Review
TREM-1: intracellular signaling pathways and
interaction with pattern recognition receptors
Rob J. W. Arts, Leo A. B. Joosten, Jos W. M. van der Meer, and Mihai G. Netea1
Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i),
Nijmegen, The Netherlands
RECEIVED MARCH 17, 2012; REVISED OCTOBER 7, 2012; ACCEPTED OCTOBER 9, 2012. DOI: 10.1189/jlb.0312145
ABSTRACT
TREM-1 is an important signaling receptor expressed
on neutrophils and monocytes that plays an important
role in systemic infections. Here, we review the intra-
cellular signaling pathways that mediate the immuno-
logical effects of TREM-1. Because of the absence of
signaling motifs, TREM-1 constitutively associates with
DAP12 for induction of intracellular signals. After phos-
phorylation of DAP12, production of chemokines and
cytokines is induced. Moreover, TREM-1 also modu-
lates signaling pathways induced by known classes of
PRRs, such as TLRs and NLRs. The exact mechanisms
through which TREM-1 influences TLR and NLR path-
ways are still largely elusive. J. Leukoc. Biol. 93:
209 –215; 2013.
Introduction
TREM-1 is an activating receptor expressed on neutrophils
and monocytes. Engagement of TREM-1 on the surface of the
cell membrane leads to activation of a cascade of intracellular
events that result in inflammatory effects, such as cytokine pro-
duction, degranulation of neutrophils, and phagocytosis [1].
Up-regulation of TREM-1 appears to be a crucial step during
the initiation of the overwhelming cytokine response in septic
Abbreviations: Akt⫽protein kinase B, Bcl-10⫽B cell lymphoma/leukemia 10,
Btk⫽Bruton’s tyrosine kinase, CARD⫽caspase-recruitment domain,
CLR⫽C-type lectin receptor, CpG ODN⫽CpG oligodeoxynucleotide,
DAP12⫽DNAX-activating protein 12, Grb2⫽growth factor receptor-bound
protein 2, HMGB1⫽high-mobility group box 1, HSP70⫽heat shock protein
70, IRAK⫽IL-1R-associated kinase, IRF⫽IFN regulatory factor,
mBD2⫽murine ␤-defensin 2, Malt1⫽mucosa-associated lymphoid tissue
lymphoma translocation protein 1, MMP⫽matrix metalloproteinase,
NLR⫽neuronal apoptosis inhibitory protein, MHC class II transcription acti-
vator, incompatibility locus protein from Podospora anserina, and telomer-
ase-associated protein-leucine-rich repeat receptor, NOD⫽nucleotide-
binding oligomerization domain-containing protein, Nrf2⫽NF-erythroid
2-related factor 2, NTAL⫽non-T cell activation linker, p38/p50/
p100⫽protein 38/50/100, RAF⫽proto-oncogene serine/threonine-protein
kinase, RAS⫽rat sarcoma, RelA⫽transcription factor protein 65,
RIP⫽receptor-interacting protein, Sos1⫽son of sevenless homolog 1,
sTREM-1 soluble triggering receptor expressed on myeloid cell 1,
TBK⫽TRAF family member-associated NF-␬B activator-binding kinase,
TIRAP⫽Toll-IL-1R domain-containing adaptor protein, Tollip⫽Toll-interacting
protein, TREM⫽triggering receptor expressed on myeloid cell
0741-5400/13/0093-209 © Society for Leukocyte Biology
shock [2, 3], as well as in other infections, such as corneal
Pseudomonas aeruginosa infection [4]. Also, the amount of
sTREM-1 correlates with disease activity in cutaneous systemic
sclerosis and intestinal Behcet’s disease [5, 6], and the devel-
opment of the latter appears to be strongly associated with
TREM-1 single nucleotide polymorphisms [7]. These findings
suggest a pathophysiological role for TREM-1 in these diseases.
Stimulation of TREM-1 also appears to exert effective antibac-
terial responses, as shown in a mice model of pneumococcal
pneumonia and asthma induced by Aspergillus fumigatus [8, 9].
Understanding the (patho)physiology of TREM-1 bioactivity is
necessary, as it represents a therapeutic target in sepsis and
other hyperinflammatory conditions.
TREM-1 is a member of the Ig superfamily. It is a 30-kDa
glycoprotein receptor containing an ectodomain of the Ig-like
V-type, a transmembrane part, and a short intracytoplasmic
domain [10]. As the intracytoplasmic domain does not contain
any signaling motifs, it must associate with a signaling unit to
induce intracellular pathways. DAP12, a transmembrane pro-
tein with an ITAM, has been proposed to act as this signaling
unit [11]. Constitutive association of TREM-1 with DAP12 acti-
vates intracellular pathways, directly inducing cytokine produc-
tion. However, apart from this direct stimulation, there also
appears to be molecular cross-talk between the TREM-1 signal-
ing cascade and the intracellular signaling cascades of TLR2
and -4 and possibly TLR3, -5, -7/8, and -9, as well as some of
the NLR receptors [12–14].
In this review, we will discuss, on the one hand, the intracel-
lular pathways induced by TREM-1 engagement after associa-
tion with DAP12 and on the other hand, the molecular cross-
talk between the TREM-1 signaling cascade and PRR (TLR
and NLR) signaling pathways. This will lead to understanding
the broad effects of TREM-1 in immunity.
REGULATION OF TREM-1 EXPRESSION
Although the expression of TREM-1 can be influenced by dif-
ferent mediators, this process is not the main focus of this re-
1. Correspondence: Dept. of Medicine (463), Radboud University Nijmegen
Medical Center, Geert Grooteplein 8, 6525 GA Nijmegen, The Nether-
lands. E-mail: m.netea@aig.umcn.nl
Volume 93, February 2013 Journal of Leukocyte Biology 209
view. Nevertheless, the nuclear proteins that regulate the gene
transcription of TREM-1 will be mentioned shortly, as most of
them are also players in the intracellular pathways induced by
TREM-1 itself (Fig. 1).
One of the main mechanisms mediating the expression of
TREM-1 is activation of NF-␬B. After stimulation of RAW264.7
cells with LPS, the amount of RelA increases, whereas the
amount of p50 remains the same. It was suggested that the
homodimer p50/p50 down-regulates TREM-1 transcription,
whereas the p50/RelA heterodimer, which is increased after
LPS stimulation, up-regulates its transcription [15]. In addi-
tion, C/EBP␣ appears to be important for the basal transcrip-
tion of the mouse TREM-1 gene, as it can activate the CRE site
regardless of its phosphorylation level [16]. Secondly, CREB
activates the CRE site when it is phosphorylated by PKA [17].
Thus, CREB is responsible for the up-regulation of TREM-1
during inflammation [15].
Figure 1. Intracellular signaling pathways of TREM-1, TLR2, and
TLR4 and their putative interactions. An additional pathway mediating
the cross-talk between the TREM-1 and TLR pathways may be repre-
sented by IRAK1 and CARD9 (they have not been depicted in this fig-
ure, as the exact cascade through which this interaction may be medi-
ated remains unknown). CARD9 itself may also be important for medi-
ating the TREM-1 signal pathway. TRAM, Toll/IL-IR domain-
containing adapter-inducing IFN-␤-related adaptor molecule; TRIF,
Toll/IL-IR domain-containing adapter-inducing IFN-␤; MKK/MEK,
MAPK kinase; PDK1, phosphoinositide-dependent kinase 1; PIP3, phos-
phatidylinositol (3,4,5)-trisphosphate; PIP2, phosphatidylinositol 4,5-
biphosphate; IP3, inositol 1,4,5-triphosphate.
210 Journal of Leukocyte Biology Volume 93, February 2013
Another transcription factor important for up-regulation of
TREM-1 is AP-1, which is composed of c-fos and c-jun and acti-
vated by ERK and JNK, respectively. The expression of these
products also increases after stimulation of RAW264.7 cells
with LPS (Fig. 1) [15, 18].
Down-regulation of TREM-1 is not only regulated by the ho-
modimeric complex p50/p50 but also by PU.1. Stimulation of
RAW264.7 cells with LPS and P. aeruginosa, under conditions
in which the PU.1 gene was silenced, appeared to lead to an
increased TREM-1 induction. Thus, PU.1 appears to be a nega-
tive regulator of TREM-1 expression [18]. In addition, the
transcription factor Nrf2, which is activated by PGs, has also
been suggested to play a role in down-regulation of expression
of TREM-1. In experimental sepsis, Nrf2-deficient mice showed
more activation of NF-␬B in response to stimulation with LPS
than control mice [19]. In line with this, activation of regula-
tory PGs resulted in activation of Nrf2 and therefore, a decline
in TREM-1 expression [20].
In addition to the pathways regulating the expression of the
TREM-1 gene, an important mechanism that regulates the ex-
pression of the protein on the cell membrane is likely to be
represented by its shedding from the cell membrane by enzy-
matic processes, such as activation of MMPs [21]. MMPs are
up-regulated upon stimulation with several different bacterial
products [22, 23] and in the case of LPS, by a pathway depen-
dent on PGE2 or PI3K, Akt, and NF-␬B in a pathway reminis-
cent of that involved in the induction of TREM-1 [17, 22, 24].
The exact mechanism of how TREM-1 expression may be con-
trolled by MMPs or another mechanism of cleavage remains to
be defined and hence, is an interesting field for future re-
search.
THE TREM-1/DAP12 SIGNALING
CASCADE
Before the signaling cascade of TREM-1 is started, TREM-1 has
to bind its ligand, which is, up until now, unknown, although
several putative ligands have been proposed. For example, it
was shown that sTREM-1 is able to bind platelets and that
these could enhance neutrophil activation in the presence of
LPS, suggesting the presence of a TREM-1 ligand on platelets
[25]. Also, HMGB1 and HSP70 have been suggested as
TREM-1 ligands, as blocking TREM-1 resulted in decreased
IL-6, IL-8, and TNF production by monocytes after stimulation
with HMGB1 and HSP70 [26]. A different hypothesis suggests
that the ligand of TREM-1 is present on pathogens. Although
the exact ligand still has to be determined, there are sug-
gestions that peptidoglycans on the surface of Gram-positive
bacteria and endotoxins on Gram-negative bacteria may be
involved in the stimulation of TREM-1 [3, 9, 27–33], but
more detailed studies are necessary to prove this hypothesis.
The search for the putative endogenous and exogenous
TREM-1 ligands is still ongoing.
As TREM-1 lacks signaling motifs [1], initiating a signaling
event upon ligation depends on its association with DAP12.
Phosphorylation of the ITAM domain of DAP12 is, in turn,
induced by Src family kinases. Subsequently, Syk will be acti-
vated by the phosphorylated ITAM part of DAP12 [34]. This
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initiates an intracellular signaling pathway that is not yet fully
understood but uses PI3K, PLC␥, and ERK as major signaling
molecules [30]. A putative cascade based on several studies is
depicted in Fig. 1 [1, 34 – 45]. These signaling cascades will be
discussed further in the following paragraphs.
Recently, it has been suggested that Btk plays an important
role in the TREM-1/DAP12 cascade. After activation of the
TREM-1/DAP12 cascade, Btk becomes phosphorylated in a
Syk-dependent manner. Blockade of Btk resulted in a signifi-
cant decrease of calcium influx, PLC␥ and ERK phosphoryla-
tion, and IRAK1 activity. Thus, Btk was suggested as the main
factor in PLC␥ phosphorylation [41]. The influence of Btk on
the activity of IRAK1, which is involved in TLR signaling as
well, suggests a cross-talk between the TREM-1 and TLR path-
ways. As this is a very interesting observation, the role of
IRAK1 as a connector between the TREM-1 and TLR pathways
should be explored.
Another central regulation molecule is NTAL. After phos-
phorylation by Syk, it has two important effects. First, NTAL
represses the TREM-1-induced phosphorylation of ERK and
the production of TNF-␣ and IL-8, by binding Grb2 and Sos1,
which results in less activity of the RAS pathway [1, 39, 42].
Secondly, it was shown that inhibition of NTAL resulted in
reduced and delayed calcium mobilization after ligation of
TREM-1 [39], indicating a role of NTAL in the regulation of
calcium influx. However, the exact pathway remains unknown.
Because of these opposite effects, NTAL has been postulated
to act as a gatekeeper and to regulate the DAP12-initiated cas-
cade.
The calcium influx and production of DAG result in activa-
tion of two main pathways: one pathway results in NF-␬B pro-
duction and is regulated by PKC␪ [30], whereas the second
causes activation of the MAPK/ERK pathway [30] (Fig. 1).
Furthermore, it has been shown previously that CARD9,
which forms a complex with Bcl-10 and Malt1 [45], is essential
for the NF-␬B-dependent cytokine production after stimulation
of TREM-1 [43]. Moreover, CARD9 has been suggested to be
involved in the induction of cytokine production by TLRs, as
after stimulation of TLRs and IRAK1, a RIP-induced CARD9-
Bcl-10-Malt1 complex will be formed, which activates MAPKs
and leads to NF-␬B activation [43]. Whether these two observa-
tions can be combined to support a central role of CARD9 for
the synergy between TLRs and TREM-1 remains to be eluci-
dated. Moreover, besides the central role of CARD9 in cas-
cades from receptors, such as TREM-1 or FcR, osteoclast-associ-
ated receptor, and myeloid-associated Ig-like receptor II[43],
the most important role of CARD9 is its mediation of effects
induced by CLRs [46]. No interaction between TREM-1 and
CLRs has been reported to date. Hence, the role of CARD9 is
a very interesting subject for future research, especially its role
for the intracellular signaling induced by the TREM-1 pathway,
both at the level of the putative interaction of CARD9 with
TREM-1 on the one hand and TLRs and CLRs on the other
hand.
Downstream of CARD9, p38 kinase phosphorylation is an
important event induced after stimulation of MyD88-depen-
dent TLR pathways [47]. It also appears that after blocking
TREM-1, p38 phosphorylation is attenuated, and p38 is up-
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Arts et al. TREM-1 interaction with PRRs
regulated after TREM-1 stimulation [17, 26, 37]. Thus, apart
from the TLR cascade, also, the TREM-1 cascade is dependent
on activation of the p38 kinase. It is unclear whether this acti-
vation is CARD9- or IRAK1-dependent and whether other cas-
cades are involved.
In neutrophils, it has also been shown that p38 can influ-
ence the activity of PI3K and that phosphorylation of ERK was
preceded by an enhanced activation of p38 after stimulation of
TLR4 and TREM-1. This indicates a role for PI3K to connect
the two pathways. As suggested in Fig. 1, p38 might directly
induce PI3K activation, which via PLC␥, PKC␪, and RAF, could
cause phosphorylation of ERK [37, 41].
Another protein of interest is mBD2. It plays a role in up-
regulation of MyD88-mediated and NF-␬B-dependent produc-
tion of cytokines and maturation of DCs [48 –51]. It was shown
that TREM-1 decreases the production of mBD2 in corneal P.
aeruginosa infection [4] and therefore, moderates cytokine re-
sponses.
THE TREM-1/DAP12 PATHWAY IN
NEUTROPHILS
In neutrophils, besides the nuclear activity that results in
production of cytokines and chemokines, the production of
ROS, lactoferrin, and MPO is also up-regulated after
TREM-1 stimulation. Subsequently, this results in increased
neutrophil degranulation and a higher phagocytic activity
[1, 14]. Phagocytosis is mainly influenced by p38 and PLC␥,
whereas the production of ROS is, besides p38, also regu-
lated by PKC␪ activation via PI3K and PLC␥ phosphoryla-
tion (Fig. 2) [37, 52].
Most of the monocyte and neutrophil intracellular pathways
elicited by TREM-1 results in production of cytokines and
chemokines. TREM-1 engagement induces production of pro-
inflammatory cytokines, such as IL-1␤, IL-2, IL-6, IL-8, IL-
12p40, and TNF-␣; of chemokines, such as MIP-1␣, membrane
cofactor protein-1 and -2, and GM-CSF; and of costimulatory
molecules, such as CD1a, CD86, and MHC class II, whereas a
decrease in IL-10 production has been reported [1, 12, 32,
39]. The increase of cytokine and chemokine production is
mainly regulated by four different pathways, namely Jak-STAT,
Akt, ERK1/2, and NF-␬B [1, 36, 53–55]. The induction of
gene transcription of inflammatory mediators by TREM-1 is
heavily dependent on the NF-␬B pathway. Activation of NF-␬B
occurs in the cytosol following degradation of an inhibitory
I␬B subunit, which then allows the formation of the active
p50/RelA heterodimer that translocates to the nucleus to acti-
vate gene transcription [55]. This process is regulated by sev-
eral proteins, as depicted in Fig. 1.
In conclusion, binding of TREM-1 leads to DAP-12-depen-
dent activation of intracellular pathways, with Jak-STAT, Akt,
ERK, and NF-␬B signaling as main elements of these pathways,
leading to production of cytokines, chemokines, up-regulation
of TREM-1 expression, and in neutrophils, also increased de-
granulation and phagocytic activity.
Volume 93, February 2013 Journal of Leukocyte Biology 211

Figure 2. The intracellular activation cascades of TREM-1 and TLRs in
neutrophils. Depicted is the putative interaction of the TLRs and
TREM-1 and how it leads to production of ROS and degranulation.
Prolonged stimulation of TLR4 can be accomplished by driving TLR4
into lipid rafts, which can be positively mediated by TREM-1.
TREM-1 AND PRR SIGNALING
In addition to the direct effects induced by TREM-1 through its
own signaling cascade initiated through DAP12, an increasing
body of evidence has demonstrated the cross-talk between innate-
immunity pathways induced by TREM-1 and two important
classes of PRRs: TLRs and NLRs. Interactions with CLRs or reti-
noic acid-inducible gene 1-helicases, the other two major families
of PRRs have not been reported and should be explored. Under-
standing this interaction is crucial for a full appreciation of the
biological effects of TREM-1 engagement. Putative interactions
between the TREM-1 and TLR pathways with roles for CARD9
[43], Btk and IRAK1 [41], p38 [26], and mBD2 [4] have already
been mentioned above.
INTEGRATION OF TREM-1 AND TLR2
PATHWAYS
Various studies have suggested that TREM-1 and TLR2 path-
ways can exert synergistic effects at the level of cytokine induc-
tion [12, 14, 18, 56]. How this synergy is realized exactly is not
clear yet. However, two clues have been revealed recently.
First, TLR2 ligands up-regulate TREM-1 expression through a
MyD88-dependent pathway [9, 18]. Secondly, the TREM-1/
TLR2 synergy could be exerted at the level of NF-␬B, as this
molecule is integrated in both cascades [35, 56]. NF-␬B activa-
tion is induced via a MyD88/IRAK/TRAF6 pathway by TLR2
[44], and by TREM-1 following PLC␥-mediated calcium influx
and subsequent PKC␪ activation [36]. The full elucidation of
the mechanisms leading to the synergy between the TREM-1
and TLR2 cascades is an interesting subject for further re-
search.
212 Journal of Leukocyte Biology Volume 93, February 2013
INTEGRATION OF TREM-1 AND TLR3
Whether there is synergy between TREM-1 and TLR3 is not
clear yet, although a moderate up-regulation of TREM-1 ex-
pression has been observed after stimulation of monocytes
with the TLR3 ligand polyinosinic:polycytidylic acid [12]. Oth-
ers were, however, unable to confirm the up-regulation of
TREM-1 [56], the increase in TNF-␣ production [27], or an
increase of the activation of neutrophils [14] after stimulation
of TREM-1 and TLR3 compared with the stimulation of
TREM-1 alone.
INTEGRATION BETWEEN TREM-1 AND
TLR4
The interaction between TREM-1 and TLR4 has been investi-
gated in relative detail. TREM-1 is presumed to modulate the
activity and availability of key proteins of the TLR4 signaling
cascade. It appears that monocytes with decreased expression
of TREM-1 also display significantly less MyD88 and CD14.
However, no differences were found in the expression of other
key proteins of the TLR4 pathway, such as TIRAP, RIP, IRAK1
(in contrast to ref. [41]), and IRAK2 [57]. Moreover, the
NF-␬B pathway, which is induced by TLR4, was down-regulated
in monocytes in which TREM-1 was knocked down. The
amounts I␬B␣, I␬B␤, and p100 were decreased significantly by
TREM-1, whereas the amounts of MAPKs, JNK, and c-fos re-
mained the same [57].
In neutrophils, it has been shown previously that engage-
ment of TREM-1 causes an increase in phophorylation of
IRAK1 in neutrophils, which could be one of the mechanisms
at the basis of the interaction between TREM-1 and the TLR4
signaling cascade [36]. Moreover, PI3K appears to have a
prominent place in the cross-talk between the cascades of
TREM-1 and TLR4 signaling, leading to a synergistic release of
ROS. Stimulation of TREM-1 (via DAP12) and TLR4 (via
MyD88) leads to an increase in p38 and PI3K activation [52].
PI3K, in turn, triggers ERK and Akt cascades, which lead to
increased transcription and cytokine production. PI3K also
activates PLC␥, which causes an increase in calcium concentra-
tion and therefore, activation of PKC␪. These events result in
the induction of ROS production and their release from neu-
trophils [37].
Lipid rafts are important domains on the cell membrane,
and they become larger and more stable by cross-linking of
signaling receptors (e.g., TREM-1) being able to regulate the
initiation and prolongation of signaling processes [58]. It has
been shown that TREM-1 and TLR4 associate together in the
GM1-lipid rafts after stimulation with LPS or agonistic TREM-1
ligands. Therefore, it has been suggested that TREM-1 is able
to positively influence the TLR4 signaling cascade by driving
TLR4 into the lipid rafts [36].
TREM-1 AND INTEGRATION OF OTHER
TLR PATHWAYS
Little is known regarding the interaction between TREM-1
with TLR5. It appears that stimulation of monocytes with the
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TLR5 ligand flagellin combined with TREM-1 engagement re-
sulted in a significantly higher production of TNF-␣ compared
with stimulation with flagellin alone [13]. Also, in mice, injec-
tion of flagellin led to an increased production of sTREM-1
[59]. Combined stimulation of TREM-1 and TLR7/8 by
R-848 increases the respiratory burst and degranulation of
neutrophils, whereas phagocytosis was not influenced [14].
The mechanisms responsible for this effect have not been
elucidated yet. In addition, stimulation of monocytes with
CpG ODN, a TLR9 ligand, had no effect on expression of
the TREM-1 gene and thus, did not show any up-regulation
of cell-surface TREM-1 expression [56, 60]. However, stimu-
lation of monocytes with CpG ODN and agonistic TREM-1
ligands resulted in a higher amount of TNF-␣ than stimula-
tion with CpG ODN alone [43], suggesting synergistic ef-
fects between TLR9 and TREM-1 stimulation in monocytes
after all. Further research needs to be done to reveal the
mechanisms of these putative interactions between TLRs
and TREM-1.
TREM-1 AND NEGATIVE REGULATORS
OF THE TLR PATHWAYS
Mice treated with agonistic TREM-1 ligands and thereafter,
infected with Streptococcus pneumoniae showed decreased pro-
duction of negative regulators of TLR signaling cascades.
IRAK-M decreases the formation of the IRAK-1–TRAF6 com-
plex, as it inhibits the dissociation of IRAK-1 from MyD88
[61]. Tollip is an additional negative regulator of TLRs that
forms a complex with IRAK-1 and prevents the formation of
this complex [62], and therefore, the TLR signaling cascade
is inhibited. It was shown that the production of IRAK-M,
which interacts with TLR2, -4, and -9, and the induction of
Tollip, which interacts with TLR2 and -4, were down-regu-
lated significantly after engagement of TREM-1 [8]. This
could lead to less inhibition of TLR pathways and therefore,
an increased cytokine response, a possible explanation of
some synergistic effects between TREM-1 and TLRs.
Whereas in certain situations of over-inflammatory reaction,
such as acute sepsis, this may be deleterious, Lagler et al.
[8] also showed that a moderate decrease of IRAK-M and
Tollip resulted in more survival of infected mice in situa-
tions in which bacterial growth is the main inducer of mor-
tality.
In corneal P. aeruginosa infection, it was shown that TREM-1
also down-regulates the expression of single Ig IL-1-related re-
ceptor and ST2 [4], which are negative regulators of the IL-
1R, TLR2, and TLR4 pathways, as they interact with main ele-
ments, such as MyD88, IRAKs, MyD88 adapter-like, and TRAF6
[63– 68]. Down-regulation of these negative regulators causes
up-regulation of the TLR signaling cascade and increased cyto-
kine production. Only few experiments have been done with
TREM-1 and the negative regulators of TLRs. These negative
regulators are of main interest, and more research in this area
is needed to further elucidate the cross-talk between TREM-1
and TLRs.
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Arts et al. TREM-1 interaction with PRRs
INTEGRATION OF TREM-1 AND NLR
PATHWAYS
In addition to the extracellular recognition by TLRs and
CLRs, the intracellular receptor family of NLRs comprises re-
ceptors that recognize peptidoglycans of intracellular bacteria
on the one hand and components of the inflammasome com-
plex that activates inflammatory caspases on the other.
TREM-1 has been shown to have synergistic effects on the pro-
inflamamatory cytokine production induced by recognition of
peptidoglycans by NOD1 and NOD2 [13]. A few synergistic
mechanisms between TREM-1 and NOD2 have been suggested
[13]. Firstly, NOD2 stimulation increases TREM-1 expression,
although this is unlikely to be the main cause of synergism, as
this effect was rather small. Secondly, an increase in NOD2
expression has been, in turn, induced by TREM-1 stimulation,
with an activation of the serine/threonine kinase RIP 2/RIP-
like-interacting caspase-like apoptosis regulatory protein/
CARD-containing IL-1␤-converting enzyme-associated kinase,
causing NF-␬B activation and cytokine production [69].
Thirdly, NLRs contain a CARD domain, which subsequently
induces activation of the proinflammatory caspase-1, which
induces an increase in the processing and release of proin-
flammatory cytokines, such as IL-1␤ and IL-18 [70]. In addi-
tion, possibly MAPKs and the induction of NF-␬B play a role
in the interaction between the TREM-1 and NOD2 pathways,
as both are main elements of these pathways [71–73]. How-
ever, the interplay between TREM-1 and NOD1 remains illu-
sive, as the NOD1 pathway is IFN-stimulated gene factor 3-de-
pendent, with TRAF3, TBK1, and IRF7 as main proteins, and
it operates independently of MAPKs and NF-␬B [73]. Hence,
these interactions warrant further investigation.
TREM-2: SIMILARITIES AND
DIFFERENCES WITH TREM-1
Besides TREM-1, other members of the TREM family have
been identified, of which, TREM-2 is of main interest. In con-
trast to TREM-1, TREM-2 is only expressed on immature DCs,
bone marrow-derived macrophages, macrophage cell lines,
and microglia [74 –76]. It has been shown that TREM-2 signal-
ing is also followed by a DAP12-dependent calcium influx and
activation of PI3K and ERK1/2 [74, 77]. However, in contrast
to TREM-1, there is no degradation of the inhibitory I␬B sub-
unit and no translocation of NF-␬B to the nucleus [74]. More-
over, in immature DCs, this partly unknown, intracellular path-
way is followed by up-regulation of CD40, CD86, and MHC
class II molecules, just as after TREM-1 activation [74]. This
suggests at least partly corresponding pathways between
TREM-1 and -2.
A number of studies suggest an opposing physiological role
of TREM-2. First, it appeared that after stimulation of bone
marrow-derived macrophages with LPS, the expression of
TREM-2 was found down-regulated, contrary to TREM-1 [74,
75]. Secondly, bone marrow-derived macrophages and DCs
from TREM-2 knockout mice appeared to produce more type
I IFN and TNF after stimulation with TLR ligands (zymosan,
LPS, and CpG DNA) [75, 78, 79]. Thirdly, overexpression of
Volume 93, February 2013 Journal of Leukocyte Biology 213
TREM-2 in microglia led to less TNF production compared
with microglia with normal amounts of TREM-2 [80]. These
observations suggest a regulating role for TREM-2 in the pro-
inflammatory response of TREM-1. Since the exact signaling
pathways of TREM-2 are elusive, experiments that explore the
cross-talk between TREM-1 and TREM-2 are needed.
CONCLUSIONS
Accumulating data in the literature suggest that TREM-1 is an
important amplifier of inflammation. In the present review, we
describe the complex molecular pathways through which
TREM-1 induces inflammation by itself, as well as by amplifica-
tion of TLR- and NLR-induced inflammation. Knowledge of its
regulation during health and inflammatory diseases may lead
to a better understanding of the pathophysiology of diseases
associated with exaggerated inflammation (e.g., sepsis, inflam-
matory bowel diseases, etc.) and may represent a potential,
novel target in these clinical conditions. Whereas progress has
been made regarding deciphering its biological effects and the
interaction with other immune pathways (such as those medi-
ated by TLRs and NLRs), much remains to be learned regard-
ing TREM-1 biology before effective immunotherapeutic strate-
gies based on modulating TREM-1 signaling could be de-
signed.
ACKNOWLEDGMENTS
M.G.N. was supported by a Vici grant of the Netherlands Orga-
nization for Scientific Research.
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KEY WORDS:
TLR 䡠 NLR 䡠 DAP12 䡠 signaling cascade 䡠 myeloid cells
Volume 93, February 2013 Journal of Leukocyte Biology 215