International Journal of Research Studies in Medical and Health Sciences
Volume 2, Issue 7, 2017, PP 1-7
ISSN : 2456-6373

The Pattern Recognition Receptors and Lipopolysaccharides(LPS)-induced Systemic Inflammation
Yung-Li Hung1 and Katsuhiko Suzuki2
1
2

Graduate School of Sport Sciences, Waseda University, Tokorozawa, Mikajima, 359-1192, Japan.
Faculty of Sport Sciences, Waseda University, Tokorozawa, 2-579-15 Mikajima, 359-1192, Japan.

*Corresponding Author: Katsuhiko Suzuki, MD & PhD, Faculty of Sport Sciences, Waseda
University, Japan.
ABSTRACTThe inflammatory response of innate immune system deals with infection of microorganism, tissue injury andmalfunction. It is triggered by pattern recognition receptors (PRRs) which recognize pathogen-associatedmolecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Among PRRs (toll-likereceptors (TLRs), C-type lectin receptors (CLRs), retinoic acid-inducible gene (RIG)-I-like receptors (RLRs),
nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) and receptor for advanced
glycation end products (RAGE)), toll-like receptor 4 (TLR4) is a pivotal receptor to recognize
lipopolysaccharides (LPS), and mediates several signaling to produce pro-inflammatory mediators andcytokines. The uncontrolled inflammation leads to overproduction of pro-inflammatory mediators andcytokines, and contributes to systemic inflammatory response syndrome (SIRS), multiple organ failure andsepsis. Thus, to regulate TLR4-mediated signaling plays an important role in therapeutic targets for LPSinduced systemic inflammation.
Keywords: inflammation, pattern recognition receptors, toll-like receptor 4, lipopolysaccharides, and sepsis

INTRODUCTION OF INFLAMMATIONThe redness, swelling, fever, pain anddysfunction of tissue are the features of acuteinflammation. From cellular and molecular
aspects, the increasing recruitment of leukocytes
and production of pro-inflammatory mediatorsand cytokines lead to such acute inflammation.
It is initiated by harmful stimuli and conditions
such as infection of microorganism, tissue injury
and malfunction. Inflammation plays an importantrole in process of host defence and tissue repair[1]. The inflammatory response of innate immune
system is the primary response to microbial
infection and damaging cells. The phagocytic
cell, macrophages and dendritic cells (DCs) not
only produce pro-inflammatory mediators andcytokines against microorganism, but also havea role in antigen presentation to induce adaptive
immune system [2]. Inflammatory response of
immune cells is initiated by germline-encoded
pattern recognition receptors (PRRs) which
recognize compounds of microorganisms andthe molecules of damaging cells. The pathogenassociated molecular patterns (PAMPs) areconsidered that microbe-specific molecularcompounds
includebacterial
lipopolysaccharides (LPS), flagellins, CpG-DNA,fungal glucans and viral DNA/RNA. The
damage-associated molecular patterns (DAMPs)
are regarded that molecules represent
endogenous alarms. DAMPs are released formsof damaged cells such as mitochondrial andnuclear DNA and advanced glycation end
products (AGEs). A part of DAMPs are
considered that danger signals to induce
inflammatory responses such as high mobility
group box 1 (HMGB1), heat-shock proteins andS100 proteins [3, 4]. The PRRs include toll-likereceptors (TLRs), C-type lectin receptors(CLRs), retinoic acid-inducible gene (RIG)-Ilike receptors (RLRs), nucleotide-binding andoligomerization domain (NOD)-like receptors(NLRs) and receptor for advanced glycation end
products (RAGE) [5, 6].

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The Pattern Recognition Receptors and Lipopolysaccharides (LPS)-induced Systemic Inflammation

The Pattern Recognition Receptors
The TLRs are important PRRs in host cellrecognition and response to various microbial
pathogens such as bacteria, mycobacteria,
viruses, fungi and parasites. TLRs comprise
extracellular domain leucine-rich repeat (LRR)
motifs to recognize pathogens and cytosolic
domain toll-interleukin-1 receptor (TIR)
domains to transduce signaling pathways [7].
TLRs, including transmembrane receptor TLR1,
TLR2, TLR4, TLR5, TLR6, cytoplasmic
receptor TLR3, TLR7, TLR8, and TLR9, play
critical roles in recognition of PAMPs and
DAMPs. The ligands of transmembrane receptor
TLR1 are lipopeptides, TLR2 (lipoprotein/lipopeptides), TLR4 (LPS, HMGB1 and heatshock proteins), TLR5 (flagellins), and TLR6
(lipopeptides), whereas cytoplasmic receptor
TLR3 recognizes double-stranded RNA, TLR7
(single-stranded RNA), TLR8 (singe-strandedRNA), and TLR9 (CpG-DNA) [8, 9]. Until now,the ligand of TLR10 is unknown.
The CLRs such as Dectin-1, Dectin-2, mannose
receptor(MR),
Dendritic
cell-specificintercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) and macrophage-inducible
C-type lectin (Mincle) recognize bacterial,
fungal and viral carbohydrates, and directly
contribute to antifungal immune response [10].
Dectin-1 recognizes β-glucan which is thecomponent of fungal cell wall and transduces
the spleen tyrosine kinase (Syk) signaling.
Dectin-2 and MR contribute to binding of highmannose-type carbohydrates. DC-SIGN binds
high mannose and fucose to recognize fungi andvirus. In particular, Mincle not only binds with
α-mannose and glycolipids, but also recognizes
spliceosome-associated protein 130 (SAP130)
which is ribonucleoprotein of death cells [11].
The RLRs are cytoplasmic receptors thatrecognize RIG-I, melanoma differentiationassociated gene 5 (MDA5) and laboratory ofgenetics and physiology gene 2 (LGP2). The
viral double-stranded RNA activates RIG-I andMDA5. Activated RIG-I and MDA5 bind with
RLRs, and transduce the essential adaptor
protein mitochondrial antiviral signaling(MAVS) to trigger antiviral immune response.
By contrast, LGP2 is a negative regulator of
RIG-I and MDA5 [12]. Thus, the RLRs are
critical PRRs that recognize RNA virus andexert antiviral effects.
The NLRs are cytoplasmic receptors thatrecognize not only PAMPs such as microbial
toxins, bacterial peptidoglycans and viral RNA,2

but also bind to DAMPs such as monosodium
urate (MSU) crystals and adenosine triphosphate(ATP). NLRs include four subfamilies
NLRA/ClassIItransactivator(CIITA),NLRB/neuronal apoptosis inhibitor proteins(NAIPs), NLRC, and NLRP [13]. Additionally,
NLRs contain a C-terminal series of LRR andan N-terminal homotypic protein-protein
interaction domain. The interaction domain of
NLRAs is acid transactivation domain. NLRBs
contain baculovirus inhibitor of apoptosis
protein repeat (BIR). NLRCs comprise a
caspase-recruitment domain (CARD), and pyrin
domain (PYD) is in NLRPs [14]. Among NLRC,
NOD 1 and NOD 2 initiate inflammatory
response by recognition of peptidoglycan from
Gram-negative and Gram-positive bacteria.
NLRPs are key regulators of inflammasomes
which are a group of protein complexes andproduce pro-inflammatory cytokine interleukin1β (IL-1β) and IL-18 [15].
The RAGE is a transmembrane receptor of
DAMPs such as AGEs, HMGB1, S100 proteins,
phosphatidylserine and advanced oxidation
protein products (AOPPs). However, RAGE
also recognizes LPS and triggers inflammatory
response [6]. RAGE is a crucial regulator for
inflammation and cell migration by recognitionof different ligands. The engagement of
HMGB1 induces monocyte migration, andbinding with S100 proteins initiates synthesis ofpro-inflammatory cytokines [4].
Taken together, the different PRRs recognize
different set of microbial pathogens such as
RLRs for virus recognition, but TLRs wildlyrecognize a variety of microbe-specificmolecules and endogenous alarms. TLRs play
an important role in recognition of PAMPs and
DAMPs. It is considered that TLRs initiate
several signaling transduction pathways toinduce inflammation [7].
TLR4 Signaling Transduction Pathways
Among several TLRs, TLR4 is a pivotal
receptor to recognize bacterial LPS and initiates
inflammatory response. TLR4 combines withmyeloid differentiation 2 (MD2) to recognize
LPS, and then LPS-binding protein (LBP) andCD14 enhance LPS binding to TLR4/MD2
receptor complex. Subsequently, TIR-likedomains are recruited, and transduce signal toother adaptor proteins. The downstream adaptor
proteins include myeloid differentiation primary
response protein 88 (MyD88), MyD88 adaptorlike (Mal) as known as TIR domain containing
adaptor protein (TIRAP), TIR domain-

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The Pattern Recognition Receptors and Lipopolysaccharides (LPS)-induced Systemic Inflammation

containing adaptor inducing interferon-β (TRIF,
also known as TIR-containing adapter molecule1 (TICAM-1)), TRIF related adaptor molecule(TRAM, also called TICAM-2) and sterile-α
and armadillo motif containing protein (SARM)[16].

It has been defined MyD88-dependent pathway
and TRIF-dependent pathway (MyD88independent pathway) in TLR4 signalingtransduction pathways. The MyD88-dependent
pathway is early stage of acute inflammation,and the TRIF-dependent pathway is late stage ofacute inflammation [17]. In the MyD88dependent pathway, the recruitment of MyD88
activates IL-1R-associated kinases 1 (IRAK1),
IRAK2, IRAK4 and TNF-receptor-associatedfactor 6 (TRAF6). Subsequently, transduce
transforming growth factor β-activated kinase 1(TAK1)-binding protein 2 (TAB2) and TAK1binding protein 3 (TAB3) are activated, andthen TAB2 and TAB3 induce activation of
TAK1, which mitogen-activated protein kinasekinase kinase (MAPKKK) controls MAPKs
activity. MAPKs including c-JUN N-terminal
kinase (JNK), p38 MAPK and extracellularsignal-regulated kinases (ERK) are crucial
regulator of downstream transcription factors
such as activator protein-1 (AP-1) and nuclear
factor-𝜅B (NF-𝜅B) [8]. These transcription
factors regulate production of pro-inflammatory
mediators and cytokines. Moreover, the Mal(TRIF) regulates activation of NF-𝜅B throughthe bridging of MyD88-dependent pathway.
On the other hand, the TRIF-dependent pathway
is triggered by recruitment of TRIF and TRAM,
and activates TRAF3, tank-binding kinase 1(TBK1) and Inhibitor-κB kinase 𝜀 (IKK𝜀).
These signaling transduction factors induce
nuclear translocation of interferon regulatory
factor-3 (IRF-3) and IRF-7. Subsequently, type I
interferon (IFN), interferon inducible protein-10(IP-10) and regulated on activation, normal T
cell expressed and secreted (RANTES) areproduced [9]. TRIF and TRAM also regulate

activation of NF-𝜅B independent of MyD88[18]. Furthermore, the SARM is a negative
regulator of TRAM, and inhibits activation of
IRF-3, IRF-7 and NF-𝜅B by TRAM [17].
Taken together, the LPS-induced TLR4
signaling is regulated by these five adaptor
proteins, and produces pro-inflammatory
mediators and cytokines by activatedtranscription factor AP-1, NF-𝜅B, IRF-3 andIRF-7. The MyD88-dependent pathway is apivotal regulator of inflammatory host response
to LPS. For this reason, the signalingtransduction factors of MyD88-dependent
pathway are critical contributors for acuteinflammation such as MAPK and NF-𝜅B.
LPS-induced Pro-inflammatory Mediators
and Cytokines
The several pro-inflammatory mediators andcytokines are produced by LPS-activatedmacrophages. The LPS-induced TLR4 signalingtransduction factors play a crucial role in
inflammatory response of LPS stimulation. The
major pro-inflammatory mediators including
nitric oxide (NO) and prostaglandin E2 (PGE2)
lead to redness, swelling, fever and pain.
Inducible NO synthase (iNOS, also called NOS2)
synthesizes NO by converting L-arginine to Lcitrulline. The production of iNOS is regulated
by NF-𝜅B after immunological stimulation [19].
NO is converted to cytotoxic free radical
peroxynitrite (ONOO-) by superoxide (O2-), andexerts microbicidal effects by free radical
reaction. The overproduction of NO contributes
cell death (necrosis and apoptosis) and tissue
destruction by cytotoxicity and oxidative stress[20]. Additionally, iNOS is a harmful enzyme
involved in pathogenesis of inflammatory
diseases [21].
Another major pro-inflammatory mediator,
PGE2 is a lipid pro-inflammatory mediator. The
cell membrane phospholipid and phospholipase
A2 (PLA2) release arachidonic acid (AA), andcyclooxygenase-2 (COX-2) converts AA to
PGH2 by cyclooxygenase and peroxidase
activity. Subsequently, PGH2 is converted to
PGE2 by PGE synthase [22]. These are theprocess of prostanoid biosynthesis. The PGE2
contributes to vascular hyper permeability,
plasma leakage and immune cell infiltration in
acute
inflammation.
Therefore,
COX-2
inhibitors suppress prostanoid biosynthesis, anddecrease vasodilatation, vascular permeability
and recruitment of immune cells ininflammation [22]. On the other hand, NO leads

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The Pattern Recognition Receptors and Lipopolysaccharides (LPS)-induced Systemic Inflammation

to vascular dysfunction characterized by
vascular hyperpermeability due to endothelial
cell death [20]. Interestingly, it has beenreported that there is a cross-talk between iNOS
and COX-2. NO elicits prostaglandin synthesis
via upregulation of COX-2 activity. In contrast,
COX-2 inhibitor does not affect iNOS
expression [23].
TNF-α, IL-1β and IL-6 are central proinflammatory cytokines produced by LPSactivated macrophages and lymphocytes. TNF-α
and IL-1β contribute to fever and coagulation in
inflammation, and activation of immune cells.
Particularly, TNF-α is a master regulator of
inflammatory cytokine production. Both TNF-α
and IL-1β augment inflammatory cascades byactivated macrophages, and induce severe
inflammatory reaction in an autocrine andparacrine manner. IL-6 is also a contributor offever, and activate B and T lymphocytes [24].
Additionally, IL-6 and IL-12 are family
cytokines that share subunit and receptor by
structural relation. IL-12 is a critical contributor
to connect innate immune system to adaptive
immune system [25].
LPS-induced Systemic Inflammation
The high plasma level of LPS (known asendotoxin) causes systemic inflammation suchas endotoxemia and sepsis. The endotoxemia
presents overspilling of LPS in the bloodstream,
which triggers production of lipid mediators andpro-inflammatory cytokines by activation andrecruitment of leukocytes. Subsequently, these
uncontrolled immune responses cause harmful
systemic inflammation referred to systemic
inflammatory response syndrome (SIRS). SIRS
is defined by two or more clinical finding (1.
body temperature <36°C or >38°C, 2. heart rate
>90 beats/min, 3. respiratory rate >20 times/min
or PaCO2 <32 mmHg, 4. white blood cell (WBC)count >12000 cells/μl or <4000 cells/μl, or>10% immature (band) forms) [24].
The Pathogenesis of Sepsis
In the pathogenesis of sepsis, the infection ofgram-negative bacteria and other pathogens leadto sepsis. The bacterial LPS and othermicroorganism components initiate harmful
systemic host response by innate immune cells.
The overproduction of pro-inflammatory
mediators and cytokines by activated innate
immune cells causes cell death (apoptosis andnecrosis). The inflammatory cascades contributeto multiple organ failure, sepsis and septic shock[26]. TLR4/MD2 receptor complex plays a4pivotal role in triggering systemic inflammationof endotoxemia, and transduces a series ofsignalings to produce pro-inflammatory
mediators and cytokines. The hypercytokinemia(known as cytokine storm or cytokine cascade)is overwhelmingly elevated cytokines in blood.
TNF-α, IL-1β, IL-6, IL-12 and IL-17 are main
cytokines in pathogenesis of sepsis. It has beenfound these pro-inflammatory cytokines areelevated in sepsis [27]. On the other hand, it has
been reported that HMGB1 is a late proinflammatory mediator in pathogenesis of sepsis[28]. HMGB1 is also a ligand of TLR4, andtriggers
TLR4-mediatedresponse.
The
hypercytokinemia leads to endothelial cell
necrosis and dysfunction, and then causes thevascular hyperpermeability and plasma leakage.
Concurrently, pyrogenic cytokine TNF-α andIL-1β contribute fever and coagulation, and IL-6also leads to fever. Additionally, these proinflammatory cytokines induce PGE2 and NO
synthesis. The hypercytokinemia contributes
fever, coagulopathy, vasodilation and capillaryleak. As such, the hypercytokinemia leads tomultiple organ failure, sepsis, and septic shock[26].
The Exercise-induced
Systemic Inflammation

Endotoxemia

andThe endotoxemia is not only initiated by theinfection of pathogenic bacteria, but also
triggered by translocation of intestinal gramnegative bacteria. The prolonged and strenuous
exercise-induced redistribution of blood flow
increases the blood supply of muscle andcardiopulmonary system, but decreases the
blood supply of gastrointestinal (GI) system.
The exercise-induced redistribution of bloodflow causes gastrointestinal ischemia, andperfusion of gastrointestinal evolves formationof reactive oxygen species (ROS) andinflammation after exercise [29]. The exerciseinduced redistribution of blood flow contributes
to hyperpermeability of intestinal epithelium via
gastrointestinal ischemia and intestinal barrier
dysfunction [29]. Concurrently, the prolonged
and strenuous exercise increases core bodytemperature that causes hyperthermia. It has
been demonstrated that exercise-induced
hyperthermia
augments
intestinal
hyperpermeability [30].
The translocation of intestinal gram-negative
bacteria increases circulatory bacterial LPS by
the intestinal hyperpermeability, and it leads toendotoxemia during prolonged and strenuous
exercise. Increasing circulatory bacterial LPS

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The Pattern Recognition Receptors and Lipopolysaccharides (LPS)-induced Systemic Inflammation

triggers production of pro-inflammatory
mediator PGE2, pro-inflammatory cytokine
TNF-α, IL-1β and IL-6 by activatedmacrophages. The PGE2, TNF-α, IL-1β and IL6 are contributor of fever. It also augments
exercise-induced hyperthermia by pyrogenic
response, and even result in exertional heatstroke. The heat stroke is initiated by not only
hyperthermia but also endotoxemia-induced
inflammatory response [31]. Lim and Suzuki
suggested that the pathogenesis of heat stroke is
explained by dual-pathway model (DPM) of
hyperthermia and endotoxemia [32].
Although non-steroidal anti-inflammatory drugs(NSAIDs) decreases core body temperature by
inhibition of COX-2, it has been found that
NSAID aspirin and ibuprofen increase
permeability of intestine [33]. The probiotic
supplementation improves exercise-induced
intestinal barrier dysfunction, but the result ofpro-inflammatory cytokine production after
exercise showed no significant difference
between probiotic supplementation and placebo[34, 35]. On the other hand, the ascorbic acidsupplementation suppresses the increase ofplasma LPS and nitrite levels after exercise [36],and reduces sepsis-induced organ damage [37].
Many natural products from herbs andfunctional foods exhibit anti-oxidant and antiinflammatory effects and these natural products
might attenuate LPS-induced inflammation andsepsis [38-40].

CONCLUSION
The uncontrolled LPS-triggered inflammatory
response causes systemic inflammation, multiple
organ failure, sepsis, and septic shock. TLR4mediated signaling cascades are crucial
regulators of LPS-induced inflammation. Hence,
TLR4-mediated signaling factors are therapeutictargets for LPS-induced systemic inflammation.
Many natural products have some potentiality tosuppress TLR4-mediated signaling.

ACKNOWLEDGEMENT
We are very grateful for the English editing of
Dr. Hiroaki Sako.

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AUTHOR’S BIOGRAPHY
Yung-Li Hung, PhD Course, Graduate School of Sport Sciences, Waseda
University, Japan (2012~). M.Sc. Department of Physiology & Master’s
Program, Kaohsiung Medical University, Taiwan (2007~2009). B.A.
Department of Sports Medicine, Kaohsiung Medical University, Taiwan(2003~2007).

Katsuhiko Suzuki, Professor, Faculty of Sport Sciences, Waseda University,
Japan (2008~2013~). Adjunct Professor, Institute of Biomedical Innovation,
School of Biomedical Sciences, Faculty of Health, Queensland University ofTechnology, Australia (2013~2014). President, International Society of
Exercise and Immunology (ISEI) (2015~2017).
http://www.f.waseda.jp/katsu.suzu/english

Citation: Hung Y, Suzuki K. The Pattern Recognition Receptors and Lipopolysaccharides (LPS)-induced
Systemic Inflammation. International Journal of Research Studies in Medical and Health Sciences.
2017;2(7):1-7.

Copyright: © 2017 Hung Y, Suzuki K. This is an open-access article distributed under the terms of theCreative Commons Attribution License, which permits unrestricted use, distribution, and reproduction inany medium, provided the original author and source are credited.

International Journal of Research Studies in Medical and Health Sciences V2 ● I7 ● 20177