Jpn. J. Infect. Dig., 54, 220‑224, 2001

Invited Minireview
Molecular Basis fわr Innate Immune RecognltlOn Of Microbial Components

Kiyoshi Kawasaki and Masahiro Nishijima*
Department of Biochemistry and Cell Biology, National Institute oflnfectious Diseases,
Toyama 1‑23‑1, Shinjuku‑ku. Tokyo 162‑8640, Japan(Received November 7, 2001)

SUMMARY: RecognltlOn Of bacterial envelope constituents is one mechanism used by mammalian cells to
initiate responses leading to bacterial killing, or, unfortunately, responses that also cause fatal septlC Shock.

Many cell surface receptors by which these microbial components are recognized have been identified andcharacterized over the past a few years. ln addition to CD14, which has been shown to be involved in therecognltlOn Ofmany microbial components, Toll‑like receptors and MD‑2 have been identified as factors playlng arole in the receptor complexes of these components. Here we review the recent findings regarding the molecularbasis for the recognlt10n Of microbial components.

tible disease. Microbial invasions are initially countered byIntroduction

innate defense mechanisms that exist in all individuals andMammalian defense responses to infectious pathogenic

act within minutes of infection. Only when the innate hostagents are comprised or innate and adaptlVe immune

defenses are by‑passed or evaded by microorganisms, is an

responses. AdaptlVe immune responses, which are also called

adaptive immune response induced. Innate immunitynot only
constitutes an early defense response, but also facilitates theacquired immune responses, are generated through clonal

expansion of antigen‑specific lymphocytes. The great diversity

induction or an ad叩tlVe immune response through secretionof antigen‑speci丘c lymphocytes is generated through somaticof cytokines by macrophages.

gene remgement. On the other hand, irmate immune responses
are not mediated throughclonal expansion of antigen‑specifichost defense. ln addition to engul血ent of opsonized particles

lymphocytes, and the molecules involved in innate immune

coated with antibodies and/or complement, macrophages can

responses are encoded by separate genes. A major question

recognlZe and ingest many pathogens directly. On their

The innate responses of macrophages are very lmPOrtantfor

regarding Innate immunlty is how the innate immune systemsurface, macrophages have several different receptors that

acqulreS diverse defenses against variouskinds of infectious

bind microbial components common to many pathogens, andagents･thereby induce phagocytosis and the relea.se of cytokines･ The

organisms such as plants, invertebrates, and vertebrates.

induced cytokines recruit new phagocytlC Cells and effector
molecules tothe sites of infTection. Lipopolysaccharide (LPS) is

Therefわre, it is believed that the innate immune system is

one or the most potent inducers of cytokines among microbial

evolutionally conserved. For example, the ability of elimina‑

components ･The innate immune system is present in various kinds ortion of foreign Substances by phagocytes and the defense

LPS is a constituent of the outer membrane of Gram‑negative

response involving antibacterial proteins (peptides) arebacteria, and contains a polysaccharide and a lipid A portion

conserved in mammals and insects. In 1 996, Drosophila Toll

(Fig･ 1A), the latter of which mediates many LPS responses(4)･ The importance of LPS‑induced immune r?sponses lnhost defense was demonstrated by the analysis Of LPS‑
hyporesponsive mice, C3H/HeJ. C3H/HeJ is a mutant mouse

was shown to be involved in immune responses such as theinduction ofant抗Ingal peptides (1 ). In 1 997 and 1998, human

TblHike receptors (TLRs), which are structurally related to
Drosophila Toll, were identifled (2,3),and subsequent re?earchstrain that is hyporesponsive to LPS, and macrophages

has shown that TLRs play a central role in mammalian lnnate

derived from C3H/HeJmice did not produce inflammatory

immune recognltlOn. In this paper, We summarize the recent

cytokines on LPS‑stimulation. It is noteworthy that C3HmleJ
mice were more susceptible to Gram‑negative bacteria, suchas Salmonella Ophimurium (5) and Escherichia colt (6), than
was its cognate wild type pair, C3H/HeN, and the susceptl‑

findings concernlng the mechanisms of ligand recognlt10n

by TLRs, especially TLR4.

bility ofC3H/HeJ mice to S.りphimurium is closely linked to

1mmate immunity and macrophage activation

the Lpsd allele, which govems the defective response to LPS

in C3H/HeJ mice (5). Recent research has demonstrated that

The microorganisms that are encountered in the daily life ofa nomal healthy individual only occasionally cause a percep‑

the Lpsd allele encodes TLR4 (see below).

*Corresponding author: Tel: +81‑3‑5285‑1 1 1 1 ext. 2101, Fax:

Molecules involved in LPS recognition by+8113‑5285‑1 150, E‑mail: nishim@nih.go.jp

macrophages

CD14: CD14 is expressed on the surface ofmacrophages.
Evidence supportlng a Central role of CD 14 in LPS signaling

ThisarticleisanlnvitedMinireviewbasedonalecturepresented
atthellthSymposiumoftheNationalⅠnstituteofInfTectious

includes the following: (i) LPS binds stoichiometrically to CD 14

Diseases,Tokyo,21May2001.

(7); (ii) transfection ofCD14 Confers LPS‑responsiveness on220the 70Z/3 pre‑B cell line (8) and CHO‑KI cell line (9); andimmunity was hypothesized. Also, the signaling cascade was(iii) CD 1 4‑deficient knockout mice show dramatically reduced

subsequently shown to be essential fわr the induction or anti‑

sensitivityto LPS ( 1 0)I Furtherm0.re, it has been demonstrated

fungal peptides in Drosophila (1). Toll is a transmembranethat CD14 is involved in the slgnaling induced by otherprotein that has leucine‑rich repeats in its extracellular pollion

microbial components, such as lipoarabinomannan, peptトand a cytoplasmic portion homologous to the intracellular

doglycan, and lipoteichoic acid (Fig. 1) (1 1). Intracellularsignaling domain of the type I IL‑1 receptor (designated as

signaling induced by LPS in macrophages cannot be mediatedthe TIR domain). A manTnalian family, called the TLR family,

directly by CD 14, because CD 14 is a GPl‑anchored protein anddoes not possess an intracellular slgnaling reglOn. Therefわre awhich is structurally slmilar to Drosophila Toll has beenreported. To date, ten members (TLR1‑ 1 0) have been reported

second receptor that mediates LPS and other microbial com‑

(2,3,14).

TLR4: Human TLR4 was the first reported TLR (2). Expres‑ponent signaling has been sought fわr a long time (12).

TLRs: Toll was first identified genetically as an essential

sion of constitutively active TLR4 in a human cell line induces

moleculefor embryomic patteming in Drosophila ( I 3). Because

NF‑ rcB activation, and the expression of NF‑ fC B‑Controlled

the Tわll signaling cascade showed a striking similarlty With

genes for innammatory cytokines as well as the expression

the mammalian lL‑ I ‑induced activation cascade of NF‑ ltB,
the involvement of the Toll‑signaling cascade in Drosophila

ofthe co‑stimulatory molecule B7. 1, which is required f♭r
the activation of naive T cells (2). Subsequently, LPS一

B

A･･･o&0,AA?････Nn ,H.
MeCH
I

CE

o二･二olAo駄o････l

L ･AlalI̲
oH'soG
In J

MeCH

oーん＼

NHAc

NHAc

l

C=O

･し･Ls

I

L･Ala
t

o'isoGrrt
I

L･Lys
I

D･Ala

＼

LA'abhw)‑I"annan:鞠C

ヽ､ヽ

D
PALMJTOYL ‑0‑ CHz"○箪I

PALMITOYL ‑0 ‑CH
I

CHZ
‑ S

o
′

̲̲

0
ll

0‑I‑0‑CH1
1

0
I

l

H

CHz

O N‑C一〇一C‑FII

M‑C‑0‑CIFr

OH

l

H

H

0

I

PALMITOYL‑NH‑CH‑CO‑Ser ‑Ser‑Ash‑AIQ

qb3/(pp 9?HzOH ?レoi"7ox/ /Hニ Ct‑ぐ T z I.

O"P‑0

/

LO1･A1.･J

ノ了"7
CIr

0

72

X= H. D‑lla

CH一〇一COR

LM,‑.‑C.R
Fig. 1. Structures ofmicrobial componcntsthat induce macrophagc activation･A) Lipid A, B) peptidoglycan, C) lipoarabinomannan, D) 1ipopeptide, E) ]ipoteicoic acid1

221

Table I. Ton‑like rcceptors (TLRs) and ligands

TLR Co factor Li gand Origin of ligand Rcfcrcnccs
TLR2

CD1 4

I ipopcptide/1ipoprotcin

bacterja

1

TLR6, CD14

pcptidoglycan

bactCria

18, 33, 35

CD14

1 i poarabinomannan

mycobacteria

1

TLR6

MAL㌣‑2

mycoplasma

36,

glycosylphosphatidyt inositol

protozoan

3

double‑stranded RNA

vlruS

TLR3
TLR4

TLR9

20

7

37

8

39

CD14, MD‑2

LPS

Gram‑ncgativc bactcria

CD14

lipoteichojc acidGram‑positive bacteria

MD‑2

Taxol

TTaxus brevt'fblia (plant)

CD14

heat‑shock protein 60

1luman29

glycosphingolipid

P fimbriae

E.

40

CD14

tcichuronic acids

Micy10COCCuS luteus

nagcllinbactcri

TLR5
TLR6

9,

coli

15, I 6, 22, 24
1 8
28

4 1

a

42

TLR2, CD14

pcptidoglycan

bactcria

18,

TLR2

MALP‑2

mycoplasma

36, 37

CpG DNA

bacteria

hyporesponsive mutant mice, C3H/HeJ, have been reported
to possess a p.oint mutation in TLR4 (15) that causes aninability to actlVate NF‑FCB (16). Unequivocally, TLR4 was

33,

35

43

Confer LPS responsiveness on these cells. In addition to thatof TLR4, expression of MD‑2, a molecule that physicallyassociates with TLR4, in Ba/F3 confers LPS responsivenessdemonstrated to be involved in LPS signaling, because(24)･ The eチpreSSion of CD14 enhances LPS‑induced NF‑

macrophages derived from TLR4‑deficientknOckout mice did
Interestlngly, it has been demonstrated that the slgnals

fCB activatlOn Via the TLR4･MD‑2 complex (24). A point
mutation of MD‑2 abolishes the LPS‑induced signaling ln
the CD14‑transfected CHO cell line (25). MD‑2 associates

induced by other CD14 1igands, such as lipoarabinomannanwith the extracellular portion or TLR4 and the existence or(I 7) and peptidoglycan (1 8), were mediated by TLR2 but not

the TLR4･MD‑2 Complex on macrophages has been demon‑
strated (26). These findings demonstrate that MD12, as well

not respond to LPS (16)･

by TLR4. 1n addition to these CD14 1igands, recent research

as TLR4, is involved in LPS signal transduction. A model ofthe LPS receptor complex is shown in Fig. 2. However, thefunction ofMDl2 in ligand recognltlOn by TLR4 has not beenhas shown that many other microbial components were also

recognized by TLRs; these findings are summarized in Table 1.

TLR4 is involved in the recognltlOn Or LPS, a componentof Gram‑negative bacteria, whereas TLR2 is involved in therecognltlOn Of Gram‑positive bacterial components such as

characterized well. It is possible that MD‑2 is required fわr cellsurface expression ofTLR4, because MD‑ I , which is structur‑

peptidoglycan (1 8) and lipoprotein (19,20)･ C3H/HeJ mice,

ally similar to MD‑2, is essential for cell surface expression

which are hyporesponsive to LPS, are known to be highly

orRPI05, which is structurally similar to TLR4 (27).

sensitive to infection by Gram‑negative bacteria, as describedabove･ TLR21deficient mice are highly susceptible to Gram‑

Molecular events involved im the recognition or

positive Staphylococc.us aureus infection (2 1 )･ Reductioヮof

foreign stJbstances by TLRs

cytokine production ln response tO bacterial infection lS a
cause of the susceptibility, because pretreatment with TNト

As shown in Table 1, TLRs mediate slgnals induced bya and lL‑la protects C3H/HeJ mice from lethal EI colt

various kinds of microbial components. lt has been shown

infection (6).

that TLR4 is involved in the signal transduction induced by

MD‑2: Expression ofTLR4 in the Ba/F3 pro‑B cell line

LPS, Taxol (28), 1ipoteicoic acid (1 8), and heat shock protein

60 (29). However, the molecular mechanism by which TLR4(22) and human embryonic kidney 293 cell lines (23) did notrecognlZeS these stimulants has not been characterized well.

In our experiments, '25I‑labelled LPS bound well to CD14, but

not to the TLR4･MD‑2 complex. LPS agonist Taxol, which
induces the cellular slgnal mediated by the TLR4･MD‑2complex, also did not significantly bind to the complex (28).

These results show that the TLR4･MD‑2 complex is not a
receptor that shows high affinity to its ligand. lnterestlngly,

Taxol has an LPS‑mimetic action on mouse macrophages,

but not on human maCrOPhages. We have shown that MD‑2 isinvolved in this species‑specific LPS‑mimetic action, suggest‑

ing that MD‑2 is involved in ligand discrimination (28,30),
Furthemore, the involvement ofTLR4 in the discrimination
oflipid A has been demonstrated (3 1 ,32). These丘ndings lead

us to the speculation that the TLR4･MI)‑2 Complex directly

TsignaJ transduction

recognlZeS its ligand, but that the association is weak andFig･ 2･ Molecules involved in LPS‑recognltion by macrophages･

undetectable.

222

Tb date, ten TLRs have been reported, but it is not clear

S., Silver, ∫., Stewart, C. L and Goyert, S. M. (1996):

how a restricted family of such receptors has the capacity tO

Resistance to endotoxin shock and reduced dissemina‑

recognlZe the wide spectrum of TLR stimuli known to exist･

tion of Gram‑negative bacteria in CD 1 4‑deficient mice･Interestlngly, the recognition of some TLR stimuli, such as

Immunlty, 4, 407‑4 14.

peptidoglycan and zymosan, is explained by the cooperation of

1 1. Pugin, ∫., Heumann, D., Tbmasz, A., Kravchenko, V V,

TLR2 and TLR6. In contrast, for the recognition of anotherAkamatsu, Y., Nishijima, M., Glauser, M. P., Tobias, P.

TLR2 1igand, lipopeptide, the cooperation ofTLR2 and TLR6

S. and Ulevitch, 良. J. (1994): CD14 is a pattem recognト

was not required (33). The repertoire fわr pattem recognition

tion receptor. Immunlty, 1, 509‑5 16.

ofpathogens by the innate immune system may be increased

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13. Morisato, D. and Anderson, K. V (1995): Signaling
Finally, the discovery ofTLRs is a breakthrough fわr thepathway that establishes the dorsal‑Ventral pattem or theunderstanding of innate immunlty. lt is hoped that these find‑lngS Will enable the development of new immuno‑stimulatory

Drosophila embryo. Annu. RevI Genetics, 29, 37 I‑399･
14. Akira, S., Takeda, K. and Kaisho, T. (2001): Tollllike

adjuvant and anti‑inflammatory drugs. ln addition to TLRs,

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B. and Beutler, B. (1998): Defective LPS signaling in
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