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Toll-like Receptors and SepsisKen J. Ishii, MD, PhD, and Shizuo Akira, MD, PhD*
Address
*Akira Innate Immunity Project, ERATO, Japan Science and Technology
Agency; Department of Host Defense, Research Institute for Microbial
Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.E-mail: [email protected]
Current Infectious Disease Reports 2004, 6:361366
Current Science Inc. ISSN 1523-3847
Copyright 2004 by Current Science Inc.
IntroductionThe immune system discriminates self and nonself by using
multiple components in the body [1,2,3]. Physical
barriers such as mucosal membranes in the gut and epithe-
lium in the lung play a major role in clearing infectious
organisms. Once infectious organisms invade such barriers,
innate immune cells (eg, macrophages) play a secondary
role in clearing (phagocytosis) and discriminating nonself
from self by sensing specific molecular pattern expressed in
pathogens (eg, Toll-like receptor [TLR], mannose receptor)
[4,5]. As a result, protective innate and adaptive immune
responses initiate and are followed by tissue repair/remodeling to maintain the host homeostasis.
An overwhelming burden of pathogens, as seen in
massive infection or inefficient immune responses, can
break such homeostasis, resulting in sepsis. Systemic
inflammation during sepsis develops into a syndrome with
multiple manifestations, such as tissue injury, increased
vascular permeability, and ultimately, multiorgan failure
and shock [6].
The recent discovery of TLRs has led us to further
understanding of the molecular mechanism(s) by which
infection initiates such strong innate immune activation.
Lipopolysaccharide is one of the major causative agents
of sepsis and triggers strong proinflammatory responses
and the related pathogenesis (eg, endotoxin shock), with
high mortality. Although CD14 and lipopolysaccharide-
binding proteins (LBP) were known to bind lipopolysac-
charide, a sole receptor that recognizes lipopolysac-
charide and initiates the proinflammatory response had
been sought for decades until human TLRs were found
that were homologous to the fly Toll receptors [7]. Most
strikingly, it was shown that mice mutated in or lacking
TLR4 were hyporesponsive to lipopolysaccharide [8,9].Ther ef or e, TLR4 was th e l on g- so ug ht rece ptor fo r
lipopolysaccharide. The other TLRs were also found to
recognize specific microbial products, many of which
are also known to cause a robust inflammatory response
[1017]. Since then, extensive research on TLRs has
been conducted to understand the precise mechanisms
by which these microbial products activate innate
immune responses and to understand their physiologic
relevance [4].
Such strong inflammatory responses mediated by TLRs
must have tight regulation through a negative feedback
system to maintain host homeostasis. Certain TLR-induced
genes are involved in negative regulation of secondary TLRactivation, so-called endotoxin tolerance. In addition,
cells involved in innate immunity (eg, macrophages)
possess a variety of receptors capable of recognizing a wide
range of protein, saccharide, lipid, and nucleic acid ligands
of endogenous or exogenous origin, some of which are
involved in TLR-negative regulation to balance innate
immune activation and termination/suppression. This
review focuses on the roles of TLRs and related molecules
in triggering and regulating innate immune responses
during infection, sepsis, or related pathogenesis.
Toll-like ReceptorsToll-like receptors are type I transmembrane proteins that
are evolutionarily conserved between insects and humans,
now well-known as pattern recognition receptors capable
of recognizing pathogen-associated molecular patterns
(PAMPs) [1]. Toll was first identified as an essential mole-
cule for development in Drosophila and was subsequently
shown to be essential for antifungal immunity [18]. A
homologous family of Toll receptors, the so-called TLRs, was
found in mammals [7]. Eleven members of the TLRs have
been reported (TLRs 111) [17,1922]. TLR family members
Recent evidence suggests that Toll-like receptors (TLRs)
play a major role in innate immunity to recognize specific
molecular patterns derived from pathogens, including lipid,
protein, DNA, and RNA, and to fight against pathogens.Each TLR displays a difference in the expression pattern,
intracellular localization, and signaling pathway, resulting
in the distinct immune responses. The resultant immune
activation augments host resistance to a variety of infec-
tious organisms. However, such responses may exceed
the threshold to maintain host homeostasis in the case
of sepsis. TLR-mediated innate immune activation also
induces several molecules shown to negatively regulate
TLR signaling. Thus, TLRs may play an important role in
positive and negative regulation of immune responses
during sepsis.
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362 Sepsis
are expressed differentially in a variety of cell types and
capable of recognizing and responding to different PAMPs,
including lipid, protein, DNA, and RNA. Individual TLRs
were found to recognize distinct ligands (Table 1). There are
also reports of endogenous ligands acting as TLR agonists,
some of which may not have excluded the possibility of
lipopolysaccharide contamination [23]. Although leucine-rich repeats found in all TLRs seem to be involved in
direct binding with ligands and ligand specificity, structural
analysis of TLRs and their interaction with respective ligands
is needed to clarify their specificities.
Based on the similarity in the cytoplasmic portions
(designated the TollIL-1R [TIR] domain), TLRs are related
to interleukin-1 receptors (IL-1Rs), whereas the extra-
cellular domain is quite distinct between each family [24].
TLRs are shown to activate nuclear factorB (NF-B) and
mitogen-activated protein (MAP) kinase pathways through
MyD88 (myeloid differential factor 88), a common
adaptor molecule recruited toward a TIR domain of TLRs
[25]. Subsequent studies using MyD88-deficient mice haverevealed that some TLRs possess a MyD88-independent
pathway, which is represented by interferon- production
induced by lipopolysaccharide or double-stranded RNA
stimulation [26]. TRIF, TIR domaincontaining adapter
inducing interferon, was shown to be an essential adaptor
molecule for the MyD88-independent pathway in
TLR3 and TLR4 signaling [27] . Most recently, TRAM,
the fourth TIR domaincontaining adaptor, TRIF-related
adaptor molecule, was identified and shown to be critical
for TLR4- but not TLR3-mediated TRIF-dependent pathway
[28]. These adaptor molecules are involved in distinct
TLRs, thereby resulting in the specific biologic responses
of each TLR.
Distinct Functions Between Toll-like ReceptorsToll-like receptors are expressed in a variety of cell types,
including immune and nonimmune cells. For example,
myeloid cells express TLR1 and TLR6 constitutively. Macro-
phages and myeloid dendritic cells preferentially express
TLR2, 3, 4, and 8 [29], whereas plasmacytoid dendrit ic
cells express TLR7 and TLR9 [30]. B cells express TLR7, 9,
and 10, the ligand of which is not yet known [31]. TLR2
expression in CD4+ T cells and NK cells is reported, but
its physiologic relevance must be clarified [32,33]. Such
differential TLR expression in immune cells indicates its
distinct roles in natural infection. TLR3 and TLR4 are also
expressed or upregulated in nonimmune cells [34,35].
TLR upregulation in nonimmune cells after init ial TLR-
mediated response may trigger secondary immuneresponses such as activation of endothelial cells that
augments adhesion molecule expression followed by
macrophage infiltration and vascular permeability during
infection. This cascade may result in a systemic septic
syndrome including tissue perfusions, imbalanced coagu-
lation cascade, or organ failure.
The other hallmark of TLRs is their distinct intracellular
localization. TLR1, 2, 4, 5, and 6 are shown to reside on the
cell surface, whereas TLR3 and TLR9, and possibly TLR7
and TLR8, are expressed in intracellular compartments such
as endoplasmic reticulum (ER) and phagosomes [36,37].
Cell surface expression of TLR4 was facilitated by MD-2
protein forming a complex to recognize lipopolysaccharidewi th TL R4 on th e ce ll su rf ace [38] . TL R2 an d TLR6
expressed on the cell surface are recruited and accumulated
into phagosomes during gram-positive bacterial infection
of macrophages [39]. TLR9 resides in ER, possibly recruited
to and fused into phagolysosomes through PI3 kinase
[37,40]. Although physiologic meanings of such distinct
localization of TLRs within cells are yet unclear, one
possible explanation is that cell surface TLRs recognize the
outer structure of microbes such as lipopolysaccharide
expressed on bacterial cell wall or membrane, whereas
intracellular TLRs recognize nucleic acid molecules exposed
in phagosomes or in cytoplasm by intracellular bacteria or
virus during infection. Degradation of virion or bacteriain phagolysosomes may result in release of DNA or RNA,
which then interact with TLR9 or TLR7, respectively. This
multistep TLR recognition indicates a safety mechanism of
innate immune system through 1) discriminating bacteria
(with conserved outer structure, such as lipopolysacchar-
ides, proteins such as flagellin, or lipoproteins) from
virus (with unique st ructure in nucleic ac ids such as
double-stranded or single-stranded RNA, or cytosine
phosphate guanine dinucleotide [CpG] DNA); and/or
2) discriminating between nonreplicable (lipid, protein, or
Table 1. TLRs and respective ligands
TLR Ligands and their descriptions Studies
TLR2 + TLR1 Triacylated lipoproteins or lipopeptides [10]TLR2 + TLR6 Diacylated lipoproteins or lipopeptides [11]TLR3 Double-stranded RNA during viral replication [34]TLR4 Bacterial lipopolysaccharide [8,9]
TLR5 Flagellin in bacterial flagella [13]TLR7(8) Guanine uridinerich single-stranded RNA possibly from virus [15,16]TLR9 Bacterial and certain viral DNAcontaining CpG motifs [14]
CpGcytosine phosphate guanine dinucleotides; TLRToll-like receptor.
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Toll-like Receptors and Sepsis Ishii and Akira 363
polysaccharides) and replicable agent (DNA and RNA)
derived from any microbes.
Two distinct pathways have been recently described in
TLR-mediated signaling (Fig. 1). MyD88 is an essential TLR
adaptor molecule for TLR2, 7, and 9 and is involved in
innate immune activation including NF-Bdependent
cytokine productions, upregulation of costimulatory
molecules, and productions of interferon [14,41]. Toll
interleukin-1 receptor domain-containing adaptor protein(TIRAP) specifies the MyD88-dependent pathway through
TLR2 and TLR4 [42]. In contrast, TRIF and TRAM mediate
MyD88-independent pathway through TLR4 [27]. TLR3
seems to use only TRIF. Significant difference in each TLR-
mediated signaling may shed light on the pathogenesis
in septic shock. Treatment of mice with TLR4 ligand
(lipopolysaccharide) alone causes septic shock with
mortality, whereas other TLR ligands require that the
animals are sensitized with the other agent(s) to mimic
biological phenomenon observed during sepsis or septic
shock. In addition to MyD88-dependent NF-B and MAP
kinase pathway, MyD88-independent pathway, which
regulates mostly type I interferon and related genes, hasprofound effect on lipopolysaccharide-induced shock and
lethality [43]. Hence, TLR4 induced MyD88-dependent
and -independent pathways, resulting in induction of
septic shock with high mortality.
Negative Regulation ofToll-like Receptor SignalingAs descr ibed earlier, most of the TIR-containing genes
such as IL-1/18 receptors and TLRs are activators of innate
immune cells. Conversely, two other members of the TIR
domaincontaining super family are reported to negatively
regulate TLR signaling. ST2, known to be expressed on T
helper 2 (Th2) cells but not on T helper 1 (Th1) cells [44],
was shown to inhibit TLR4- but not TLR3-mediated signal-
ing [45]. ST2 -/- mice have exaggerated cytokine responses to
the stimulation of IL-1R and TLR2, 4, and 9 but not TLR3
[45]. ST2 -/- mice have similar mortality to wild-type mice
after initial lipopolysaccharide-induced shock but fail toinduce lipopolysaccharide tolerance in vivo. Single
immunoglobulin IL-1Rrelated molecule (SIGIRR), the
other TIR domaincontaining receptor, was found to inhibit
IL-1R signaling when overexpressed in vitro, and SIGIRR -/-
mice were more susceptible to lipopolysaccharide-induced
lethality [46]. ST2 are expressed in macrophages, Th2 cells,
and mast cells, whereas SIGIRR expression is mostly
restricted in epithelial cells, suggesting that similar but
distinct functions between ST2 and SIGIRR may have a
differential role in negative regulation of proinflammatory
responses during sepsis (Fig. 2).
Among the genes that are induced or upregulated by TLR
stimulation, IL-1Rassociated kinase-M (IRAK-M) [47] andsuppressor of cytokine signaling (SOCS-1) [48,49] are
reported to act as negative regulators for TLR signaling.
IRAK-M -/- and SOCS-1 -/- mice showed exaggerated
proinflammatory responses to TLR4 ligand, and more
importantly, they were unable to induce lipopolysaccharide
tolerance. IRAK-M and SOCS-1 probably contribute to nega-
tive signaling cascades in TLR signaling that are essential for
suppression of excessive inflammation. These multiple
genes involved in negative regulation in innate immunity
may play a role in maintenance of homeostasis during
Figure 1. Summary of Toll-like receptor (TLR)localization and signaling. Distinct signalingpathways and localization of TLRs are shown.Myeloid differential factor 88 (MyD88)dependent and independent pathwaysare activated through TLR4. MyD88 is asole adaptor molecule for TLR7 and TLR9,whereas Tollinterleukin-1 receptor domain-
containing adaptor protein (TIRAP) is alsorequired for TLR2. TLR3 uses TRIF as a soleadaptor molecule. TLR1, 2, 4, and 6 areinitially on the cell surface, whereas TLR3and TLR9 (and possibly TLR7) are withinthe intracellular compartment. ERendo-plasmic reticulum; IRAKinterleukin-1receptorassociated kinase; NF-Bnuclearfactor B.
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364 Sepsis
sepsis. It will be of interest to determine whether these
genes are also involved in linking the innate and adaptive
immunity, regulating antigen-specific Th1/Th2 response
or tolerance.
Interaction of Toll-like Receptors and theother Pathogen-recognizing Receptors
Among pathogen-recognizing receptors, TLRs are equippedfor innate immune activation by eliciting proinflammatory
responses. Conversely, the other well-known pathogen-
recognizing receptors such as scavenger receptors are shown
to have a dual role in activation and suppression in innate
immunity [50]. Mice lacking scavenger receptor-A (SR-A) are
more susceptible to lipopolysaccharide-induced shock than
are wild-type mice and demonstrate an exaggerated tumor
necrosis factor response, suggesting an inhibitory role
of SR-A in lipopolysaccharide-mediated inflammatory
responses [51]. Recent evidence suggests that signaling cross-
talk between downstream of scavenger receptors and TLRs
takes place during infection. Two recent reports have
demonstrated that TLR signaling and scavenger receptormediated cholesterol efflux interfere with each other
through liver X receptors (LXRs), known as nuclear receptors
for oxysterols through low-density lipoprotein uptake in
macrophages [52,53]. LXR signaling was inhibited by
bacterial and viral infection or by stimulation of TLR3 and
TLR4, but not TLR2 or TLR9, through an interferon regula-
tory factor 3dependent manner, whereas LXR agonists
inhibit TLR4-mediated proinflammatory responses. TLR3
and TLR4 stimulation did not inhibit peroxisome prolifera-
tor activator receptor-g signaling and its target gene, CD36
[53]. It is conceivable that many more players are involved
in regulation of inflammatory responses mediated by TLR
through cross-talk during sepsis.
ConclusionsDiscovery of human TLRs has brought significant attention
to the role of innate immunity in the natural course of
infection, but also to the role of TLRs in the pathophysiol-
ogy of infection. For example, TLR4 was found to be a sole
receptor for lipopolysaccharide-mediated innate immune
activation and the resultant pathogenesis of gram-negative
sepsis. Common and specific features of TLRs and related
signaling molecules determine the course and magnitude
of the innate immune responses. These findings should
lead us to a better understanding of basic immunobiology
and to novel therapeutic approaches for sepsis and related
pathogenesis, including antagonists of TLRs, inhibitors of
TLR signaling pathways, and stimulators of the inhibitory
signaling pathways for TLRs. However, our understandingof such complex biological phenomenon during sepsis
or related pathogenesis is far from completion because
there are more questions than answers.
AcknowledgmentsWe thank all members of our laboratory for helpful discus-
sions and suggestions, and M. Hashimoto and members of
the ERATO office for secretarial assistance.
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