hypth-siz tht th trnsltin f ntri tri int thl ight ls r whn th gt ws nt th insr f infltin (fr xpl, in sittins sh

s pnni r rn injry), t gnrl lss fintstinl pithlil rrir fntins s rslt f th pr-infltry nirnnt. Rnt rsrh hs shwntht th gt n pr lrg nts f thlinsring spsis, whih r rls int intstinl l113.Cthlins tht rin fr th intstins thrgh thprtl in int th lir n ltr th fntinl stt fKup clls n hptyts thrgh

2-rnrgi rp-

tr signlling114, ltitly ntriting t th rls fpr-infltry ytkins, hptlllr ysfntinn lir filr113,115. Cthlin-in titinf Kpffr lls ight ls n iprtnt sr f thytkin str ring spsis116. Aitinl stis rrqir t intify th ll sr f intstin-rithlins ring spsis. It rins pssil thtithr th ntri nrs syst r rsint inlls in Pyrs pths n lyph ns f th intstinlsyst (r th) r rspnsil fr th gnrtin fintstin-ri thlins ring spsis.

ANStargeted therapy. mltin f th ANS ight prising pprh fr th trtnt f spsis sn ltrnti t lking pr-infltry itrsirtly (TABLe 1). Whrs th hlinrgi pthwyttnts th in rspns n is nsir t nti-infltry11, rnrgi stiltin prtsth rls f pr-infltry itrs n th

rritnt f lkyts12(fIG. 4). Gin tht n il-n twn ths tw rnhs f th ANS ntritst th lpnt f spsis, stiltin f th hlinr-gi gs nr n/r spprssin f rnrgi pth-wys ight hlp t rstr hstsis. It hs rntlyn shwn tht trnstns ltril stiltinf th gs nr ipr sril n rs thll f pr-infltry itrs in xprintlspsis104. Althgh this pprh ight nt yt ryfr s in th lini, th ft tht this trtnt fr spsiswl nn-insi n inpnnt f phrki-ntis nlik th inistrtin f rgs ks itprtilrly ttrti.

|

Cholinergicanti-inflammatory pathway

Adrenergicpro-inflammatory pathway

Vagus-nerve stimulation

Release of acetylcholine(or 7nAChR agonists)

Decreased release ofpro-inflammatory mediators

Increased release ofpro-inflammatory mediators

Suppressed inflammatory responseAmplified inflammatory response

Release of catecholamines fromadrenal medulla, sympathetic neurons,phagocytic cells and lymphocytes

Acetylcholine

7nAChR

Macrophage

Adrenergicreceptor

Catecholamine

a b

Figure 4 | Eects patwas te AnS aat r sepss. The

balance between the two branches of the autonomic nervous system (ANS) can directthe inflammatory response towards pro- or anti-inflammatory outcomes. Whereas

activation of the cholinergic anti-inflammatory pathway (part of the parasympathetic

branch of the ANS) dampens inflammation, stimulation of the adrenergic pathways

leads to amplification of the inflammatory response. a | In the adrenergic

pro-inflammatory pathway, high concentrations of circulating catecholamines amplify

the initial inflammatory response, particularly in the early phase of sepsis. Sources for

catecholamine production and release are the adrenal medulla, sympathetic neurons

and leukocytes (phagocytic cells and lymphocytes). Catecholamines exert their

immunomodulatory effects through - and b-adrenergic receptors that are expressed

by various cell types, resulting in the increased release of pro-inflammatory mediators.

b | By contrast, the activation of the cholinergic anti-inflammatory pathway in sepsis

attenuates the inflammatory response. These effects are mediated through

engagement of7-nicotinic acetylcholine receptors (

7nAChRs). Acetylcholine is

released following vagus-nerve stimulation, resulting in inhibition of the synthesis and

release of pro-inflammatory mediators such as high-mobility group box 1 protein andtumour-necrosis factor.

R E V I E W S



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(McGraw-Hill, New York, 2006).

Acknowledgements

This work was supported by grants GM-29,507, HL-31963and GM-61656 from the National Institutes of Health, USA,

to P.A.W.

DATABASESEntrez Gene:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene

antithrombin III|C3AR | C5AR |C5L2 | CD14|CD44| CD74 |

EPCR| HMGB1 | IFN| IL-1b|IL-4 | IL-5 | IL-6 | IL-10|IL-12|

IL-13 | IL-17A|MASP2 | MD2|MIF | PAI1|PAR1 | protein C|

protein S | RAGE |TAFI | TFPI | thrombin | tissue factor|TLR2|

TLR4 | TNF | TPA

FURTHER INFORMATIONPeter Wards homepage:http://www.med.umich.edu/

immprog/faculty/wardp.htm

All linkS ARE ACTivE in ThE onlinE Pdf

R E V I E W S

NATuRe RevIeWS | immunology voLume 8 | oCToBeR 2008 | 787
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