ReviewReview

Virulence 5:1, 36–44; January 1, 2014; © 2014 Landes Bioscience

Host innate immune responses to sepsis

Willem Joost Wiersinga*, Stije J Leopold, Duncan R Cranendonk, and Tom van der Poll
Center for Infection and Immunity Amsterdam (CINIMA); Center for Experimental and Molecular Medicine (CEMM); Division of Infectious Diseases; Academic Medical Center;
University of Amsterdam; Amsterdam, The Netherlands

Keywords: sepsis, innate immunity, pattern recognition receptors, pathogen-associated molecular patterns (PAMP), danger-
associated molecular patterns (DAMP), neutrophil extracellular traps (NET), myeloid related protein (Mrp)-8/14, coagulation,
activated protein C, protease activated receptors

result, severe sepsis, defined as sepsis plus organ failure, remains

The immune response to sepsis can be seen as a pattern
recognition receptor-mediated dysregulation of the immune
associated with an unacceptable high mortality ranging from
system following pathogen invasion in which a careful balance 15% to 50%.7-10 What’s more, the number of cases of severe sep-
between inflammatory and anti-inflammatory responses is sis is on the rise and now account for approximately 10–14%
vital. Invasive infection triggers both pro-inflammatory and of all intensive care unit admissions in the Western world.9-12
anti-inflammatory host responses, the magnitude of which Evidently, there is an urgent need for new, more effective treat-
depends on multiple factors, including pathogen virulence, ment strategies to counter this epidemic, and a better under-
site of infection, host genetics, and comorbidities. Toll-like standing of the pathogenesis of sepsis is imperative to unravel the
receptors, the inflammasomes, and other pattern recognition sepsis mystery.1,6,13,14 One has to realize that sepsis is too hetero-
receptors initiate the immune response after recognition geneous to treat as one disease.13 The septic response depends on
of danger signals derived from microorganisms, so-called the causative pathogen, including microbial load and virulence,
pathogen-associated molecular patterns or derived from
the makeup of the host, such as genetic composition, age, comor-
the host, so-called danger-associated molecular patterns.
Further dissection of the role of host–pathogen interactions,
bidity, and medication as well as the time that has passed since
the cytokine response, the coagulation cascade, and their initial infection. This review focuses on recent insights on host
multidirectional interactions in sepsis should lead toward the innate immune responses to sepsis. Different manuscripts in this
development of new therapeutic strategies in sepsis. issue will discuss the impact of sepsis on adaptive immunity and
immune suppression.

Key Role for the Pattern Recognition Receptors

The Mystery of Sepsis
The most frequently isolated pathogens in patients with sepsis
Although sepsis was already known as a severe condition in include the gram-positive bacteria Streptococcus pneumoniae and
the times of Hippocrates, the debate on what sepsis represents Staphylococcus aureus and the gram-negative bacteria Escherichia
and how it should be delineated continues today.1,2 Sepsis is now coli, Klebsiella spp., and Pseudomonas aeruginosa.15,16 In addition,
formally defined as a life-threatening condition that arises when fungal sepsis, mainly caused by Candida species, is on the rise, at
the body’s response to an infection injures its own tissues and least in part due to an increase in immune compromised patients.
organs.3 From a more clinical perspective it has recently been Pathogens associated with sepsis express an imposing arsenal of
proposed to include evidence of organ dysfunction in the criteria virulence factors, each of which contributes to the severity of the
for sepsis—i.e., sepsis should be defined as a systemic response to infectious insult.8,17
infection with the presence of some degree of organ dysfunction.4 Pattern-recognition receptors (PRR) are the central compo-
Of note, this slightly differs from the definition used in the also nents of the innate immune system that recognize danger sig-
recently published guidelines of the Surviving Sepsis Campaign nals such as invading bacteria and initiate the immune response
in which sepsis is defined clinically as the presence (probable or (Fig. 1).18,19 PRRs recognize conserved motifs expressed by patho-
documented) of infection together with systemic manifestations gens named pathogen-associated molecular patterns (PAMPs)
of infection and severe sepsis as sepsis plus sepsis-induced organ such as lipopolysaccharide (LPS), peptidoglycan, lipopeptides
dysfunction or tissue hypoperfusion.5 Despite an overwhelming (a component of many pathogens), lipoteichoic acid (a cell wall
increase in our knowledge on the pathogenesis of sepsis in the component of gram-positive bacteria), flagellin (a mobility fac-
past two decades, virtually all sepsis trials have failed to show tor of bacteria), and bacterial DNA.8,19 PRRs can also recognize
a benefit of newly developed immune-modulating drugs.6 As a endogenous danger signals, termed alarmins or DAMPs (dan-
ger-associated molecular patterns), which are released during
*Correspondence to: Willem Joost Wiersinga; inflammatory stress (e.g., burns, trauma, and tissue necrosis),
Email: [email protected] thereby warning the host immune system for imminent dan-
Submitted: 05/22/2013; Revised: 06/16/2013; Accepted: 06/17/2013 ger.20,21 Examples of DAMPs that cause further amplification
http://dx.doi.org/10.4161/viru.25436
of the pro-inflammatory response through TLR4 include heat

36 Virulence Volume 5 Issue 1

 Figure 1. The host response to sepsis. The host response to sepsis is characterized by both pro-inflammatory responses and anti-inflammatory
immune suppressive responses. Inflammatory responses are initiated by interaction between pathogen-associated molecular patterns (PAMPs)
expressed by pathogens or endogenous danger signals (danger-associated molecular patterns, DAMPs) and pattern recognition receptors (PRR)
expressed by host immune cells. Exaggerated inflammation with collateral tissue damage and necrotic cell death will result in the release of DAMPs
that can perpetuate ongoing inflammation. The pro-inflammatory response is enhanced by activation of leukocytes, complement, and the coagula-
tion system. The anti-inflammatory immune suppressive response depends on impaired function of immune cells, neuroendocrine regulation, and
inhibition of pro-inflammatory gene transcription. Importantly, direction, extent, and duration of the septic response is determined by both host
factors, such as genetic composition, age, comorbidity, and medication, and pathogen factors, including microbial load and virulence. LPS, lipopoly-
saccharide; LTA, lipoteichoic acid; HSP, heat shock protein; HMGB-1, high mobility group box-1 protein; IL, interleukin; IL-1RA, IL-1 receptor antagonist;
MRP8/14, migration inhibitory factor-related protein-8/14; NETs, neutrophils extracellular traps; T, T lymphocytes; B, B lymphocytes; DC, dendritic cells;
Tregs, regulatory T lymphocytes; TLR, toll-like receptor.

shock proteins, fibrinogen, S100 proteins, hyaluronic acid, and Toll–interleukin 1 (IL-1) receptor (TIR) domain is required for
high-mobility group box-1 protein (HMGB-1).22,23 PPRs can downstream signal transduction, leading to the transcriptional
be categorized on the basis of their cellular localization. After activation of inflammatory mediators.24 Thirteen mammalian
the discovery of mostly cell-membrane bound TLRs in the mid- TLRs have been identified: ten functional receptors in humans
1990s, several classes of cytosolic PRRs were identified, including and 12 in mice; of these TLR1–9 are shared by both species,
Nod-like receptors (NLRs), C-type lectins (CLRs), and RIG-I- whereas TLR10 and TLR11–13 are exclusively expressed in
like receptors (RLRs). Here we focus on PRRs that have been humans and mice respectively. TLRs can be expressed on the
studied most in the context of sepsis, i.e., TLRs and NLRs. cell surface (TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10)
Toll-like receptors (TLRs) or intracellularly (TLR3, TLR7, TLR8, and TLR9). The cellu-
TLRs express ectodomains containing leucine-rich repeats lar localization of TLRs is considered to be important for ligand
that mediate the recognition of PAMPs; the intracellular accessibility and the preservation of tolerance to self-molecules.

www.landesbioscience.com Virulence 37
Many if not all TLRs are dimeric, with some acting as homodi- tissue injury, as may occur during sepsis. Likely, TLR activation
mers and others as heterodimers (e.g., TLR2/TLR1 and TLR2/ by DAMPs released from injured cells play a major role herein.
TLR6). Some TLRs depend on other proteins to signal efficiently. TLR4 has been considered an attractive therapeutic target in
For example, proficient LPS signaling requires LPS-binding pro- severe sepsis considering its role in cellular activation by several
tein, which transfers LPS to CD14, and the extracellular protein PAMPs (most notably LPS) and DAMPs. Eventually this led to
MD-2. The interaction between LPS and its receptor complex the pivotal phase III ACCESS trial examining the effect of the
is further dependent on the glycosylation status of LPS: smooth TLR4/MD2 antagonist eritoran in patients with severe sepsis.31
LPS (with abundant O-glycosylation) requires CD14 for its Unfortunately, although a phase II sepsis trial with this com-
detection, whereas rough LPS or lipid A do not.25 In general, pound had shown promising results,32 the phase III trial revealed
ligands of TLRs are lipoproteins, lipids, and nucleic acids. TLRs no benefit whatsoever for patients treated with eritoran.31
expressed at the cell surface mainly sense microbial components Positive and negative regulation of the TLR signaling
located on the surface or in membranes of bacteria, such as lipo- TREM-1 (triggering receptor expressed by myeloid cells-1) is
proteins, lipids, and proteins. For example, the best characterized a receptor expressed on neutrophils and monocytes that has been
ligands for TLR2 are lipoproteins: TLR2 forms heterodimers shown to amplify the inflammatory cascade in response to infec-
with TLR1 and TLR6 that recognize triacyl and diacyl lipopro- tion.33 Antibody-mediated activation of TREM-1 induces mod-
teins respectively. Relevant for sepsis pathogenesis, TLR2 also est cellular activation and pro-inflammatory cytokine secretion.
senses peptidoglycan (bacterial cell wall component), lipoteichoic Importantly, co-stimulation of TREM-1 together with certain
acid (gram-positive bacteria), and zymosan (fungi). Dectin-1 (a PRRs, most notably TLRs, results in a synergistic increase in
C-type lectin) and CD36 can enhance TLR2-mediated recog- inflammatory signaling. Blockade of TREM-1 in rodent sepsis
nition of PAMPs. TLR5 recognizes flagellin, which forms the models resulted in decreased systemic cytokine production and
bacterial flagella. TLRs located in endosomes and endolysosomes improved survival, accentuating the detrimental role of excessive
mostly recognize nucleic acids from pathogens. Of these, TLR3 inflammation in fulminant sepsis.33 However, a recent murine
recognizes viral double-stranded RNA, while TLR7 and TLR8 study reported that TREM-1 deficiency resulted in a marked
recognize viral single-stranded RNA. TLR9 senses microbial increase in mortality following induction of Pseudomonas pneu-
(unmethylated CpG) DNA derived from either bacteria, viruses monia, at least in part due to deficient epithelial transmigra-
or parasites. Cleavage and trafficking of the intracellular TLRs tion of neutrophils to the primary site of infection.34 These data
are necessary for signaling. Unc-93 homolog B1 (UNC93B1) again are an example of the delicate balance of innate immu-
binds to intracellular TLRs and mediates their trafficking to the nity, wherein pro- and anti-inflammatory processes in response
endolysosome where signaling is initiated.26 Of note, TLR13, to infection must be balanced to protect against infection and to
which is mouse-specific, was recently shown to recognize 23S avoid tissue damage and organ failure.
rRNA from bacteria.27 Several mechanisms are involved in the negative regulation of
The entire TLR family signals via four adaptor proteins: TLR signaling.35,36 Transmembrane receptors that act as nega-
myeloid differentiation primary-response protein 88 (MyD88), tive regulators of TLR-mediated inflammation include single
TIR domain-containing adaptor protein (TIRAP, also known immunoglobulin IL-1R-related molecule (SIGIRR and TIR8),
as Myd88 adaptor like [Mal]), TIR domain-containing adaptor IL-1 receptor-like 1 (ST2), and radioprotective 105 (RP105).
protein-inducing IFN-β (TRIF) and TRIF-related adaptor mol- Cells that lack either one of these receptors respond more avidly
ecule (TRAM). TLR-mediated signaling can be roughly divided to TLR stimulation. In addition, the adaptor proteins involved
into two major routes: the MyD88- and the TRIF-dependent in efficient signaling by TLRs (MyD88, TIRAP/Mal, TRIF,
pathways. Most TLRs use MyD88 for signaling, except TLR3 and TRAM) are targets for negative control by several mecha-
that utilizes TRIF. TLR4 can utilize both MyD88 and TRIF nisms. For example, TAG (TRAM adaptor with Golgi dynamics
as signaling adaptors. TIRAP connects TLR2 and TLR4 to domain) is a TRAM variant that competes with TRAM for TRIF
MyD88, thus acting as a sorting adaptor in MyD88-dependent binding, thereby inhibiting the TRIF-dependent pathway.37 TAG
pathways. TRAM connects TLR4 to TRIF and permits TLR4 to also mediates internalization of TLR4 to the endosomes for sub-
traffic to endosomes. sequent degradation. Together with TMED7 (transmembrane
TLRs play a central role in sepsis pathogenesis. TLRs on the emp24 protein transport domain containing 7) TAG disrupts the
one hand are essential for the early detection of pathogens and TRAM–TRIF complex, resulting in inhibition of TLR4 signal-
the initiation of an adequate innate immune response. Indeed, ing from the endosome.38 SARM (sterile α- and armadillo-motif-
deficiency of TLR function leads to a strongly enhanced sus- containing protein) is another TIR-domain containing protein
ceptibility for infection, as demonstrated by the vulnerability of that can bind and inhibit TRIF.39 Moreover, inflammatory sig-
MyD88-deficient mice for a variety of infectious diseases.19 In naling can be shut down by ubiquitination, a process during
accordance, children deficient for MyD8828 or its direct down- which proteins are “tagged” with ubiquitin for proteasome-
stream mediator IRAK-429 develop frequent purulent infections. mediated degradation. SHP (small heterodimer partner) inhibits
Not surprisingly, polymorphisms in TLR encoding genes have TLR signaling by suppressing the ubiquitination of an essen-
been associated with an altered susceptibility to bacterial infec- tial downstream signaling molecule (TRAF6).40 Consequently,
tions.30 On the other hand, however, uncontrolled TLR stimu- SHP-deficient cells release increased levels of pro-inflammatory
lation potentially leads to disproportionate inflammation and cytokines upon LPS stimulation. USP4 (ubiquitin-specific

38 Virulence Volume 5 Issue 1

peptidase 4) also negatively regulates TRAF6, by a mechanism induces caspase-1 activation, which causes the processing of the
that involves removal of polyubiquitin chains. A20 is an essen- pro-inflammatory cytokines IL-1β and IL-18.18,44
tial intracellular negative regulator of TLR signaling, regulating The central role of the NLRs in the recognition of invad-
NFκB activation via multiple mechanisms. A20-deficient mice ing bacteria and the initiation of the innate immune system is
display spontaneous inflammation in various organs, which is by now well recognized. Activation of inflammasomes during
caused by enhanced MyD88-dependent signaling as indicated sepsis can amplify inflammatory responses. The consequence
by the fact that mice with combined A20 and MyD88 deficien- thereof, whether beneficial or detrimental, depends on the extent
cies do not show aberrant inflammation.41 Other intracellular and duration of inflammasome activation. The importance of
negative TLR regulators include MyD88 short, TOLLIP (Toll- inflammasomes for host defense against infection has been dem-
interacting protein), suppressor-of-cytokine signaling (SOCS), onstrated in many investigations. For instance, mice lacking both
and IRAK-M (IL-1 receptor associated kinase-M).36 NLRP3 and NLRC4 are markedly more susceptible to Salmonella
Inflammation following PRR activation can be further regu- Typhimurium infection45 and mice lacking NLRP3 or ASC
lated by epigenetic processes.42,43 Epigenetics is a general term showed enhanced susceptibility to S. pneumoniae pneumonia.46
encompassing mechanisms that govern gene expression patterns In patients with septic shock inflammasome mRNA expression
without modifying the underlying DNA sequence of an organ- of ASC, caspase-1 and NALP1 are significantly downregulated
ism, which can include chemical modifications of DNA and/or when compared with critically ill control subjects, which may
associated histones that result in changing the physical acces- contribute to the state of immunosuppression observed in these
sibility of the DNA to transcription factors. Peripheral blood septic patients.47 On the other hand, similar to uncontrolled TLR
mononuclear cells of sepsis patients show increased levels of activation, inflammasome activation, leading to caspase-1 activa-
repressive histone modifications at the promoter regions of both tion and the release of IL-1β, likely contributes to organ injury
interleukin (IL)-1 and tumor necrosis factor (TNF)-α, mediated during sepsis.
by dimethylation of histone 3 at lysine residue 9 (H3K9me2).
Additional results suggest that the early enhanced inflamma- The Inflammatory Response in Sepsis
tory response during sepsis may be directing the loss of specific
activating epigenetic marks at promoters of pro-inflammatory Moving away from the old SIRS and CARS division
genes in macrophages, such as acetylation of histone 4 (H4Ac) In the 1990s the term systemic inflammatory response syn-
and lysine 4 tri-methylation of histone 3 (H3K4me3). By a dis- drome (SIRS) was introduced to describe the pro-inflammatory
tinct mechanism, posttranscriptional regulation of mRNA can host response to invading pathogens, which has been considered
be accomplished by complementary gene interference driven by the hallmark sign of sepsis.48 TNF-α and IL-1 are considered the
micro-RNAs (miRNAs), resulting in reduced protein expression main pro-inflammatory cytokines that fuel the SIRS response.
through targeted degradation of specific mRNAs. We now know however that simple inhibition of TNF-α or IL-1
Nod-like receptors (NLR) does not provide clinical benefit to patients with severe sepsis.8
Microorganisms that invade the cytosol can be recognized Clearly, the hypothesis that excessive inflammation is the basis
by cytoplasmatic PRRs, most notably the NLRs and RLRs.18,19 for an adverse outcome in sepsis requires reconsideration: the
NLRs are further subcategorized based on differences in the host response to sepsis involves multiple subsequent and concur-
N-terminal domains.18,44 NODs are NLRs that recognize com- rent processes that involve both exaggerated inflammation and
mon fragments of bacterial peptidoglycan, i.e., diamino-pimelate immune suppression. SIRS has been thought to be followed
from gram-negative bacteria is the ligand for NOD1, while mur- by CARS or the “compensatory anti-inflammatory response
amyl dipeptide is the ligand for NOD2. The largest NLR group, syndrome”, a concept introduced in the late 1990s and which
comprising 14 members, has an N-terminal pyrin domain (PYD) is characterized by the induction of several anti-inflammatory
and is therefore called “NLRP” (previously called “NALP”) of mechanisms.49 Recent insights show that the induction of pro-
which ASC (apoptosis-associated speck-like protein containing and anti-inflammatory genes in critically ill patients however
a caspase activation and recruiting domain) serves as the central occurs simultaneously, which suggests that SIRS and CARS
adaptor molecule. Several members of the NLR-family, includ- are not two different subsequent phases of the septic response.50
ing NLRP1, NLRP3, and NLRC4, can assemble multimolecular Studies describing the transcriptome of circulating leukocytes in
complexes termed inflammasomes in response to various acti- patients with severe trauma or burn injury and healthy subjects
vators, leading to caspase activation. Both endogenous danger injected with bacterial LPS (an often used model to study sep-
signals, such as double-stranded DNA and uric acid crystals, sis) show that during these severe stresses a global reprioritiza-
as well as exogenous pathogen-derived molecules, such as viral tion of the leukocyte transcriptome affects >80% of the cellular
RNA or bacterial peptidoglycans, can activate inflammasomes. functions and pathways, which has been called a truly “genomic
Moreover, the NLRP3 inflammasome is assembled in response storm”.50 It should be noted however that the “genomic storm”
to potassium efflux, extracellular ATP, or reactive oxygen spe- seen in this study was a monopolar, sterile inflammatory event in
cies. As such, inflammasomes can either sense pathogens directly relatively young patients and study subjects.50 The host response
or come to be stimulated by the intracellular alterations induced might be substantially different in a typical elderly, septic patient
by pathogens or other PRRs. NLRP3 inflammasome activation with a localized infection that becomes systemic over hours to

www.landesbioscience.com Virulence 39
days by an invasive pathogen that continues to cause injury and cannot be made: some cytokines act as DAMPs and some
tissue damage for days after onset of illness. DAMPs actually are cytokines. A good example to illustrate
Cytokines: orchestrators of the septic innate immune this is myeloid related protein 8 (MRP8, S100A8) and MRP14
response (S100A9), which are the most abundant cytoplasmic proteins
The most extensively studied cytokines in sepsis are TNF-α in neutrophils.64 These proteins function as endogenous danger
and IL-1, both of which are capable to activate target cells and proteins that promote systemic inflammation through activation
induce the production of more inflammatory mediators.8 Other of RAGE or TLR4.64,65 They can form MRP8/14 heterodimers
cytokines of known importance in regulating the septic host that are released upon cell stress stimuli. MRP8/14 has direct
response include IL-6, which has both pro-inflammatory and antimicrobial effects and has been implicated in phagocyto-
anti-inflammatory properties, IL-8, IL-12, interferon (INF)-γ, sis.64,66 Patients with sepsis display elevated circulating levels of
granulocyte-colony stimulating factor (G-CSF), and the anti- MRP8/14.67 Mice lacking MRP14 (and thereby incapable of
inflammatory cytokine IL-10.8 IL-17, mainly produced by Th17 forming biologically active MRP8/14 heterodimers) are pro-
cells, is a novel pro-inflammatory cytokine implicated in sepsis tected from LPS-induced shock and E. coli-induced abdominal
pathogenesis by virtue of its capacity to mediate pro-inflam- sepsis.64,67 On the other hand, MRP14-deficient mice display
matory responses by triggering the production of among others enhanced bacterial dissemination, increased distant organ dam-
IL-1β, IL-6, and TNF-α and to provide crosstalk between lym- age, and a reduced survival during K. pneumoniae pneumosep-
phocytes and phagocytes.51 Increased IL-17A levels have adverse sis.66 These results identify MRP8/14 as an important player in
effects during experimental sepsis: in a murine model of sepsis the innate immune response to sepsis with pleiotropic functions
induced by cecal ligation and puncture IL-17A blockade was that can both harm or benefit the host depending on the caus-
associated with reduced bacteremia, reductions of systemic pro- ative pathogen and most probably the severity, the phase and/or
inflammatory cytokines and improved survival.52 compartment of the septic response.
Another cytokine involved in the septic inflammatory response Neutrophil extracellular traps (NETs)
is macrophage migration inhibitory factor (MIF), which regulates Neutrophils can be regarded as the frontline soldiers against
immune responses through modulation of TLR4. MIF-deficient sepsis, not only because of their sheer number—they are the
mice have a defective response upon LPS challenge as a direct most abundant leukocytes—but also because of their impressive
result of decreased TLR4 expression.53 Inhibition of MIF activ- weaponry to kill invading bacteria. In addition to phagocyto-
ity with neutralizing anti-MIF antibodies protected mice from sis and the release of soluble anti-microbials from their granules,
septic shock.54 Plasma MIF levels are elevated in septic patients neutrophils are capable to entrap bacteria in ejected DNA-based
and are associated with early mortality.55-57 Intriguingly however, structures containing anti-bacterial proteins such as elastase,
polymorphisms associated with higher MIF expression may have cathepsin G, MRP8/14, and myeloperoxidase, which have been
a beneficial effect in patients with pneumosepsis prompting cau- named neutrophil extracellular traps (NETs).68-70 Virtually
tion in the clinical application of anti-MIF strategies in infec- all microbes that cause sepsis are able to induce NET forma-
tious diseases in order to avoid placing patients at increased risk tion.66,68,69,71 It was recently shown that NETs released into the
of adverse outcomes.58 vasculature are able to catch bacteria from the bloodstream and
The pro-inflammatory cytokine HMGB-1, which is elevated prevent dissemination in a mouse model of E. coli sepsis.72 Plasma
during sepsis, received a lot of attention since it acts as a late from patients with severe sepsis induces platelet–neutrophil inter-
mediator of sepsis and is therefore seen as an attractive treatment actions in a TLR4-dependent fashion leading to the production
target.59,60 Along with the receptor for advanced glycation end of NETs.73 Interestingly, platelets seem to have a more potent
products (RAGE), HMGB-1 interacts with TLR2 and TLR4, NET-inductive capability than other known inducers of NETs.
which may provide an explanation for the ability of HMGB-1 NET formation can be triggered even before phagocytosis which
to generate inflammatory responses that are similar to those ini- makes sense in the event of sepsis since NETs seem to be able to
tiated by LPS.61 HMGB-1 may do so by binding other ligands entangle far more bacteria simultaneously than neutrophils can
for PRRs, considering that purified HMGB-1 triggers cells to by phagocytosis alone.73,74 Some bacteria, such as certain strains
produce TNFα strictly via TLR4.62 Treatment of mice with of S. pneumoniae and P. aeruginosa, have developed mechanisms
antibodies to HMGB-1 diminishes endotoxin lethality.63 Taken to circumvent NET-mediated killing.68,71,75 Importantly, how-
together, it is now well established that bacterial infection leads to ever, overwhelming NETosis or a reduced clearance capacity
the activation of a whole range of pleiotropic pro-inflammatory of NETs can be detrimental for the host and can contribute to
cytokines. The balance between these mediators and anti-inflam- ongoing inflammation and/or exhaustion of the immune system
matory cytokines or soluble inhibitors of pro-inflammatory cyto- during sepsis.68 Indeed, in the context of sepsis, free circulating
kines eventually determines the net pro-inflammatory activity of DNA should be regarded as a DAMP by itself.76 Of note, human
the cytokine network. DNA can only become immune stimulatory by associating with
Mrp8/14 as an example of DAMPs nuclear, cytoplasmic, and serum proteins upon which it can be
Invasive infection and accompanying inflammatory mecha- internalized in cells and sensed by DNA receptors such as TLR9;
nisms can cause tissue damage that is associated with release of this in contrast to bacterial DNA which CpG motifs directly act
DAMPs. A clear distinction between cytokines and DAMPs as powerful immune stimulants.76

40 Virulence Volume 5 Issue 1

 Complement system in its cell-associated form, TF can reside in microparticles that
Complement factors are released as part of the inflamma- can be shed from leukocytes, endothelial cells, vascular smooth
tory reaction to infection.77 In experimental and clinical sepsis, muscle cells, and platelets. Microparticles can transfer TF to cells
elevated plasma levels of the anaphylatoxins C3a and C5a can that do not generate this procoagulant protein themselves, such
be detected, indicative of activation of the complement system. as granulocytes, and have been implicated in activation of both
C5a is generated from C5 following activation of complement coagulation and inflammation in sepsis.88
by either the classical, alternative or lectin pathway. Preclinical Procoagulant events are controlled by three major antico-
research has provided evidence for a key role of C5a and its recep- agulant proteins: antithrombin, TF pathway inhibitor (TFPI),
tors (C5a receptor and C5L2) in the progression of polymicro- and activated protein C (APC).81 Antithrombin is the main
bial abdominal sepsis induced by cecal ligation and puncture.77 inhibitor of thrombin and factor Xa. The inhibitory function
C5a binds with high affinity to its receptors, which are not only of antithrombin is enhanced by endogenous glycosaminogly-
present on phagocytes (especially neutrophils) but also on several cans, among which heparan sulfates. TFPI is the main inhibitor
non-myeloid-derived cells, including endothelial cells. Activation of the TF-factor VIIa complex. Normally, TFPI is attached to
of the C5a receptor by C5a results in a cascade of signaling events the endothelium via proteoglycans, which facilitates its TF fac-
with responses such as priming for cell responses to a second tor VIIa–factor X inhibiting properties on the endothelial sur-
stimulus (for example produced by a PAMP), release of cytoplas- face. In sepsis pro-inflammatory cytokines reduce the synthesis
mic granule contents, reactive oxygen species production, and of glycosaminoglycans on the endothelial surface, which likely
chemotactic responses. Clearly, these responses are part of protec- impairs the function of antithrombin and TFPI. The protein
tive immunity during infection. However, excessive C5a activity C system represents an important anticoagulant mechanism by
can be harmful in the setting of fulminant sepsis. Indeed, neu- virtue of the capacity of APC to proteolytically inactivate the
tralization or genetic absence of C5a receptor or C5L2 improves coagulation cofactors Va and VIIIa. APC is formed from protein
survival during abdominal sepsis or endotoxemia in mice.78,79 Of C when thrombin binds to thrombomodulin, a receptor pres-
note, an important inhibitor of C5a and C3a is thrombin-activat- ent on the vascular endothelium. The activation of protein C to
able fibronolysis inhibitor (TAFI), by generation of carboxypep- APC by thrombomodulin-bound thrombin is amplified by the
tidase activity, which is induced by thrombin–thrombomodulin presence of the endothelial protein C receptor (EPCR). During
complexes on the vascular endothelial surface.80,81 Inhibition sepsis the protein C system is impaired as a result of multiple fac-
of C5a activity is currently considered an attractive therapeutic tors, most notably decreased synthesis of protein C by the liver,
option in sepsis.77 increased consumption of protein C and impaired activation of
Coagulation system protein C by diminished thrombomodulin and EPCR expres-
Sepsis is associated with multiple alterations in procoagulant sion on endothelial cells. Many studies have supported the anti-
and anticoagulant mechanisms.81 Hemostatic disorders in patients coagulant potency of the protein C system in vivo.89 Infusion
with infection may range from subtle activation of coagulation of APC confers anticoagulant, anti-inflammatory, and protective
detected by sensitive laboratory tests to fulminant disseminated effects in multiple sepsis models. In addition, the importance of
intravascular coagulation (DIC). DIC is commonly seen in sepsis the endogenous protein C system for protection against exces-
and in particular in septic shock where the incidence is somewhere sive coagulation and inflammation has been firmly established
between 30% and 50%.82 Sepsis results in a net procoagulant by multiple studies using several strategies to inhibit the function
state that promotes fibrin deposition through three main path- of this pathway. The anti-inflammatory functions of APC rely on
ways: tissue factor (TF)-mediated thrombin generation, dysfunc- its interaction with protease activated receptor-1 (PAR1).
tional physiological anticoagulant mechanisms, and impaired PARs form the crucial link between coagulation and inflam-
fibrin removal due to depression of the fibrinolytic system. mation.90 Four PARs (1 to 4) have been identified, each of which
Coagulation activation in sepsis is primarily driven by TF. can be activated by several proteases. Thrombin can activate
TF is not exposed to circulating blood cells in a resting state, PAR1, 3, and 4; these receptors can also be activated by plas-
but becomes exposed on the surface of mononuclear cells and min, trypsin or cathepsin-G. PAR2 can be activated by tryp-
endothelial cells when they are stimulated by bacteria or by bac- sin, mast cell tryptase, leukocyte proteinase-3, and a number
terial products like LPS or by pro-inflammatory cytokines such of bacteria-derived enzymes. TF can induce cell signaling via
as TNF-α. TF binds and activates factor VII. The TF/factor PAR1 or PAR2; factor Xa and APC can exert cellular effects via
VIIa complex that is generated after exposure of TF-presenting PAR1. Curiously, although APC and thrombin can both acti-
cells to blood initiates coagulation activation by activation of vate PAR1, APC affects the vascular endothelium in a way that
factor X, producing factor Xa and finally leading to prothrom- clearly is distinct from thrombin signaling. The divergent cel-
bin conversion to thrombin. Sepsis patients and healthy humans lular effects of APC and thrombin are especially remarkable with
intravenously injected with LPS show enhanced TF expression regard to endothelial barrier function. APC potently inhibits
on circulating mononuclear cells.83,84 Inhibition of the TF/fac- thrombin-induced vascular hyperpermeability by a mechanism
tor VIIa pathway abolishes coagulation activation elicited by dependent on trans-activation of the sphingosine 1 phosphate
administration of LPS or bacteria in humans85 and non-human (S1P) receptor 1 (S1P1), whereas thrombin induces vascular
primates,86,87 and in lethal sepsis models in baboons, TF inhibi- hyper-permeability dependent on another S1P receptor, S1P3.
tion prevented multiple organ failure, and mortality.86,87 Besides Preclinical evidence indicates that the anti-inflammatory, rather

www.landesbioscience.com Virulence 41
than the anticoagulant, effects of APC are important for protec- which can probably be seen as a PRR-mediated dysregulation of
tion against sepsis lethality: studies using APC mutants that lack the immune system following the invasion of pathogens. Indeed,
anticoagulant properties were as protective as wild-type APC.91,92 two decades of failed sepsis trials have forced one to rethink the
Considering the abundant preclinical evidence that interfer- pure hyperinflammatory sepsis paradigm. New human sepsis
ence with coagulation may beneficially impact on sepsis outcome, studies should also consider the substantial heterogeneity in the
it is not surprising that anticoagulant therapies have been stud- patients and type of infections included in sepsis trials as well
ied extensively in patients with severe sepsis.93 These investiga- as the predominant phenotype of the immune response, pro- or
tions focused on the restoration of (supra) physiological levels of anti-inflammatory/immune suppressive, at time of inclusion.13,99
antithrombin, TFPI, and APC. Antithrombin and TFPI failed to Furthermore, in recent times it has become clear that the host
reduce mortality in randomized clinical trials in sepsis patients.94,95 response to infection and non-infectious injury is not funda-
Recombinant human APC did reduce 28-d mortality in a first mentally different; whole blood genome response in patients
pivotal phase III trial (PROWESS),96 but did not show any ben- with trauma, burn, or sepsis result in highly similar genomic
efit in a subsequent study in septic shock patients (PROWESS- responses.100 In depth knowledge of the interconnections between
SHOCK),97 which resulted in retraction of this protein from innate immune pathways should help to unravel the mystery of
the market by the manufacturer. Nonetheless, the debate on the sepsis and identify new treatment strategies to cope with this
possible value of APC for sepsis treatment has continued.98 APC endemic syndrome.
mutants lacking anticoagulant properties would be attractive drugs
to study in clinical trials: these proteins retain the capacity to pro- Disclosure of Potential Conflicts of Interest
tect animals from sepsis induced death (via an effect on PAR1) but No potential conflicts of interest were disclosed.
do not expose patients to the risk of bleeding complications.
Acknowledgments
Conclusion W.J.W. is supported by research grants of the Netherlands
Organisation for Health Research and Development (ZonMW)
A careful balance between the inflammatory and anti-inflam- and The Netherlands Organization for Scientific Research
matory response is vital for a successful host response to sepsis, (NWO).
9. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont 17. Merrell DS, Falkow S. Frontal and stealth attack strate-
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44 Virulence Volume 5 Issue 1