동맥경화증에서 dendritic cell의 역할에 대한 고찰 · 2013-03-07 · cell 등 다른...

52 © 2013 Hanyang University College of Medicine http://www.e-hmr.org

Current Understanding of Dendritic Cells in Atherosclerosis Jae-Hoon Choi

Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Korea

서 론

수지상세포(dendriticcell,DC)는외부로부터유입된항원(anti-gen)또는내부에존재하는항원을탐식하고분해한후peptidefragment를majorhistocompatibilitycomplex(MHC)와결합된형태로세포표면으로제시하여항원에특이적인Tcell의증식과활성을유도할수있는대표적인antigenpresentingcell(APC)로잘알려져있다.DC는RalphM.Steinman박사와ZanvilA.Cohn박사에의해1973년도에처음명명되어보고되었다.연구원과지도

교수관계였던당시이두DC연구의선구자들은마우스면역기관

에서나뭇가지모양의돌기를지속적으로뻗어내는세포를발견하

고이를그리스어로나무를의미하는단어에서유래된“dendritic”이라는단어를사용하여“dendriticcell”이라지칭하였다[1,2].초기에는DC가면역계에서매우중요한역할들을수행하고있는독

립된lineage의면역세포로인정되지못했고,심지어대식세포와명확하게구분할수없는mononuclearphagocytesystem(MPS)에포함된다고주장되기도했다[3].그러나최근의일련의연구들을통해다양한종류의DCsubset들이존재하고이들은림프기관및다양한말초조직에존재하고대식세포와기능적으로명백하게다르다는점이확인되었다[4].나아가다른면역세포군처럼독립된분화과정을거치는면역세포군임이밝혀졌다[5].마우스림프기관에존재하는대표적인DCsubset으로는CD8+DC,CD8-DC,plas-macytoidDC(pDC),monocyte-derivedDC(Mo-DC)등으로나눌수있고,말초조직에존재하는DC들도많은종류의subset들이부위에따라존재하지만크게CD11b+DC와CD103+DC로구분

할수있다[4].이들DCsubset들은크게두가지pathway에의존적

으로발달하게되는데,fms-liketyrosinekinasereceptor-3(Flt3)/flt3ligand(Flt3L)에의존적으로발생하는classicalDC(cDC)와

Hanyang Med Rev 2013;33:52-58http://dx.doi.org/10.7599/hmr.2013.33.1.52

pISSN 1738-429X eISSN 2234-4446

Dendritic cells (DCs), first identified in 1973, have been shown to be the principal cells in-volved in antigen presentation to T cells, and are more potent in the presentation of anti-gen than B cells or macrophages. Atherosclerosis is a representative chronic vascular in-flammatory disease in which various immune cells have been implicated in the formation of atherosclerotic plaque. Thus, the quantification and elucidation of activity of immune populations in atherosclerotic vessels are very important in understanding the pathogen-esis of atherosclerosis. Several current studies demonstrate that DCs which exist in athero-sclerotic lesion appear to play several important roles in atherosclerosis. This review sum-marizes current understandings on the function of DCs in atherosclerosis, and also sug-gests future directions for research of DC function in inflammatory atherosclerotic vascular disease.

Key Words: Dendritic Cells; Blood Vessels; Inflammation; Atherosclerosis

동맥경화증에서 Dendritic Cell의 역할에 대한 고찰 최재훈

한양대학교 자연과학대학 생명과학과

Correspondence to: Jae-Hoon Choi우133-791 서울시 성동구 왕십리로 222, 한양대학교 자연과학대학 생명과학과 516호 516-ho, Department of Life Science, College of Natural Sciences, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Korea Tel: +82-2-2220-2540 Fax: +82-2-2299-3495 E-mail: [email protected]

Received 26 November 2012Revised 4 January 2013Accepted 12 January 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecom-mons.org/licenses/by-nc/3.0) which permits un-restricted non-commercial use, distribution, and reproduction in any medium, provided the origi-nal work is properly cited.

Hanyang Med Rev 2013;33:52-58 http://www.e-hmr.org 53

최재훈 • 동맥경화증에서 Dendritic Cell의 역할에 대한 고찰 HMR

pDC가있고,M-CSF에의존적으로발생하는Mo-DC로나누어진

다.이들DCsubset들은면역반응에서다양한역할을수행하는것으로알려져있다.특히마우스에서CD8+DC는cross-presenta-tion에뛰어난능력을보이고[6],pDC의경우TLR7/TLR9을활성

화시키며,typeIinterferon을분비하여virus감염을억제한다[7].Mo-DC는염증반응시monocyte로부터분화되어염증반응에관여하는것으로알려져있다[8].또한장에서CD11b+DC들은Th1,Th17의분화를촉진하고,반면CD103+DC들은조절T세포(regu-latoryTcell,Treg)로의분화를촉진할수있는것으로알려져있다

[9].이와같이많은조직들에서DC의역할에대한연구가수행되

고있고,중요한사실들이많이발견되었다.반면혈관에존재하는DC및심혈관질환발생시에그역할에대해서는아직까지밝혀야할부분이많이있다.본논문에서는다양한심혈관계질환중동맥

경화발병과정에서현재까지알려진DC의역할에대해고찰하고앞으로더이해해야할부분에대해논하고자한다.

본 론

1. 동맥경화증의 발병기전

동맥경화증은동맥벽에지질과섬유질의축적및염증세포들의침윤이특징적인만성염증성질환으로특히뇌혈관,관상동맥등에서발생하면뇌졸중,허혈성심질환등의치명적인결과를초래한

다.동맥경화증의발병요인들에는고지혈증이가장흔한원인이되고,그외고혈압,당뇨병,스트레스,운동부족등다양한요인에의해서도유발이촉진될수있다.동맥경화초기에는혈중의저밀

도지단백질(lowdensitylipoprotein,LDL)이혈관내피하(subinti-malspace)에유입되어쉽게산화적으로변형될수있다.이렇게산화된LDL은혈관내피세포에서다양한염증관련인자를발현시키

고,병변부로의단핵구들의침윤을유도한다.침윤된단핵구들은지질들을탐식하게되어동맥경화에서특이적으로관찰되는포말세포(foamcell)를형성하게된다[10].T림프구역시동맥경화병변

으로침윤되게되고,다양한시토카인(cytokine)을분비하여병변

을촉진하는역할을수행한다[11].사람에서T림프구활성에중요하게작용하는자가항원은산화지질(oxidizedLDL)이다.이산화지

질은MCP-1등다양한염증성시토카인들을발현시켜동맥경화

를촉진시킨다[11].

2. 새로운 동맥경화 세포표적 발굴의 필요성

이전에서술한대로동맥경화는다양한면역세포들이관여하고있는면역질환이므로정상및동맥경화증이발병된혈관에서면역반응및관련된면역세포들의역할을규명해내는것이아주중요하다.현재까지세계시장매출상위15대의약품중콜레스테롤조절제인Lipitor(atorvastatincalcium)(PfizerInc.,NewYork,NY,

USA)와Crestor(rosuvastatincalcium)(AstraZenecaInc.,UK),혈전형성을억제해서동맥경화관련질환을완화시킬수있는Plavix(clopidogrel)(Sanofi-AventisInc.,France)와같은동맥경화증을억제하기위한다양한약물들이개발되어사용되고있음에도불구하고동맥경화증으로입원하거나사망하는환자의수는줄어들

지않고있다.따라서많은연구자및제약회사에서새로운개념의치료제개발의필요성을제기하고있다.신개념의동맥경화치료제

를개발하기위해서는보다새로운접근법을이용해서동맥경화발병시keyplayer로역할을하는세포를새롭게찾아내는것이매우중요하다.그동안여러면역세포군중대식세포와T림프구의동맥

경화발병에미치는역할에대해많은연구들이수행되었고,이를통해서많은동맥경화치료제개발에대한연구가이들세포들을대상으로연구가되었다.현재이들세포들을억제할수있는많은동맥경화치료후보물질들이발굴되었으며실제임상에사용하기위한연구가진행되고있다.그러나상대적으로동맥경화에서DC의기능및DC를이용한새로운동맥경화치료제의개발은미진한편이다.최근의동맥경화연구에서밝혀진DC의다양한역할은DC가동맥경화치료제개발에있어중요한타깃이될수있음을보여준다.

3. 사람의 동맥경화 형성에 있어 DC의 역할에 대한 현재까지의

이해

1995년도에Bobryshev박사가사람의정상동맥에서S-100에대한면역염색을통해처음으로DC-likecell들이존재한다고보고하

였다[12].이후DC가다양한혈관질환에서역할을수행하고있다

고보고되었다.예를들어giantcellarteritis(GCA)가형성된혈관

에서S-100+DC들은주로외피(tunicaadventitia)에존재하며,Tcell의활성을유발함으로써병변형성을증가시킬것으로예상되

었으며[13],Takayasu’sdisease환자의혈관에형성된병변에서많은수의DC가관찰되고,이들은T림프구와의상호작용을통해병변을촉진하는것으로파악되었다[14].따라서혈관에존재하는DC는여러염증성혈관질환에관여하고있음을알수있다.최근동맥경화증의발병과정에서DC의역할에대해많은관심이집중

되고있고,이에대한연구결과들도많이발표되고있다.초기의혈관DC연구에서정상적인혈관의내피(tunicaintima)에존재하는S-100+DC들은보통의동맥경화가잘일어나지않는혈관부위보

다는동맥경화가일어나기쉬운부위의혈관내피에많이분포하고있다는것이밝혀졌다[12].또한이세포들은피부상피조직에서관찰되는Langerhanscell의특징인Birbeckgranule을함유하고있는것으로알려졌다[15].이러한DC들의혈관에서의네트워크는10세이전의어린사람에서도관찰된다고보고되었다[16].따라서정상혈관에서DC들은동맥경화병변이형성되기전이미병변형성에취약한부위에존재하고있다.그러나아직까지정확하게동

Hanyang Med Rev 2013;33:52-5854 http://www.e-hmr.org

Jae-Hoon Choi • Current Understanding of Dendritic Cells in AtherosclerosisHMR

맥경화병변형성에취약한부위에어떤기전으로병변형성이전

에DC가침윤될수있는지에대해서는더연구가필요하다.동맥경화가형성된혈관에서DC는더욱더많이관찰되며,그중

일부는T림프구와소수의대식세포와접촉하고있다.특히초기동맥경화병변을가진젊은(15-34세)환자들의대동맥에서다수의DC가존재한다는사실을두고판단하면,DC는동맥경화병변이개시되는초기부터관여하고있는것으로보여진다[17].나아가진행된동맥경화증의경우,병변이형성된혈관의adventitia에혈관

내피세포,T림프구,B림프구,대식세포그리고CD21-positivefol-licularDC들을포함하는nodularlymphoidfollicle들이형성되는

데[18],이러한현상은DC가동맥경화병변형성과정의초기뿐만아니라심화되는과정의전반에걸쳐서관여하고있음을보여준다.서론에서도이야기했지만DC에는다양한subtype들이존재한

다.각subtype별로그역할이다르기때문에혈관에서의정확한DCsubtype의규명및그기능에대한이해는매우중요하다고할수있다.PlasmacytoidDCs(pDCs)는동맥경화가발생한부위에존재하는것이발견되었으며cytotoxicTcell의활성을증가시키는것으로알려졌다[19].또다른연구에서BDCA-1+myeloidDCs와BDCA-2+plasmacytoidDCs는심화된동맥경화병변부의혈관이새로형성되는자리에모인다는것이밝혀졌다[20].따라서사람의동맥경화형성과정에DC의다양한subtype들이관여하고있다는것은명확해보인다.그러나아직까지그들의역할에대한이해는미흡한편이다.

4. 마우스모델을 이용한 동맥경화에서의 DC의 역할에 대한

분석

마우스혈관에서존재하는DC에대한초기연구들은주로전자

현미경이나면역염색을통한형태학적인분석을통해이루어졌다.특히2006년에MyronI.Cybulsky박사의연구팀은정상마우스혈관의내피조직에CD11c+CD68+DC들이다수존재하고,이들위치는동맥경화병변이잘형성될수있는위치에분포하고있다는사실을보고하였다[21].또한Klausley박사의연구팀에서도유세

포분석기(flowcytometry,FCM)를통해정상혈관에CD11c+MH-CII+DC가존재한다고보고하였다[22].그러나이들논문에서는DC고유의기능들을보여주지않았으나,이후RalphSteinman박사팀에서마우스정상혈관에서CD11c+MHCII+DC를FACSsort-ing을통해분리하고,이들이T림프구를효과적으로활성화시키

는DC고유의능력을보여줌으로[23],DC가정상혈관의동맥경화병변형성에취약한부분에미리존재하고있음을궁극적으로증명하였다(Fig.1).동맥경화증을연구하기위해널리사용되는마우스모델로는저

밀도지단백질수용체결핍(LDLreceptordeficient,Ldlr-/-)마우스

와아포단백질E결핍(apolipoproteinEdeficient,Apoe-/-)유전형

의마우스를모델로하여연구를하고있다[24].2000년도에동맥

경화에서DC의구체적인역할에대한보고가있었는데,그연구에

서혈관평활근세포특이적으로LacZ를발현하고있는Apoe-/-마우스를제작하고이마우스에β-galactosidase의peptide를loading한DC를투여한결과동맥경화병변형성이증가되었다[25].이는DC에의해동맥자체에존재하는항원이T림프구에제시되고,이에의해동맥경화가촉진될수있다는점을보여준다.나아가고지

혈증상태의마우스에서분리된DC들은정상적으로T림프구들

을활성화시킬수있으며[26],또한말초에존재하는DC들은고지

혈상태에서주변림프절로의이동이억제된다고보고되었다[27].이는고지혈상태에서동맥경화병변이형성되고있는혈관자체에존재하는DC들의역할이중요하다고할수있다.Granulocytemac-rophagecolony-stimulatingfactor(GM-CSF)는병변의CD11c+DC들의수를증가시키고병변형성을촉진하며,특히초기동맥경

화에서혈관내피에존재하는DC들의증식을조절하는것으로알려졌다[28,29].또다른보고에따르면,혈관내피에존재하는DC들은케모카인수용체인CX3CR1을발현하고있으며,이수용체가결핍된마우스에서는혈관DC의수가감소하고동맥경화병변형성

도저해된다[30].최근에는사람의Bcl-2를CD11cpromoter를이용하여CD11c+세포들에선택적으로발현시켜서DC들의수명을증가시키면T림프구의활성이높아지고산화항원에특이적인IgG2c의농도가증가한다[31].따라서이들연구결과들을종합해보면DC는동맥경화병변형성에관여하고있음은명확하다.

DC는발달과정에따라서여러DCsubset들로분화되는데,최근연구에따르면마우스의정상및동맥경화혈관에는최소두개의DCsubset들이존재하고있음이알려졌다[32].이들은DCpre-cursor로부터분화된CD11b-CD103+CD207+classicalDC(cDC)와monocyte로부터분화된CD11b+CD14+DC-SIGN+DC(MoDC)로나누어진다.cDC의분화에중요한fms-liketyrosinekinase3(Flt3)가결핍된마우스의림프조직과혈관에는cDC의수가급격하게감소되어있는데,이마우스와LDL수용체결핍마우스와교배하여동맥경화병변형성양상을분석해보면대조군에비해Flt3가결핍된마우스에서병변형성이증가되어있다.이는감소된조절T림프구(regulatoryTlymphocyte)의감소와연관이있으며,따라서cDC는Treg의조절을통해동맥경화를억제하는것으로보여진다[32].반면MoDC의역할을이해하기위해MoDC만선택적

으로제거할수있는마우스모델의개발이필요하고,이를통해동맥경화에서의역할을이해할수있을것으로보인다.

pDC의경우정상적인혈관에는거의존재하지않으나,동맥경화

가진행되는과정에서증가하는것으로보인다.이들은interferon-α를분비하여cytotoxicTcell을자극하여동맥경화를촉진하는것으로알려졌다[19].또한자가항원과DNA의복합체가pDC를활성화시키고,pDC를제거할수있는anti-PDCA1항체를투여하면



동맥경화병변형성이감소된다[33].이들결과는pDC의활성이동맥경화를촉진한다는것을의미한다.그러나또다른연구에서120G8항체를투여하여pDC를제거한결과indoleamine-2,3-di-oxygenase에의한T림프구의억제가일어나지않고동맥경화가촉진되는것으로보아pDC는동맥경화를억제한다고보고하였다

[34].따라서기존의연구들의결과가상충되는면이있는데,이는항체를이용하여pDC를제거하는과정에서나타날수있는오류

라고판단된다.따라서정확한pDC의역할을규명하기위해서는좀더개선된모델을사용해야할것으로보여진다.예를들어현재pDC를invivo에서제거하기위한형질전환마우스모델로는BD-CA2-DTR과Siglech-DTRtransgenic마우스가있다[35,36].이들마우스에diphtheriatoxin을투여하면선택적인pDC의ablation이유도된다.이들마우스를이용한다면,더욱정확한pDC의역할

에대해분석이가능할것으로보인다.

또한최근보고에따르면CCL17을발현하는DC가동맥경화병변에축적되고이는동맥경화를촉진한다고보고되었다[37].이CCL17+DC는CD11c,CD11b를발현하고높은수준의MHCII와CD40,CD80,CD86을발현하고있으나,CD8,CD115,F4/80,PD-CA-1은발현하고있지않으므로기존에보고된cDC나MoDC와는다른DC로판단된다.이DC는Treg의증가를억제함으로써동맥경화를촉진하는것으로보여진다.그러나CCL17+DC의정확한기원과동맥경화에서의역할을분석하기위해서는더많은연구가필요할것으로보인다.

DC는특정항원에대해tolerance를유발하여염증반응을억제할수있다.DC가이러한역할을수행하는데Treg의작용을필요

로한다.Treg은자가면역질환및만성염증등다양한면역관련병증을제어하는데중요하다고알려졌다[38].동맥경화에서Treg의증가는병변의감소와관련되어있다[39,40].예를들어CD80과

Intima CD11c

Adventitia

Intimal densitiy of CD11c+DCs

A> B> C

Diaphragm

Heart

A

B

C

Aortic sinus

Aortic arch

Thor

acic

aor

ta

× 630

× 250

Fig. 1. Distribution of dendritic cells in normal mouse aorta. Left panels show immunofluorescence staining of CD11c in normal aorta. The aorta was perfused with ice-cold 4% paraformaldehyde in PBS via the left ventricle. After removing perivascular tissues, the segments of aortic sinus, aortic arch and thoracic aorta were opened longitudinally and further fixed in 4% paraformaldehyde at 4°C for 30 min. After permeabilization using 0.2% triton X-100, staining for CD11c was performed using the Tyramide amplification (TSA) kit (Invitrogen) under the manufacturer’s protocol. Right figure shows the relative density of intimal CD11c+ DCs in normal aorta. Reds indicate areas with numerous DCs.



CD86이결핍된마우스의경우Treg의homeostasis에문제가생기

고,이는동맥경화의악화로이어진다.게다가Treg이거의없는CD28결핍마우스의splenocyte들을Apoe-/-Rag2-/-마우스에이식하면동맥경화병변형성이촉진되고,CD25항체를이용하여Treg을depletion시키면동맥경화가악화된다.이러한현상은TGFβ의signaling이결핍된마우스의경우에는나타나지않는것으로봐서TGFβ의signaling이Treg형성에중요하고동맥경화병변억제에도중요하게작용한다.DC는Treg의homeostasis에중요한것으로알려져있는데[41,42],cDC의수를증가시키는Flt3ligand를마우스에투여하면Treg의수가증가하고이는자가면역질환이나염증을억제시키는것으로나타났다[43].Flt3가결핍된마우스의경우cDC와Treg의수가감소되어있으며,반면동맥경화병변의형성은증가되어있었다[32].이는DC가Treg을조절하고이를통해동맥경화병변형성에영향을미친다는것을보여준다.

6. Diphtheria toxin (DT)/DT receptor 시스템을 이용한 DC의

역할 분석

DT는Corynebacterium diphtheriae에서분비되는exotoxin으로서사람에서상부호흡기질환인diphtheria를유발한다.그러나마우스의경우DT에대한수용체가사람과달라서toxin에의한세포사멸등의효과가나타나지않는다.이러한특성을이용하여,세포특이적인프로모터를통해세포특이적으로DT수용체를발현시킨후DT를투여하면선택적으로세포를제거하여그기능을분석할수있다.최근연구에서는CD11cpromoter에diphtheriatoxinreceptor(DTR)유전자를연결하여CD11c+세포에DTR을선택적으로발현시킨Apoe-/-마우스에DT를투여한결과동맥경

화병변의초기형성이상당부분감소한것을확인하였다[44].그러

나이들연구들의문제점은DC를분석하기위해CD11c를염색하

거나DC를제거또는수명을늘리기위한유전자발현을CD11cpromoter를이용하여유도하였다는점이다.CD11c는DC의좋은cellsurfacemarker이기는하지만macrophage,일부T림프구,NKcell등다른세포에서도발현되고,특히산화지질을대식구에처리하여lipid의uptake를유도하면CD11c의발현도증가된다[45].실제동맥경화병변을CD11c에대한항체를이용하여면역염색을실시해보면거의모든foamcell들이CD11c항체에염색되는것이관찰된다.따라서좀더정확한DC의기능을분석하기위해서는좀더DCspecificpromoter에의해control되는마우스모델을사용

해야한다.현재까지개발된수지상세포제거에특이적인DTR마우스에는Langerin-DTR,BDCA2-DTR,zDC-DTR마우스등이있다.이중zDC-DTR마우스는cDC를선택적으로제거할수있는것으로알려졌는데,이마우스를이용한다면동맥경화에서DC의역할에대해좀더정확하게분석할수있을것으로보인다.

7. DC를 이용한 동맥경화 치료법의 개발

기존의연구에서DC기능의변화는동맥경화병변형성에영향

을줄수있기때문에,이를잘이용하면DC를이용한동맥경화의치료제개발이가능할것으로보인다.예를들어,활성형(activeform)VitaminD3를마우스에경구투여하면tolerogenicDC와Treg의수가증가하고,동맥경화병변형성이억제된다[46].또한DC에산화LDL을처리한후이를Ldlr-/-마우스에주입하면,대조

군에비해동맥경화병변형성이억제되고,병변의안정성이높아

진다[47].최근에는아포단백질B100을loading하고있는DC와IL-10을함께마우스에투여하면아포단백질B100에특이적인tol-eragenicDC가만들어지고,이는아포단백질B100에특이적인Treg의증식을유도하여동맥경화형성이억제된다고보고되었다

[48].위의결과들을종합해보면동맥경화특이적항원에대한tol-erogenicDC의형성이동맥경화를효과적으로억제할수있고,이는치료제개발에아주좋은타깃이될수있을것으로보인다.

결 론

최근에발표된많은연구들을통해DC기능에대한이해에많은진전이있었으며,특히DC의각subset들이동맥경화병변형성에다양한역할을수행할것이라여겨진다.현재혈관에존재하는각DC의subset에대해연구하기위해특정DCsubset에서greenflu-orescenceprotein(GFP)발현하는마우스를이용하여혈관내에서

의분포및병변형성시변화양상에대해분석할수있으며,또한기존에제작된DC에특이적인DTR마우스들을이용하여동맥경

화에서각DCsubset의역할을이해할수있다.이렇게DCsubset들에대한분석이진행된다면궁극적으로특정DCsubset을타깃

으로한동맥경화치료제의개발이가능할것으로보여진다.

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