International Reviews of Immunology

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Triggering receptor expressed on myeloid cells-1

(TREM-1) as a therapeutic target in infectious and
noninfectious disease: a critical review

Pedro Henrique dos Santos Dantas, Amanda de Oliveira Matos, Ernandes da

Silva Filho, Marcelle Silva-Sales & Helioswilton Sales-Campos

To cite this article: Pedro Henrique dos Santos Dantas, Amanda de Oliveira Matos,
Ernandes da Silva Filho, Marcelle Silva-Sales & Helioswilton Sales-Campos (2020): Triggering
receptor expressed on myeloid cells-1 (TREM-1) as a therapeutic target in infectious
and noninfectious disease: a critical review, International Reviews of Immunology, DOI:
10.1080/08830185.2020.1762597

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Published online: 07 May 2020.

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INTERNATIONAL REVIEWS OF IMMUNOLOGY
https://doi.org/10.1080/08830185.2020.1762597

REVIEW

Triggering receptor expressed on myeloid cells-1 (TREM-1) as a therapeutic

target in infectious and noninfectious disease: a critical review
Pedro Henrique dos Santos Dantas
, Amanda de Oliveira Matos
, Ernandes da Silva Filho ,
Marcelle Silva-Sales , and Helioswilton Sales-Campos
Institute of Tropical Pathology and Public Health, Federal University of Goias, Goi^ania, Goias, Brazil

ABSTRACT ARTICLE HISTORY

The triggering receptor expressed on myeloid cells-1 (TREM-1) is an innate immune receptor Received 23 December 2019
found in the surface of several immune and non-immune cells. Since its first description in Accepted 23 April 2020
2000, this molecule and its soluble form (sTREM-1) have been implicated in many diseases
KEYWORDS
with infectious and noninfectious origins. As an amplifier of inflammation, the membrane-
Anti-inflammatory drugs;
associated TREM-1 (mTREM-1) isoform induces the production of pro-inflammatory media- inflammation; TREM-1
tors, thus contributing to the pathogenesis of diseases such as sepsis, arthritis, colitis and
infections. In this context, many studies have used molecules capable of inhibiting TREM-1
activity as anti-inflammatory drugs. In this regard, a few peptides have been showing prom-
ising results in the amelioration of detrimental immune responses. Some commercially avail-
able drugs, including corticosteroids and antibiotics, with known anti-inflammatory effects,
have also shown activity in TREM-1 signaling. Therefore, considering the potential of this
receptor as a therapeutic target, the present review encompasses the main compounds
explored so far in TREM-1 modulation, highlighting and critically discussing its effects and
major drawbacks of such approaches.

Introduction endothelial cells and gastric epithelial cells, especially

The immune system is constantly challenged by sev-
eral infectious and noninfectious inflammatory trig-
gers [1]. These molecules are initially recognized by
pattern recognition receptors (PRRs), that are located
on the surface and intracellularly of immune and
non-immune cells recognizing damaged-associated
molecular patterns (DAMPs), and microbial-associated
molecular patterns (MAMPs) [2]. Among these PRRs,
the family of the triggering receptor expressed on
myeloid cells (TREM) has attracted considerable
attention in the last decades. Composed of TREM-1,
TREM-2, TREM-3 and the ITIM-bearing TREM-like
transcripts (TLT-1, 2, 3, 4, 5) [3], these recep-
tors were first described by Bouchon and colleagues
in 2000 [4].
In the pioneer study, TREM-1 was reported to be
expressed on the surface of monocytes and neutro-
phils activated by lipopolysaccharide (LPS), and was
implicated in acute inflammation [4]. In addition,
TREM-1 has also been shown to be expressed on the
surface of non-immune cells, such as hepatic
during inflammatory processes [5]. In these contexts,
TREM-1 was proposed to act as an amplifier of sig-
naling by other PRRs, such as Toll-like receptor 4
(TLR-4), thus helping to increase the inflammatory
response [6]. However, the amplification of inflamma-
tion may result in undesirable side effects, such as
those observed in sepsis and in other immune medi-
ated diseases with infectious and noninfectious origins
[4,7,8]. This role as an amplifier of inflammation was
reinforced in TREM-1 knockout mice exposed to
inflammatory and infectious agents [9]. After dextran
sulfate sodium-induced colitis, the receptor deficiency
was associated with reduced expression of inflamma-
tory cytokines and inflammatory infiltrate in colon,
thus resulting in a better clinical outcome [9]. Despite
the similarity regarding the reduction in inflammatory
infiltrate and morbidity after parasite and viral infec-
tion, TREM-1 deficiency had no impact on pathogen
clearance [9]. These data suggest that targeting this
receptor may represent an advantageous and safe

CONTACT Helioswilton Sales-Campos tonsales@ufg.br Instituto de Patologia Tropical e Sa ublica – IPTSP, Universidade Federal de Goias –
ude P
UFG, Rua 235 S/N Setor Leste Universitario, Goi^ania, Goias 746050-050, Brazil

These authors equally collaborated to this manuscript.
ß 2020 Taylor & Francis Group, LLC
2 P. H. DOSSANTOSDANTAS ET AL.

Figure 1. TREM-1 signaling pathway and compounds that modulate its activity. The triggering receptor expressed on myeloid
cells-1 (TREM-1) can be observed in two isoforms: membrane bound (mTREM-1) and soluble (sTREM-1). After activation, immunore-
ceptor tyrosine-based activation motifs (ITAM) are phosphorylated, and anchors Zeta-associated protein of 70 kDa (ZAP70) and tyro-
sine-protein kinase (SYK), which results in the activation of the intracellular pathways janus kinase (JAK), extracellular signal-
regulated kinase (ERK), phosphoinositide 3-kinases (PI3K) and phospholipase C-gamma (PLCe). These pathways activate the tran-
scription factors NFAT, AP-1, STAT3/STAT5 and NF-jB, involved in the production of inflammatory mediators. The activity of
mTREM-1 may be inhibited by numerous compounds: LR12 and LP17 act as decoy receptors, competing for the ligands of
mTREM-1 and blocking the oligomerization of the receptor; GF9 and sneaking ligand construct to triggering receptor expressed on
myeloid cells-1 (SLC-TREM-1) seems to interfere with the interaction between mTREM-1 and DAP12 in cell membrane; Vasoactive
intestinal peptide (VIP), Corticosteroids and statins inhibit the activity of NF-jB; Rapamycin inhibits mTOR and ERK1/ERK2 path-
ways, besides of inhibiting the activity of the transcription factor AP-1. The inhibitory mechanisms attributed to LL-37, Doxycycline,
Clarithromycin, Azithromycin, Imipenem and Tacrolimus, are still unclear. The pattern recognition receptors depicted in the figure
includes: toll-like receptors 2 (TLR2) and 4 (TLR4), nucleotide-binding oligomerization domain-like receptors (NLRs), nucleotide-bind-
ing oligomerization domain-like (NOD) and NOD-like receptor pyrin domain-containing protein 3 (NLRP3). Arrow – Activation or
agonist. Blunted arrow: Inhibition or antagonist.

approach in microbial control, which is not observed
when other inflammatory mediators are targeted.
Therefore, due to the importance of TREM-1 on
the development of inflammation and pathogenesis of
several diseases, this review aims to evaluate the role
of peptides and other immune modulatory drugs in
the modulation of this PRR. In the following sections,
TREM-1 structure, signaling pathways, activation mol-
ecules and role as a pharmacological target will be
critically addressed.
Structure, ligands, expression, signaling and
functions of TREM-1
Structure and ligands
The genes encoding the TREM family of receptors are
located on chromosome 6p21 in humans and are
glycoproteins [10,11]. So far, two isoforms of this
molecule were identified: the membrane-bound
(mTREM-1) and soluble (sTREM-1) forms [12,13].
The mTREM-1 ( 30 kDa) has an extracellular
immune globulin-like V-type domain; a transmem-
brane region and a short cytoplasmic tail [10,11].
Because the receptor doesn’t present immunoreceptor
tyrosine-based activation motifs (ITAMs) in its intra-
cellular portion, it needs to be associated with an
adaptor protein, DAP12, for signaling transduction
[14]. This association occurs through a positively
charged lysine in the receptor and a negatively
charged aspartic acid in DAP12 [14]. Studies regard-
ing its structure have generated conflicting results in
the past years, but recently, the receptor was proposed
to display both monomeric and oligomeric forms
[10,11,15]. The former is described as the inactive

form and the latter is observed after activation (Figure
1) [15].
The molecules that are able to bind and activate
mTREM-1 are still a matter of strong investigation.
Among the putative ligands, it is possible to highlight
actin in platelets [16,17], PGLYRP1 [18], HMGB1,
Hsp70 [5,19] and the recently described extracellular
cold-inducible RNA-binding protein (eCIRP) [20].
Moreover, LPS, observed in the membrane of gram-
negative bacteria, may act as a ligand because it is
involved in TREM-1 activation [4,15]. However, it is
still not clear if LPS activates TREM-1 directly or
indirectly through TLR-4 activation [7]. Other pos-
sible MAMPs recognized by this receptor are zymo-
san, HIV gp120, Schistosoma mansoni egg antigens
and Marburg virus glycoprotein [21–25].
The sTREM-1 has only the Ig-like domain that is
important for antigen recognition and to compete
with mTREM-1 for the same ligands [26], thus it
is assumed to play an anti-inflammatory role in
different contexts. The origin of sTREM-1 is not
fully understood, and it is most likely to occur due
to proteolytic cleavage of mTREM-1 by metallopro-
teinases (MMPs), such as MMP-9 [27]. Therefore,
the release of sTREM-1 depends on the activation
of TREM-1 in the membrane followed by its cleav-
age [27,28].
Expression and signaling of TREM-1
Different situations and molecules have been impli-
cated in the up-regulation of mTREM-1, including:
hypoxia in dendritic cells [29], vitamin D3 [30], oxi-
dized low-density lipoprotein [31], Tumor necrosis
factor alpha (TNFa), Interleukin 1 beta (IL-1b), GM-
CSF [32,33], PGE2 [34], cAMP [35] and compounds
derived from microorganisms, such as LPS and lipo-
teichoic acid (LTA) [36]. So far, these effects have
been associated with the activity of transcription fac-
tors including the activator protein 1 (AP-1) and the
nuclear-factor kappa B (NF-jB) [37,38].
As mentioned above, mTREM-1 activity depends
on DAP12 for activation and intracellular signaling
[14] (Figure 1). After activation, ITAM motifs are
phosphorylated by Src kinases [39,40]. Then, these
domains anchor zeta-chain-associated protein kinase
70 (ZAP70) and spleen tyrosine kinase (SYK) [40].
After that, SYK phosphorylates casitas b-lineage lymph-
oma (CBL), son of sevenless protein (SOS) and growth
factor receptor binding protein-2 (GRB2), leading to
the activation of Jakus kinase (JAK), Extracellular sig-
nal-regulated kinases (ERK), Phosphoinositide 3-kinase
INTERNATIONAL REVIEWS OF IMMUNOLOGY 3
(PI3K) and Phosphoinositide phospholipase C gamma
(PLCc) pathways [41](Figure 1). These pathways acti-
vate the transcription factors Elk-1, NFAT, AP1, c-Fos,
c-Jun, STAT3/STAT5 and NF-jB, all involved in the
production of inflammatory mediators such as IL-6,
IL-8, IL-1b and TNF-a (Figure 1), besides inducing cal-
cium mobilization and changes in the actin cytoskel-
eton [42]. The activation of mTREM-1 also inhibits
pro-apoptotic molecules (BID, BAD and BAX) and the
release of cytochrome C by mitochondria, thus main-
taining mitochondrial integrity and prolonged cell sur-
vival [5,35].
On the other hand, the expression of mTREM-1 is
downregulated by PU.1, which is a transcription factor
present in myeloid and lymphoid cells [38,43,44], and
anti-inflammatory cytokines such as IL-10 [32,45] and
TGF-b [45]. In addition to cytokines, other com-
pounds capable of decreasing mTREM-1 activity
include cathelicidin LL-37 and CpG-ODN, that are
both inhibitors of the activation induced by
LPS [46,47].
Interaction between TLR and TREM-1
The mTREM-1 increases and amplifies the TLR4 sig-
naling pathway, and this in turns leads to the
increased expression of mTREM-1 [7], suggesting a
possible mechanism of mutual cooperation between
TREM-1 and TLRs. The relationship between
mTREM-1 and TLR is critical for enhancing the
immune response, as together they are able to amplify
both innate and adaptive immune responses through
the increase of pro-inflammatory molecules [5,35].
The interaction between TLR4 and TREM-1 relies on
the adaptor molecule MyD88 that is critical for the
onset of their intracellular signaling [5,35]. In add-
ition, MyD88 activity is linked to the activation of
transcription factors such as NF-jB and AP-1 that
regulate TREM-1 expression [4,48,49]. On the other
hand, the inhibition of mTREM-1 seems to not dir-
ectly interfere with TLR4 expression [5,50]. However,
the inhibition of mTREM-1 downregulates several
genes involved in the TLR-4 intracellular signaling,
such as MyD88, CD14 and IkBa [5,50], thus suggest-
ing that TLR4 has a greater and direct influence on
TREM-1 activity, and the latter has mainly an indirect
role over TLR4 functionality.
Aside from the role of TLR4 in mTREM-1 activa-
tion, other TLRs may also contribute to the activity of
mTREM-1 in different contexts. The binding of LTA
to TLR2 enhances TREM-1 mRNA expression [36,51].
The mTREM-1 is able to amplify cellular signaling
4 P. H. DOSSANTOSDANTAS ET AL.

Table 1. Peptides and drugs that modulate TREM-1 activity.

Compound Mechanism Model/Disease/Effects Reference
LR12 Decoy Receptor Mice/Septic shock/#IL-6, IL-8, TNFa, IL-10;#complications [54]
Mice/Septic shock/#complications [59]
Pigs/Septic shock/#TNFa and IL-6;#complications [60]
Monkey/Sepsis/#IL-6, IL-8, TNFa;#complications [61]
Human primary monocytes/P.gingivalis/#IL-1b, TNFa, IL-8 [62]
Mice/IR/#TNFa [6]
Mice/AMI/#TREM-1;#IL-6, TNFa;#complications [63]
Pigs/AMI/#complications of disease [64]
Mice/Atherosclerosis/#TNFa, IL-12, IFN-c;#complications [65]
Mice/ALI/#IL-1b, TNFa, IL-6;"IL-10;#complications [66]
Mice/ALI/#IL-1b, TNFa, IL-6;"IL-10;#complications [58]
Mice/Colitis/IL-6, IL-1b, TNF-a;#complications [67]
LP17 Decoy receptor Mice/Sepsis/#TNF-a, IL-1b, IL-6;"sTREM-1;#complications [12]
Mice/Sepsis/#complications [68]
Rats/Sepsis/#TNF-a, IL-1b, IL-6;#sTREM-1;#complications [69]
Leucocytes/neonatal sepsis/#TNFa, IL-8, IL-6;#complications [70]
MonoMac-6/P.gingivalis/#TNFa, IL-6;#complications [71]
Mice/Periodontitis/#IL-17;#complications of disease [72]
Mice/Pneumonia/#IL-1b, TNFa, IL-6;#complications [73]
Mice/Empyema/#IL-1b, TNFa, IL-6;#complications [74]
Zebrafish and rats/PD/#TREM-1;#complications [75]
Rats/Early Brain Injury/#complications [76]
Mice/Ischemic shock/#IL-1b, IL-6;#complications [77]
Mice/Nephritis/#complications [78]
Mice/IR/#CXCL1 [6]
Mice/Colitis/#TNF-a, IL-6, IL-1b;#complications [79]
Rats/Acute Pancreatitis/#TNFa, IL-1b;#complications [80]
Rats/Acute Pancreatitis/#complications [81]
VSMCs/In-stent restenosis/#TREM-1;#complications [82]
Macrophages/Atherosclerosis/#IL-6 [31]
Rats/Hemorrhagic shock/#TNFa, IL-6;#complications [83]
Mice/Pneumonia/#TNF-a, IL-1b, IL-6;#complications [26]
Mice/ARDS/#TNF-a, IL-1b;#complications [84]
GF9 Blockade of mTREM-1 and DAP12 interaction Mice/Tumor and Sepsis/#TNF-a, IL-6, IL-1b;#complications [85]
Mice/Arthritis/#TREM-1;#IL-1, TNF-a, IL6;#complications [86]
Mice/Alcoholic Liver Disease/TNF-a, IL-1b;#TREM-1;#complications [87]
SLC-TREM-1 Blockade of mTREM-1 and DAP12 interaction Mice / Sepsis /#IL-8;#complications;#sTREM-1 [88]
LL-37 n.d. Mice/sepsis/#IL-1b, IL-6,sTREM-;#complications [89]
PBMCs/LPS/#mTREM-1 [46]
VIP n.d. Mice/ALI/#TREM-1 [90]
Dexamethasone Inhibition of NF-jB Mice and in vitro/P. aeruginosa / #TREM-1; #TNF-a; [91]

Methylprednisolone Inhibition of NF-jB Human patients / ARDS / #sTREM-1 ;#complications [92]

Azithromycin n.d. Mice/Sepsis /#TREM-1; #IL-6, TNF-a, IL-1;b #sTREM-1; #complications [93]
Clarithromycin n.d. Humans/Sepsis/"TREM-1;"sTREM-1;#complications [94]
Rapamycin Inhibition of mTOR Mice/IPA/#IL-6, IFN-c, "sTREM-1; #complications [95]
Tacrolimus n.d. Mice / Fungal keratitis /#TREM-1; #TNF-a, IL-1b [96]
Doxycicline n.d. Monocytes/P. gingivalis /#IL-8;#sTREM-1;#TREM-1 [97]
Iminipem n.d. Mice/Sepsis/#TNF-a, IL-6;#sTREM-1 [98]
Pravastatin Inhibition of NF-jB Mice/Artherosclerosis/#TREM-1;#IL-1, TNF-a;#TREM-1 [99]
PBMCs/LPS/#TREM-1;#IL-6, TNF-a;#sTREM-1 [100]
n.d: not determined; #:decrease;":increase; IR:Renal Ischemia Reperfusion; AMI: Acute Myocardial Infarction; ALI: Acute Lung Injury; P.D: Parkinsons disease;
VSMCs: Vascular Smooth Muscle Cells; ARDS: Acute respiratory distress syndrome; PBMCs:Peripheral Blood Cells; mTREM-1: Triggering expressed on mye-
loid cells 1 (membrane); sTREM-1: Triggering expressed on myeloid Cells 1 (Soluble); IL: Interleukine; NF-jB: nuclear-factor kappa B; mTOR: mammalian
target of rapamycin; TNF-a: Tumor necrosis factor alpha.

and the immune response triggered by TLR2 and
TLR4 besides inhibiting the expression of negative
regulators of these pathways, such as Tollip, ST2,
SIGIRR and IRAK-M [52,53]. The abrogation of
TREM-1 activity decreases the production of the pro-
inflammatory cytokines TNF-a and IL-6, which are
commonly produced after TLR4-activation [7,31]. The
activity of mTREM-1 seems also to be dependent on
TLR since the triggering receptor is apparently unable
to generate a sustained immune response without
TLR activation [36,54]. On the other hand, the
activation of TLR9 by CpG-ODN, increases the pro-
duction of sTREM-1 [47], thus inhibiting the activity
of mTREM-1.
In general, the interaction between TLRs and
TREM-1 seems to rely on a mutual contribution, and
is mainly dependent on the modulation of proteins
and pathways related to the activity of both family of
receptors. Further, the outcome of the mutual inter-
action between TREM-1 and TLR seems to rely on
the nature of the ligands and the localization (mem-
brane or intracellular) of the TLR.

Interaction between NLR and TREM-1
The family of nucleotide-binding oligomerization
domain like receptors (NLR) are involved in the regu-
lation of inflammation and apoptotic responses [55]
and, similarly to TLR, it cooperates with mTREM-1
functionality [56,57]. The interaction between NLRs
and mTREM-1 leads to the activation of monocytes,
which triggers and amplifies the phosphorylation of
Akt, besides of inducing the production of MAPK
and pro-inflammatory mediators such as IL-1b and
IL-6 [56,57].
The activation of mTREM-1 is capable of inducing
the expression of NOD2 and NF-jB, resulting in the
production of IL-1b and IL-6 [56]. TREM-1 seems
also to interact with NLRP3, one of the main compo-
nents of the inflammasome [58] whose downstream
activation promotes cleavage of pro-IL-1b and pro-
IL18 by caspase 1, leading to the production of the
active forms of these cytokines [55]. This mutual
interaction is reinforced by the inhibition of mTREM-
1 by the peptide LR12, which reduced the expression
and activation of NLRP3 and the production of IL-1b
in C57BL/6J mice with acute lung injury [58]. These
results suggest that the interaction between NLRs and
TREM-1 is important for the amplification and pro-
duction of inflammatory mediators [56]. However, the
mechanisms of this cooperation and the nature of the
ligands with reciprocal ability to activate both
mTREM-1 and NLRs are still unclear.
Modulation of TREM-1 by peptides
LR12
The peptide LR12 (LQEEDAGEYGCM) is based in a
conserved sequence of mTREM-1 and TLT-1 [54].
LR12 was initially described as LR17, and was shown
to inhibit mTREM-1 in Balb/c and C57BL/6 mice
with sepsis, reducing the production of IL-6, IL-8,
TNF-a and IL-10 and disease-associated complica-
tions, leading to improved survival of mice [54,59]
(Table 1). Subsequently, 5 amino acids were removed
from LR17, resulting in the 12 amino-acids peptide
(LR12) [60], that is apparently the sequence respon-
sible for the anti-inflammatory effects [60]. Thus,
LR12 was also used in treatment of septic shock in
minipigs, where it attenuated sepsis-related disorders
such as hypotension, multiple organ failure, cardiovas-
cular complications and production of TNFa and IL-6
[60] (Table 1). LR12 mitigated sepsis in monkeys
(Macaca fascicularis) with diminution of leukopenia
and production of pro-inflammatory cytokines such as
INTERNATIONAL REVIEWS OF IMMUNOLOGY 5
IL-6, IL-8 and TNF-a [61] (Table 1). These effects
were mainly attributed to the ability of LR12 to com-
pete with TREM-1 for the same ligands (thus acting
as a decoy receptor) [54] (Figure 1), and to impair
TREM-1 multimerization, which is crucial for TREM-1
activation [15].
The role of LR12 has also been addressed in peri-
odontal disease [62], that is also triggered by microor-
ganisms [101]. In human primary monocytes infected
with Porphyromonas gingivalis, the main species asso-
ciated with periodontal disease, treatment with LR12
reduced the expression of TREM-1 and production of
pro-inflammatory cytokines such as IL-1b, TNF-a and
IL-8 (Table 1) [62]. Despite the results suggesting
LR12 as a promising candidate to treat periodontal
diseases, in vivo studies are required to better under-
stand its role in this scenario.
The mTREM-1 has been implicated in the onset
and worsening of noninfectious diseases, including
renal ischemia reperfusion (IR) [6], acute myocardial
infarction (AMI) [64], acute lung injury (ALI) [58],
atherosclerosis [65] and colitis [67].
In IR, treatment with LR12 was able to reduce the
expression of TNF-a in C57BL/6 mice, but failed to
inhibit disease progression (Table 1) [6], suggesting
that mTREM-1 may not play a critical role in the
clinical development of IR.
In AMI, LR12 reduced IL-6 and TNF-a expression
and improved left ventricular function and survival in
C57BL/6 mice [63]. LR12 also reduced heart dysfunc-
tion and led to a reduction in infarcted area in pigs
with AMI [64]. Atherosclerosis is a cause of blood
vessel obstruction that leads to AMI, and treatment
with LR12 attenuated the production of TNF-a, IL-12
and IFN-c and development of atherosclerosis in
C57BL/6 ApoE-/- mice [65].
In an experimental model of ALI in C57BL/6 mice,
LR12 increased production of IL-10 and reduced pro-
duction of IL-1b, TNFa and IL-6, besides of diminish-
ing histopathological changes, leukocytes infiltration,
oxidative stress and disease worsening, mainly due to
a reduction in NF-jB and NLRP3 activity [58,66].
LR12 also ameliorated colitis, leading to improve-
ment in histopathological features and clinical status
in C57BL/6 mice due to attenuation of mTOR activ-
ity [67].
These results suggest LR12 as a prominent mol-
ecule in the treatment of inflammatory diseases in
which TREM-1 plays a pivotal role. Interestingly,
pharmacokinetics and different formulations of LR12
have been tested in vivo [102]. LR12 was administered
in rats by in situ implants of poly-lactide-co-glycolide
6 P. H. DOSSANTOSDANTAS ET AL.
and poly-lactide (that provided sustained release of
the peptide) for seven days, and presented good bio-
availability [102]. This peptide is now commercially
known as NangibotideV R , and was tested through con-
tinuous intravenous administration in humans, show-
ing to be safe and well tolerated even at high doses (6
milligrams/kg, uninterruptedly during 7 h and
45 minutes) [103]. Furthermore, patients treated with
NangibotideV R displayed few adverse events, and did
not develop any side effects 28 days after its adminis-
tration [103]. Hence, LR12 may be safely used in
humans due to good pharmacokinetic parameters, tol-
erability and stability.
LP17
The peptide LP17 (LQVTDSGLYRCVIYHPP) is com-
posed of highly conserved regions of the extracellular
portion of murine and human mTREM-1 [12].
Initially, LP17 was explored in septic mice, in which it
reduced TNFa, IL-1b and IL-6, and increased
sTREM-1, leading to a reduction in complications and
lethality in Balb/c and C3H/HeN mice [12,68]. These
effects were also observed in rats with sepsis, where
LP17 also inhibited the increase of sTREM-1 [69].
Interestingly, LP17 diminished the secretion of IL-8,
TNF-a and IL-6 in leukocytes stimulated with LPS,
obtained from the umbilical cord of newborns [70],
suggesting a putative protective role of LP17 in neo-
natal sepsis [70]. The effects of LP17 in sepsis can be
at least partly attributed to the inhibition of NF-jB
[12]. The mechanisms concerning LP17 activity on
mTREM-1 still need further clarification, however,
two hypotheses have been postulated in this regard.
The most accepted theory is that LP17, as LR12, acts
as a decoy receptor, competing with mTREM-1 for its
natural ligands [68,83,104,105] (Figure 1 and Table 1).
Also, similarly to LR12, it is hypothesized that LP17
may block mTREM-1 dimerization [15,104].
LP17 has been reported attenuating mTREM-1-
mediated inflammation caused by microorganisms in
periodontal disease, periodontitis, pneumonia and pul-
monary empyema [71–74]. In periodontal disease,
LP17 inhibited the secretion of TNF-a and IL-6
stimulated by P. gingivalis in the myelomonocytic cell
line MonoMac-6 [71], showing that LP17 is an inter-
esting approach to treat periodontal diseases. Further,
LP17 attenuated in C57BL/6 mice, periodontitis-
related complications and decreased the expression of
IL-17, that is associated with worsened periodon-
titis [72].
In lungs, LP17 inhibited the deleterious effects
caused by Staphylococcus aureus and Pseudomonas
aeruginosa infection in Wistar rats, leading to
increased survival [73,74]. The beneficial effect of
LP17 in lungs were mainly attributed to a reduction
in the production of pro-inflammatory cytokines
(IL-1b, TNFa and IL-6) that prevented tissue damaged
and improved disease outcome [73,74] (Table 1).
Interestingly, LP17 has no antimicrobial role, thus
these beneficial effects are most likely due to the
downregulation of TREM-1-related inflamma-
tion [72,73].
Pharmacological inhibition of mTREM-1 by LP17
has been also explored in experimental models of dis-
eases affecting the brain, kidneys, intestine, blood ves-
sels and lungs [5]. In brain, LP17 was used to treat
neuroinflammation using in vitro and in vivo
approaches, especially in disturbances in which
mTREM-1 has been intrinsically related to, such as
Parkinsons disease (PD), ischemic stroke and sub-
arachnoid hemorrhage [75–77]. In PD, LP17 reduced
TREM-1 expression and activity of nitric oxide syn-
thase (iNOS), cyclooxygenase-2 and NF-jB, all related
to inflammatory responses in microglia [75]. In zebra-
fish and rats, treatment using LP17 increased the
expression of proteins favoring autophagy, thus
decreasing the locomotor deficiency observed in PD
caused by chemical compounds [75].
In situations of neurological bleeding conditions,
such as subarachnoid hemorrhage and ischemic shock,
a strong participation of mTREM-1 in the develop-
ment of inflammation in rats and C57BL/6J mice has
been reported [76,77]. In rats, the inhibition of this
receptor by LP17 was associated with attenuation of
early brain injury after subarachnoid hemorrhage by
inhibiting the activity of p38 mitogen protein kinase
and MMP-9, which are critical for disease develop-
ment [76]. In C57BL/6J mice with ischemic shock,
treatment with LP17 ameliorated neuronal infarction
and injury and promoted cell proliferation, synaptic
plasticity in hippocampus, inhibition of M1-microglia
polarization, decreased neutrophil recruitment and
expression of pro-inflammatory mediators such as IL-
1b and IL-6 [77]. The beneficial activity attributed to
LP17 was associated to a reduced activation of
CARD9/NF-jB and NLRP3/caspase 1 that induced
the expression of spleen tyrosine kinase (SYK), which
is a promoter of neuroinflammation in post-ischemic
shock [77]. Based on these data, LP17 is a promising
candidate to treat brain disorders in which mTREM-1
plays a central role, and such modulation may favor

the reduction in inflammation and a better outcome
(Table 1).
In kidneys, mTREM-1 upregulation has been asso-
ciated with IR and nephritis in C57BL/6J mice [6,78].
Treatment with LP17 in C57BL/6J mice with nephritis
induced a reduction in proteinuria, inflammatory cell
infiltrates, thus leading to a better clinical outcome
[78]. Despite the effects toward the inhibition of
CXCL1 and Myd88 in IR, LP17 was not able to pre-
vent the development of nephritis [6]. Thus, due to
conflicting results and the reduced number of studies
exploring the role of LP17 on kidney diseases, it is
difficult to address the potential of this peptide in this
scenario. However, the beneficial role of LP17 cannot
be underestimated in renal conditions (Table 1).
The mTREM-1 has been implicated in the develop-
ment of diseases affecting the intestine [106]. In this
context, LP17 was used to inhibit mTREM-1 in colitis
and colitis-associated tumorigenesis in C57BL/6 mice
[79]. Treatment with the peptide reduced mortality,
tumor size and production of TNF-a, IL-6 and IL-1b
[79]. Further, LP17 attenuated the proliferation of epi-
thelial cells [79], thus suggesting that LP17 can be
used to treat intestinal inflammation and to attenuate
inflammation-related tumorigenesis in gut.
The beneficial role of LP17 was also investigated in
mesenteric ischemia-reperfusion. In this context, LP17
attenuated inflammation and disease severity mainly
by reducing TNF-a, IL-6, and NF-jB activity, thus
resulting in diminished mortality in diseased rats
[105] (Table 1).
Pancreatitis is another inflammatory condition in
which the role of LP17 has been addressed [80,81].
Treatment with the peptide in Wistar rats inhibited
the expression of TNF-a and IL-1b, and attenuated
tissue damage in this organ [80]. Interestingly, LP17
also mitigated the hepatic and renal dysfunction
observed in Wistar rats with acute pancreatitis [81]
(Table 1).
The mTREM-1 is also involved with inflammation
that affects the blood vessels such as in-stent resten-
osis, atherosclerosis and hemorrhagic shock [5]. In the
in-stent restenosis, LP17 attenuated disease progres-
sion by reducing TREM-1 expression, and through
the inhibition of cell proliferation and migration in
experiments with vascular smooth muscle cells [82].
In atherosclerosis, LP17 mitigated foam cell formation
in oxLDL-treated macrophages and drastically inhib-
ited IL-6 production, leading to an improvement in
inflammation [31]. In hemorrhagic shock, treatment
using LP17 reduced the levels of TNF-a and IL-6, and
inhibited disease-associated complications such as
INTERNATIONAL REVIEWS OF IMMUNOLOGY 7
cardiovascular collapse, lactic acidosis, lung permeabil-
ity and organ dysfunction, thus improving survival of
Wistar rats [83]. These results suggest LP17 as a puta-
tive candidate to treat blood vessel-related diseases
and their complications. However, the lack of transla-
tional studies exploring the role of LP17 in humans in
such conditions, make difficult any further observa-
tion (Table 1).
Because of the role of mTREM-1 in lung diseases
such as pneumonia and acute respiratory distress syn-
drome (ARDS) [73,84], the role of LP17 in these scen-
arios have also been explored [73,84]. In Wistar rats
with pneumonia, LP17 was effective in attenuating
disease-associated complications and reducing inflam-
mation by decreasing the production of TNF-a, IL-6
and IL-1b, thus leading to increased survival in rats
[73]. In ARDS, LP17 reduced TREM-1 expression,
production of TNF-a and IL-1b and lung injury in
C57BL/6 mice [84] (Table 1). Based on this, a formu-
lation of LP17 in nanomicelles was tested in ARDS,
and showed higher efficacy in decreasing inflamma-
tion and tissue injury [84] (Table 1). These effects of
LP17 on inflammation in ARDS were partially attrib-
uted to a downregulation of miR-155. This microRNA
positively influences mTREM-1 activity mainly
through the blockade of inhibitory molecules such as
SOCS-1, thus favoring the expression of pro-inflam-
matory cytokines (TNF-a and IL-1b) [84,107].
Therefore, the role of LP17 in this context is appar-
ently indirect, but further studies may elucidate these
effects [84,107].
Altogether, these findings suggest the potential of
LP17 to treat a myriad of diseases that are aggravated
by mTREM-1 activity. However, the pharmacokinetic
and pharmacodynamics parameters of this peptide,
besides of its toxicity, are aspects that still need fur-
ther clarification.
GF9
GF9 is a peptide (GLLSKSLVF) based on mTREM-1
transmembrane region, designed to interfere with the
interaction between the receptor and its adaptor pro-
tein, DAP12, in the cell membrane [85] (Figure 1).
GF9 was shown to inhibit the signaling pathway of
mTREM-1 through DAP12, with a concomitant
reduction of inflammatory mediators in murine mod-
els of lung tumor, sepsis, arthritis and alcoholic liver
disease [85–87]. Treatment with GF9 retarded lung
tumor growth in NU/J mice injected with the tumor
cell line H292 and A549 [85] (Table 1). These effects
were must probably a consequence of reduced release
8 P. H. DOSSANTOSDANTAS ET AL.
by macrophages of compounds that stimulate the
growth of neoplastic cells such as the vascular endo-
thelial growth factor (VEGF), Platelet-derived growth
factor (PDGF) and TGF-b, which production is indir-
ectly influenced by mTREM-1 signalization [108,109].
The beneficial effects of GF9 were further explored in
C57BL/6 mice with LPS-induced sepsis, leading to
prolonged survival and reduction in TNF-a, IL-6 and
IL-1b [85] (Table 1).
In collagen-induced arthritis in DBA/1 mice, GF9
reduced the levels of IL-1, TNF-a and IL-6, thus low-
ering the arthritis-associated complications [86].
Similarly, GF9 attenuated TREM-1 expression and
diminished production of pro-inflammatory cyto-
kines (TNF-a IL-1b) in C57BL/6 mice with alcoholic
liver disease, resulting in decreased steatosis and tis-
sue damage in liver [87]. Importantly, when GF9
was delivered by a HDL-mimicking nanoparticle
system, its therapeutic effects and pharmacokinetic
parameters were drastically increased, probably due
to macrophage recognition of the peptide-nanopar-
ticle molecule via scavenger receptor, thus favoring
the endocytosis and consequently the action of GF9
[85–87]. Therefore, GF9 seems to be a promising
candidate to treat complications in lung tumors,
sepsis, arthritis and alcoholic liver disease (Table 1).
Besides, these results reinforce the beneficial role of
nanosystems as key carriers of TREM-1-inhibi-
tory peptides.
SLC-TREM-1
The sneaking ligand construct (SLC-TREM-1) is com-
posed by 3 portions: E-selectin, exotoxin A of
Pseudomonas aeruginosa and 7 amino-acids
(LSKSLVF) of the transmembrane region of mTREM-
1 [88]. The E-selectin and exotoxin A portions act
facilitating the entrance of the construct into the cyto-
sol of targeted endothelial cells, and the TREM-1-
derived peptide interacts with DAP12, similarly to
GF9, interrupting the interaction between mTREM-1
and DAP12 thus, inhibiting the downstream signaliza-
tion [88] (Figure 1). Initially, SLC-TREM-1 was tested
in endothelial cells, where it inhibited TREM-1
expression and production of IL-8 [88]. Then, the
construct was administered to C57BL/6 mice with
sepsis, leading to reduced neutrophil transmigration
and increased mice survival [88] (Table 1). Despite
the limited availability of data regarding the role of
SLC-TREM-1 to treat inflammation, it may become a
promising drug to treat inflammatory disorders.
LL-37
Cathelicidins are peptides that demonstrated activity
against fungi, viruses, bacteria and parasites [110,111].
The most important among them is the LL-37
(LLGDFFRKSKEKIGKEFRIVQRIKDFLRNLVPRTES),
a cationic molecule capable of modulating inflamma-
tory and immune responses [110,111]. However, the
immunomodulatory features attributed to LL-37 are
quite controversial and may have either inhibitory or
stimulatory activity, depending on the context [110].
As an anti-endotoxin molecule, LL-37 inhibits the
production of inflammatory mediators, such as TNF-
a, produced after LPS stimulation in monocytes [112].
LL-37 inhibited the production of TNF-a and expres-
sion of mTREM-1 in PBMCs stimulated by LPS [46],
thus evidencing the influence of LL-37 on mTREM-1
activity. In other study, LL-37 constrained the effects
of LPS-induced sepsis in Balb/c mice also through the
inhibition of mTREM-1 signaling, thus resulting in
diminished production of IL-6 and IL-1b, alongside a
decreased expression of mTREM-1 in monocytes and
sTREM-1 in plasma and peritoneal fluids [89].
LL-37 also showed antibacterial proprieties,
decreasing the number of bacteria in plasma and peri-
toneal fluid, besides of improving survival in septic
Balb/c mice [89] (Table 1 and Figure 1). The peptide
has a high potential to be used alone or in combin-
ation to treat sepsis, acting in the blockade of
mTREM-1 activity and expression, which has been
associated to clinical worsening in septic subjects
[46,89]. However, before the onset of clinical studies,
several aspects still need further clarification, includ-
ing those concerning its interaction and modulatory
activity toward mTREM-1, its toxicity, and the mecha-
nisms regarding its interaction with other drugs fre-
quently used to treat sepsis.
Vasoactive intestinal peptide
The vasoactive intestinal peptide (VIP) is a 28 amino
acids pleiotropic neuropeptide
(HSDAVFTDNYTRLRLQMAVKKYLNSILN), mainly
produced in brain, peripheral nervous system,
immune and endocrine cells, that possess modulatory
effects in macrophages, lymphocytes, mast cells and
neutrophils [113]. In innate immunity cells, VIP was
shown to have inhibitory activities impairing the pro-
duction of pro-inflammatory mediators and stimulat-
ing the production of IL-10 in LPS-stimulated
macrophages [113]. Further, VIP reduced the recruit-
ment of phagocytes and the upregulation of TLRs,
thus preventing macrophages and neutrophils from

being stimulated by exogenous and endogenous
ligands [113]. Thus, because of its anti-inflammatory
effects [90], it is reasonable to assume that VIP may
have inhibitory activity over mTREM-1. Indeed, VIP
inhibited the expression of TREM-1 in lung cells and
increased the expression of the anti-inflammatory iso-
form TREM-2, in kunming mice with LPS-induced
acute lung injury (ALI), on the other hand, in ALI-
non treated mice, the expression of TREM-1 was
increased [90] (Table 1). These effects seems to be
related to the downregulation, mediated by VIP recep-
tor, of the transcription factors AP-1 and NF-jB,
which are directly involved in TREM-1 expression
[90,113] (Figure 1). Taken together, these findings
suggest that VIP may become a new therapeutic
approach in the modulation of TREM-1 in the future.
Classic drugs with activity over TREM-1
As mentioned beforehand, TREM-1 has a central role
in the onset and amplification of inflammation and,
for this reason, this receptor has been implicated in
the pathology and worsening of different diseases
[5,35]. Therefore, it is reasonable to assume that
pharmacological treatments with known activity
toward other players in inflammation and infection,
such as antibiotics [93], corticosteroids [92] and sta-
tins [99], may also interfere with mTREM-1
functionality.
Corticosteroids
Corticosteroids are suppressors of the immune
response, used in the treatment of allergies, auto-
immune and uncontrolled inflammatory diseases
[114]. Unfortunately, prolonged use and high doses of
this class of drug can promote osteoporosis, skin atro-
phy, diabetes, abdominal obesity, hypertension among
others disturbances [114]. Despite these undesirable
effects, corticosteroids are widely used and have their
role in TREM-mediated diseases already
explored [91,92].
Treatment with dexamethasone decreased the
expression of TREM-1, the release of sTREM-1 and
the production of TNF-a in neutrophils and mono-
cytes stimulated by Pseudomonas aeruginosa [91]
(Table 1). The effects of this drug on the transcription
of TREM-1 seems to be dependent on TNF-a activity,
as in C57BL/6 TNF-/- mice, dexamethasone had no
effect on the transcription of TREM-1 [91] (Table 1).
However, the mechanism that dictates the influence of
TNF-a on TREM-1 functionality is unclear. In
INTERNATIONAL REVIEWS OF IMMUNOLOGY 9
another study, treatment with methylprednisolone in
acute respiratory distress syndrome, reduced the levels
of sTREM-1 in the bronchoalveolar lavage and
improved lung injury score when treated and
untreated patients were compared [92]. The activity of
corticosteroids on TREM-1 expression may be
explained by the inhibitory activity over NF-jB, which
is one of the key molecules in the transcription of
TREM-1 [115] (Figure 1), however, further studies are
needed to better elucidate this interaction.
Antibiotics
The relationship between antibiotics and inflammation
is widely explored [116,117]. To better illustrate this,
it is possible to highlight the role of macrolide antibi-
otics in inhibiting oxidative burst, transmigration of
neutrophils and production of inflammatory cyto-
kines, such as IL-6 and TNF-a [116,117].
Macrolides are lactones widely used to treat bacter-
ial infections, targeting the bacterial 50S ribosomal
subunit, thus preventing protein synthesis and leading
to the death of the pathogen or preventing their
multiplication [116,117]. Moreover, these drugs have
anti-inflammatory properties as mentioned beforehand
[116,117]. Therefore, the role of some macrolides such
as azithromycin, rapamycin and tacrolimus, was
explored in the modulation of TREM-1. Azithromycin
inhibited the activity and expression of mTREM-1,
besides reducing the levels of TNF-a, IL-6, sTREM-1
and IL-1b, thus resulting in a higher survival of septic
Balb/c mice [93]. In fungal infections, rapamycin and
tacrolimus also inhibited mTREM-1 activity [95,96].
For invasive pulmonary aspergillosis (IPA), treatment
with rapamycin inhibited the release of sTREM-1, IL-
6 and IFN-c, and induced the production of IL-10
[95] (Table 1). The mechanism behind the modulation
of rapamycin on sTREM-1 activity is mainly attrib-
uted to the inhibition of the mTOR pathway, which is
a known inducer of mTREM-1 expression [95]
(Figure 1). Another macrolide with activity on
mTREM-1 in fungal infections is tacrolimus [96]. This
antimicrobial drug reduced the transcription and
expression of mTREM-1, TNF-a and IL-1b in fungal
keratitis induced by Aspergillus fumigatus, leading to
reduced corneal damage in C57BL/6 mice [96] (Table
1 and Figure 1). Treatment with clarithromycin in
200 septic patients, increased the expression of
TREM-1 and release of sTREM-1 [94] (Table 1 and
Figure 1). Furthermore, clarithromycin decreased the
IL-10/TNF-a ratio in serum, thus suggesting that
treatment with this antibiotic reestablished the
10 P. H. DOSSANTOSDANTAS ET AL.
cytokine balance during sepsis, constraining its devel-
opment and the risk of multiple organ dysfunc-
tions [94].
Other antibiotics like doxycycline and iminipem
also have modulatory activity over mTREM-1 [97,98].
In vitro experiments with monocytes infected by P.
gingivalis and treated with doxycycline, showed a
reduction in expression of mTREM-1, besides dimin-
ishing levels of IL-8 and sTREM-1 [97]. Combined
treatment of imipenem with cornuside (a secoiridoid
glucoside derived from Cornus officinalis) in Sprague-
Dawley rats with sepsis, reduced the levels of sTREM-
1, TNF-a and IL-6, besides increasing the production
of IL-10 [98]. Although promising in microbial infec-
tions, the interactions between antimicrobial drugs
and TREM-1 activity still needs further clarification,
especially regarding toxicity, drug interaction and
metabolism (Table 1 and Figure 1).
Statins
Statins are a class of drugs that inhibits the enzyme 3-
hydroxy-3-methylglutaryl-coenzime A (HMG-CoA)
reductase involved in the synthesis of cholesterol
[118]. These drugs have pleiotropic effects including
anti-inflammatory and immunomodulatory properties
based on their inhibition on the production of inflam-
matory mediators such as IL-6, IL-8, TNF-a, IL-1b
and IFN-c [118]. Interestingly, statins were reported
to be capable of inhibiting the activity and expression
of TREM-1 in myeloid cells [99,100,119].
Pravastatin inhibited the expression of TREM-1
and the release of sTREM-1 in PBMCs stimulated
with LPS [100]. Furthermore, it reduced the produc-
tion of IL-6 and TNF-a in culture supernatant [100]
(Table 1). These effects seemed to be related to a
blockade in NF-jB activity [100] (Figure 1), which
may explain the reduced expression of TREM-1. In a
different study, pravastatin ameliorated atherosclerosis
in C57BL/6 ApoE-/- mice, reducing the numbers of
lipid deposits and inflammatory cells in atherosclerotic
plaques [99]. Further, treatment with pravastatin also
decreased the expression of TREM-1, DAP12, TNF-a
and IL-1 [99] (Table 1). Altogether, these results
suggest that the activity of TREM-1 is indirectly
constrained by statins mainly by the inhibition in
NF- jB activity.
Conclusions and future perspectives
In general, regardless the source or the biochemical
nature of the compounds described in the present
study, the modulation of mTREM-1 leads to the
inhibition of key pro-inflammatory mediators and
induction of anti-inflammatory molecules such as IL-
10, which alone or in combination, can be explored to
treat inflammatory conditions. The mTREM-1 seems
to be influenced by and to influence the functionality
of other PRRs in different ways, thus suggesting that
therapies aiming at modulating such receptors may
represent a promising strategy to treat infectious and
noninfectious conditions in which these receptors play
a central role. Canonical transcription factors and
pathways generally associated to the onset of inflam-
matory response are also related to the activity of
mTREM-1, which broads the possibility of drugs able
to constrain its functionality. Despite these encourag-
ing results, the majority of studies using mTREM-1 as
a therapeutic target were performed in experimental
models using rodents, which compromise the extrapo-
lation to humans bearing similar conditions. Finally,
there is a lack of data concerning toxicity, pharmaco-
kinetics and interaction between regularly used drugs
and other modulators of mTREM-1 activity, which
reinforces the necessity for more research in the field.
Disclosure of interest
The authors report no conflict of interest.
Funding
The authors would like to thank Coordenaç~ao de
Aperfeiçoamento de Pessoal de Nıvel Superior (CAPES) for
A.O.M and P.H.S.D scholarships.
ORCID
Pedro Henrique dos Santos Dantas http://orcid.org/
0000-0001-9413-0954
Amanda de Oliveira Matos http://orcid.org/0000-0001-
5676-5959
Ernandes da Silva Filho http://orcid.org/0000-0002-
2926-5120
Marcelle Silva-Sales http://orcid.org/0000-0002-
4275-9627
Helioswilton Sales-Campos http://orcid.org/0000-0003-
3252-2834
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