Skip to main content
Download PDF

Triggering receptor expressed on myeloid cells-1 in sepsis, and current insights into clinical studies

Critical Care volume 28, Article number: 17 (2024) Cite this article

Abstract

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor and plays a critical role in the immune response. TREM-1 activation leads to the production and release of proinflammatory cytokines, chemokines, as well as its own expression and circulating levels of the cleaved soluble extracellular portion of TREM-1 (sTREM-1). Because patients with sepsis and septic shock show elevated sTREM-1 levels, TREM-1 has attracted attention as an important contributor to the inadequate immune response in this often-deadly condition. Since 2001, when the first blockade of TREM-1 in sepsis was performed, many potential TREM-1 inhibitors have been established in animal models. However, only one of them, nangibotide, has entered clinical trials, which have yielded promising data for future treatment of sepsis, septic shock, and other inflammatory disease such as COVID-19. This review discusses the TREM-1 pathway and important ligands, and highlights the development of novel inhibitors as well as their clinical potential for targeted treatment of various inflammatory conditions.

Background

There has been great interest in triggering receptor expressed on myeloid cells-1 (TREM-1) since its discovery in 2000 [1]. Indeed, researchers recently published the interesting results of a phase 2b trial in which patients with sepsis were treated with nangibotide, a TREM-1 inhibitor [2]. TREM-1 belongs to the family of pattern recognition receptors (PRRs) [1, 3,4,5]. These receptors, which are located intracellularly and on the surface of immune and non-immune cells, recognize microbial/damage-associated molecular patterns (MAMPs/DAMPs) and therefore play a crucial role in host immune defense [6]. Consistently, TREM-1 was first found to be expressed on the surface of monocytes and neutrophils [1], but it is also expressed on non-immune cells like hepatic endothelial cells and gastric epithelial cells. TREM-1 expression on these cell types seems to be dependent on ongoing inflammatory processes [5], highlighting the role of TREM-1 in the immune response [7]. These effects are synergistically enhanced with other well-studied PRRs such as Toll-like receptors (TLRs), especially TLR4 [5], leading to an amplification of the inflammatory response. The role of TREM-1 and other TREM receptors is recently evaluated in more depth in a review by Colonna et al. [8].

Sepsis presents a dysregulated immune response, and TREM-1 has attracted attention as a potential contributor to this condition that often ends in death [9]. The circulating levels of the cleaved soluble extracellular portion of TREM-1 (sTREM-1) are elevated in patients with sepsis and associated with increased mortality in patients with septic shock [10,11,12]. A study with TREM-1-deficient (Trem1−/−) mice and dextran-sulfate-sodium-induced colitis generated convincing results. The lack of TREM-1 led to a better outcome without negatively impacting pathogen clearance in bacterial and viral infections [13]. In addition, blockade of TREM-1 with the TREM-1 Fc fusion protein (TREM-1/Fc) was carried out first in 2001. It protected mice against lipopolysaccharide (LPS)-induced shock, as well as microbial sepsis caused by Escherichia coli or cecal ligation and puncture (CLP). After the treatment with TREM-1/Fc, mice showed reduced tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) serum levels and improved survival rates compared with mice that did not receive a specific treatment [3]. Therefore, there have been substantial efforts to develop TREM-1 inhibitors to treat sepsis. LR12, a 12-amino-acid peptide, known as nangibotide (Inotrem, Paris, France), has entered clinical trials. The data are promising for the future therapy of sepsis and septic shock [2, 14], especially considering the current challenges in sepsis therapy. Although its importance is recognized, immune status monitoring is not used in clinical practice as there are currently no direct therapeutic implications. However, current research on adjunctive therapies indicates that there is no therapeutic principle that is suitable for all septic patients, and immune profiling that allows predictive enrichment in current and future treatment scenarios remains a challenge. Furthermore, the use of machine learning and artificial intelligence techniques might improve the development of workable algorithms to guide clinical decisions that make precision medicine for sepsis patients a reality and improve their outcome.

In this review, we critically address the role of TREM-1 as an important PRR in the development and pathogenesis of inflammation and sepsis. We also discuss the latest insights into the safety, efficacy, and therapeutic options of the different TREM-1 inhibitors, including nangibotide.

TREM-1 and its ligands in the inflammatory state

Receptor family, structure, isoforms, and pathways

The TREM receptor family—TREM-1, TREM-2, and TREM-3/4/5 (only in mice)—and the immunoreceptor tyrosine-based inhibition motif (ITIM)-bearing TREM-like-transcripts (TLT-1/2/3/4/5) are encoded by genes located on human chromosome 6p21 [15,16,17].

TREM-1 is a cell surface receptor belonging to the immunoglobulin superfamily with a related extracellular immunoglobulin-like V-type domain [17]. Besides the membrane-bound isoform (around 30 kDa), a soluble isoform is known, sTREM-1; it contains only the immunoglobulin-like domain, which is essential for antigen recognition and ligand binding [10, 11, 18]. TREM-1 lacks ITIMs in its intracellular domain, and signal propagation is dependent on an adaptor protein, namely DNAX-activating protein of 10 kDa and 12 kDa (DAP10 and DAP12, respectively) [19, 20]. The connection between the two molecules occurs through binding of a positively charged lysine in the receptor and a negatively charged aspartic acid in DAP10/12 [19, 20] and leads to phosphorylation of DAP10/12 and, subsequently, downstream cascades via the activation of spleen tyrosine kinase (Syk) [21]. Multiple signal propagation pathways lead to activation of different molecules and signal cascades involved in inflammatory reactions, leading to enhanced proinflammatory cytokine secretion [8, 12, 19, 21, 22].

Important ligands for the inflammatory response

The description of TREM-1 ligands is critical for the development of targeted sepsis treatment. Despite the discovery of TREM-1 in 2000 [1], the description of its ligands remains incomplete to date.

One of the first successes in this field was the discovery of peptidoglycan receptor protein 1 (PGLYRP1) [23]. This antimicrobial protein binds to essential factors of the bacterial cell membrane (peptidoglycan and LPS) and induces oxidative stress and lethal cell membrane depolarization [5, 12, 23, 24]. PGLYRP1 activates TREM-1 [18, 25, 26] and binds to sTREM-1 [27].

LPS itself is discussed as a potential ligand of TREM-1, because of its role in TREM-1 activation [1, 9]. However, it might be no direct ligand of TREM-1, but interacts indirectly with TREM-1 after binding to TLR4, stimulating the immune system [21].

High mobility group box 1 (HMGB1) was originally described as a DNA-binding protein acting as a cofactor to regulate transcriptional activity [28]. It has subsequently received attention for its role in inflammation. HMGB1 is a DAMP that activates TLRs and is a ligand for the receptor for advanced glycation endproducts (RAGE) [29, 30], which both trigger various cellular cascades leading to inflammatory phenotypes in vitro and in vivo [31]. In 2012, researchers demonstrated in a murine model of hepatocellular carcinoma that HMGB1 released from necrotic hepatocytes bound to TREM-1 with a binding dissociation constant (KD) of 35.4 × 10–6 M [12, 32, 33]. In human THP-1 cells, a monocytic cell line, HMGB1 has been shown to increase cytokine production via activating TREM-1.

Hsp70 isoforms are chaperones, which are involved in a wide variety of cellular protein remodeling, and degradation processes. Therefore, they are crucial for protein homeostasis and have a direct impact on human health [34]. In normal conditions, Hsp70 expression remains low, but it increases strongly in pro-inflammatory states [12, 35]. In 2000, Asea et al. [36] reported that Hsp70 has an additional role as a cytokine and cytokine release driver. This ability increased interest in the role of Hsp70 in inflammation. In 2007, researchers found that Hsp70 along with HMGB1 enhanced the pro-inflammatory response through TREM-1 activation after release from necrotic cells [35]. Recently, researchers showed that Hsp70 can bind to sTREM-1 immobilized on a cyanogen-bromide-activated Sepharose column as well as to TREM-1 on the monocyte surface [12, 37]. This Hsp70/TREM-1 interaction activated interferon (IFN)-γ and TNF-α messenger RNA (mRNA) expression in monocytes and stimulated IL-2 secretion by peripheral blood mononuclear cells [37].

There are high rates of necrosis and apoptosis in sepsis. This leads to a high amount of extracellular actin, which can have fatal effects on the organism including the induction of endothelial cell death. These negative consequences underline the importance of the extracellular actin clearance system and its potential role in the pathogenesis of septic shock [38].

In an early study, researchers reported an unknown ligand expressed on platelets that activates TREM-1 in sepsis. Extensive studies using gel analysis of total protein from platelets and recombinant TREM-1 (rTREM-1) revealed that the ligand is actin [39, 40]. The researchers treated murine RAW267.7 cells, a macrophage cell line, with LPS-stimulated platelets and LPS with recombinant actin. They used confocal microscopy to confirm the co-localization of TREM-1 and actin. [12, 40]. Moreover, actin enhanced the release of TNF-α from RAW267.7 cells and peritoneal macrophages via LPS stimulation. The ability of actin to activate TREM-1 could be attenuated by treatment with the TREM-1 inhibitor LP17, as well as peritoneal macrophages isolated from Trem1−/− mice [40]. LP17 was one of the first peptides developed to inhibit TREM-1 through a mechanism analogous to that of decoy receptors [41]. The 17-amino-acid sequence (LQVTDSGLYRCVIYHPP) is derived from a highly conserved sequence between the TREM-1 and TLT-1 extracellular domain in both mice and humans [12, 41].

Another endogenous ligand of TREM-1 was recently described: extracellular cold-inducible RNA binding protein (eCIRP). This DAMP was originally identified in the blood of patients with hemorrhagic shock and sepsis. In cell models under hypoxic conditions, macrophages could be stimulated by recombinant CIRP (rCIRP) to release TNF-α and HMGB1 and thereby induce an inflammatory response [42]. Denning et al. [43] demonstrated that murine rCIRP binds to recombinant murine TREM-1 (rmTREM-1) with a KD of 11.7 × 10–8 M, which indicates strong affinity. This could also be shown in murine RAW264.7 cells and peritoneal macrophages. To demonstrate that this could have a clinical impact, researchers treated rmCIRP-injected mice with LP17. They observed an attenuated systemic and pulmonary inflammatory response. This study suggests that eCIRP is an endogenous ligand of TREM-1.

sTREM-1 and its role as a biomarker in sepsis and septic shock

The origin of sTREM-1 is not yet fully understood. Its origin is most likely from proteolytic degradation of TREM-1 by MMPs, such as MMP-9 [44]. Therefore, TREM-1 activation by different triggers such as LPS would be necessary for its cleavage and production [9, 44]. Another relevant source is the translation of a TREM-1 mRNA splice variant lacking the sequence encoding the transmembrane and cytoplasmic regions of TREM-1 [8]. sTREM-1 was first detected in mouse and human serum [41, 45, 46], as well as in bronchoalveolar lavage fluid (BALF) from patients with ventilator-associated pneumonia [47]. In BALF, sTREM-1 is more accurate than any other clinical or laboratory findings to predict the presence of bacterial or fungal infections [8]. High levels of sTREM-1 only occur in infected patients [41, 45, 48], underlining the hypothesis that the origin of sTREM-1 is TREM-1 activation itself. Therefore, sTREM-1 levels indicate TREM-1 pathway activation.

There have been several studies investigating whether sTREM-1 might also be useful as a biomarker of disease severity in different inflammatory settings, especially when an inadequate immune response results in a fatal outcome. Patients with septic shock show extremely high sTREM-1 levels compared with healthy controls (814 pg/mL compared with 1.77–135 pg/mL) [49]. Based on published studies sTREM-1 is only detectable in 19% of healthy controls [1, 3]. In sepsis and septic shock, high sTREM-1 levels are associated with disease severity indicators, including Sequential Organ Failure Assessment (SOFA) score, the Acute Physiology and Chronic Health Evaluation (APACHE) II score, and 28-day mortality [14, 41, 49,50,51].

In COVID-19, a dysregulated immune state seems to be at least partly responsible for the development of a severe disease course [52]. In COVID-19 [53,54,55,56], but also in non-COVID-19 acute respiratory distress syndrome (ARDS) [57, 58], high sTREM-1 levels are associated with disease severity, a prolonged duration of mechanical ventilation, and a poor outcome. Da Silva Neto et al. [54] showed that the best cut-off sTREM-1 level for predicting in-hospital severity for patients with COVID-19 is ≥ 116.5 pg/mL. These inconclusive results concerning optimal sTREM-1 cut-off values underlie the importance of defining robust cut-off values, especially when it comes to the development of therapeutic agents.

In addition to being studied as a prognostic indicator of different inflammatory and non-inflammatory states, sTREM-1 has also been proposed to act as a decoy receptor for TREM-1 [12]. sTREM-1 binds TREM-1 ligands and reduces its activation and the subsequent pro-inflammatory cytokine release [18, 41, 59,60,—61]. First, this theory was tested in vitro. For cloning and expression, the gene for recombinant porcine sTREM-1 was transfected into E. coli. Prior to sTREM-1 treatment, porcine alveolar macrophages were stimulated with LPS and then mRNA expression of inflammatory cytokines was evaluated, showing reduced mRNA expression due to sTREM-1 treatment [62]. Interestingly, an in vivo study revealed contrary results. Yang et al. [63] reported worse outcomes in mice infected with Streptococcus suis, a bacterium that can rapidly cause streptococcal toxic-shock-like syndrome, and treatment with purified murine sTREM-1. This treatment was associated with increased 7-day mortality, elevated cytokine levels, as well as an increased bacterial load in the blood and peritoneal fluid. Notably, after infection with S. suis, mice treated with purified murine sTREM-1 in combination with ampicillin had better outcomes than mice treated with antibiotics alone [64]. Therefore, sTREM-1 agonism might help to decrease some bacterial infections, but it is also responsible for detrimental inflammatory processes leading to acute lung injury [12]. Nevertheless, many of the TREM-1 inhibitory peptides proposed for the treatment of sepsis are based on amino acid sequences found in sTREM-1. This underlines the potential of sTREM-1 as an effective anti-inflammatory mediator [12, 18].

LR12 and other TREM-1 inhibitors

LR12 (nangibotide) is a 12-amino-acid peptidic fragment that is derived from TLT-1 [22]. It is the first TREM-1 inhibitor that has entered clinical trials. Nangibotide is chemically synthesized and acts as a ligand-trapping molecule, also called a decoy receptor, that modulates the TREM-1-mediated amplification of inflammatory pathways and the inflammatory response (Fig. 1) [22].

Fig. 1
figure 1

Mechanisms of TREM-1 inhibitors in sepsis TREM-1 activation can be inhibited by different biomolecules: GF9 and SLC-TREM-1 are able to disturb the interaction between TREM-1 and its signaling partner DAP12. LR12/nangibotide, LP17, and TREM-1/Fc fusion protein act as decoy receptors. Decoy receptors are able to recognize and specifically bind ligands of other receptors without activating downstream signaling, so in this case the TREM-1 pathway is blocked. M3, was designed to inhibit a specific ligand of TREM-1, namely eCIRP. N1 is able to block the interaction between PGLYRP1 and TREM-1. Soluble TREM-1 is generated from proteolytic cleavage of membrane bound TREM-1 by matrix metalloproteinases or translation of a TREM-1 mRNA splice variant lacking the sequence encoding the transmembrane and cytoplasmic regions of TREM-1. Circulating soluble TREM-1 competitively binds TREM-1’s ligands and prevents further activation All inhibitors prevent the downstream signaling cascade that upregulates the translation of inflammatory cytokines and TREM-1 receptor. Abbreviations: DAP12 = DNAX-activating protein of 12 kDa protein; eCIRP = extracellular cold-inducible RNA binding protein; Hsp70 = heat shock protein 70; IL = interleukin; MMPs = metalloproteinases; mRNA = messenger RNA; PGLYRP1 = peptidoglycan receptor protein 1; SCL-TREM-1 = TREM-1 sneaking ligand construct; sTREM-1 = soluble triggering receptor expressed on myeloid cells-1; TREM-1 = triggering receptor expressed on myeloid cells-1

Full size image

In 2014, Weber et al. [13] generated Trem1−/− mice. They are viable and fertile, and the hematopoietic compartment shows no signs of alteration, suggesting that serious side effects involving the hematopoietic system are unlikely when receptor blockade is performed. Weber et al. [13] infected Trem1−/− mice with various bacteria and viruses. They noted lower neutrophilic infiltration as well as decreased morbidity, and the ability to control infection was comparable to the wild type (Trem1+/+) mice [13].

In a minipig model, designed to reflect human physiology more accurately than rodent models [65], researchers induced peritonitis and then either treated or did not treat the animals with LR12. After peritonitis, the mean arterial blood pressure decreased rapidly despite volume resuscitation, and the researchers treated the pigs with a norepinephrine infusion, similarly to septic shock therapy [66]. The LR12-treated pigs required less norepinephrine, indicating a protective effect of the treatment [66]. In addition, thrombopenia occurred less frequently, and in the control group the prothrombin ratio progressively decreased. Despite no differences in the fibrinogen plasma concentration between both groups, this finding suggests an attenuated sepsis-induced coagulopathy through LR12 treatment [66].

Nonhuman primates treated with an intravenous bolus of endotoxin remained normotensive following LR12 treatment. This contrasted with the placebo group, which experienced a 25–40% drop in blood pressure after infusion. In addition, LR12 treatment attenuated endotoxin-induced leukopenia, involving neutrophils, monocytes, and lymphocytes [67, 68]. Moreover, there was a 20–50% reduction in several cytokines in the LR12-treated group [67].

Taken together, these animal studies have demonstrated the impact of TREM-1 on endotoxin-induced endothelial dysfunction, cytokine release and, the inflammatory response. These findings underscore the importance of further investigation of LR12 in humans, particularly in patients with septic shock.

Additional TREM-1 inhibitors that have not been evaluated in clinical trials

As mentioned previously, LP17 is another TREM-1 inhibitor [12, 41]. Treatment with LP17 could reduce the release of cytokines in LPS-stimulated macrophages [41]. In mice and rats challenged with intraperitoneal LPS, LP17 could improve hemodynamics and survival, and there was reduced release of TNF-α, IL-1β, and IL-6 [12, 41, 69, 70]. Furthermore, LP17 has been shown to improve survival in mice after intravenous administration with Streptococcus pyogenes [69]. In septic rats induced by LPS injection, LP17 treatment attenuated sepsis severity [70]. There are also interesting results with regard to the treatment of humans. In leukocytes isolated from umbilical cord blood from full term human neonates, LP17 treatment decreased production of TNF-a, IL-6, and IL-8 after exposure to Escherichia coli revealing promising results for future therapies of life threating neonatal sepsis [71].

TREM-1/Fc, which is a combined form of the extracellular domain of mouse TREM-1 and the Fc portion of human IgG1, was developed as a TREM-1 decoy receptor [3, 12]. TREM-1/Fc promotes the clearance of TREM-1 ligands from the circulation via Fc receptor–mediated endocytosis [3]. In LPS-, CLP-, and E. coli–induced sepsis, mice had improved survival rates due to TREM-1/Fc treatment [3]. These findings were reproduced in two other mouse studies with TREM-1/Fc therapy. Mice showed better survival rates and decreased serum levels of TNF-α, IL-6, and IL-1β [69, 72].

M3, a 7-amino-acid sequence (RGFFRGG), was designed to inhibit a specific ligand of TREM-1, namely eCIRP. It was designed based on homology between PGLYRP1 and CIRP [12, 23, 43]. M3 was successfully tested in vitro and in vivo. It decreased TNF-α and IL-6, and improved 7-day survival in mice which were subjected to LPS-induced endotoxemia [43].

Sharapova et al. [73] synthesized a 10-amino-acid inhibitory peptide based on PGLYRP1 to investigate the effects on blocking the interaction between PGLYRP1 and TREM-1. They demonstrated binding of it to sTREM-1, respectively, TREM-1 and named it N1. Monocytes and lymphocytes exposed to PGLYRP1/Hsp70 and treated with N1 showed decreased lactate dehydrogenase (LDH) release. In addition, N1-treated cells had lower TNF-α, IFN-γ, IL-1β, and IL-6 mRNA expression after exposure to LPS. In an in vivo model, mice received bronchial instillation of LPS as well as α-galactosylceramide and developed acute lung injury. Afterwards, they were treated with intravenous N1 and were protected against the fatal cytokine storm, denoted by decreased serum levels of INF-γ and IL-4. Additionally, a histological evaluation showed reduced pulmonary inflammation in the treated animals [73].

There are other TREM-1 inhibitors that are not designed to influence the interaction between TREM-1 and its ligands. One of these is GF9, a ligand-independent peptide (GLLSKSLVF) derived from the transmembrane region of murine TREM-1. It was designed by Singalov and is able to disturb the interaction between TREM-1 and its signaling partner DAP12 [74, 75]. In LPS-stimulated macrophages and mice, GF9 treatment could decrease serum TNF-α, IL-1β, and IL-6 levels and was associated with higher survival rates in treated animals [12, 75].

TREM-1 sneaking ligand construct (SLC-TREM-1) is another inhibitor of the interaction between TREM-1 and DAP12. SLC-TREM-1 comprises three modules: an E-selectin targeting domain to bind to the endothelial cell surface, P. aeruginosa exotoxin A to facilitate translocation from the endosomal vesicular system into the cytosol, and a 7-amino-acid peptide (LSKSLVF) that contains the interaction site between TREM-1 and its adaptor protein DAP12 [12, 76]. To investigate the in vitro potential of SLC-TREM-1, endothelial cells were stimulated with LPS. They showed decreased TREM-1 expression and activation after treatment with SLC-TREM-1. In an in vivo study, mice subjected to CLP and injected intraperitoneally with SLC-TREM-1 showed improved 10-day survival [76].

LR17 is a 17-amino-acid peptide close to LP17 [12, 22, 66, 77]. Of note, it is the precursor of LR12. After some promising results concerning sepsis treatment in mice with LR17 [22, 77], it turned out that just 12 amino acids accounted for LR17’s anti-inflammatory effects, and a new peptide containing this sequence (LQEEDAGEYGCM) was designed [9, 12, 22] and is the first TREM-1 inhibitor that has been tested in clinical trials. Besides nangibotide,- several other promising TREM-1 inhibitors (mentioned above) have been identified [12] to treat sepsis. Further studies are needed to investigate their potential for clinical trials (Fig. 1).

Current insights from clinical trials

In 2018, nangibotide was initially administered in a phase 1 trial to 27 healthy volunteers aged 18 to 45 years at doses of up to 6 mg/kg/h over 7.75 h, preceded by a 15-min loading dose of up to 5 mg/kg. This was safe and well tolerated even at the highest doses, which reached the expected pharmacologically effective dose [78].

The subsequent multicenter, randomized, double-blind, phase 2a trial enrolled patients with septic shock. Treatment with nangibotide or placebo was initiated < 24 h after the onset of shock and continued for up to 5 days at doses of 0.3, 1.0, or 3.0 mg/kg/h. Nangibotide was well tolerated and safe in these patients [14]. There was no difference in inflammatory biomarkers and clinical efficacy between the study groups [12, 14], but in an indirect response model the results revealed a positive correlation between nangibotide concentration and a decrease in the IL-6 production rate [14]. The overall baseline median plasma sTREM-1 level was 433 pg/mL (range: 154–1960 pg/mL). In a subgroup analysis, patients with high levels of sTREM-1 treated with nangibotide had decreased SOFA scores after treatment [12, 14, 65].

In 2019, a double-blind, randomized, placebo-controlled, phase 2b trial (ASTONISH) was started in 42 hospitals in seven countries with medical, surgical, or mixed intensive care units and patients with septic shock. The efficacy and safety of two different nangibotide doses were compared with placebo. Another aim was to identify the optimal treatment population [2]. Like in the preceding phase 2a trial, patients were included in the study within 24 h of vasopressor initiation for the treatment of septic shock. After a loading dose of 5 mg/kg, patients received either nangibotide at 0.3 mg/kg/h (low-dose group) or 1.0 mg/kg/h (high-dose group), or matched placebo. Additionally, at baseline patients were classified according to their sTREM-1 levels as high (≥ 400 pg/mL) or low (< 400 pg/mL). This cut-off was established from observational sepsis studies and observations from the phase 2a trial. The primary endpoint was the mean difference in the total SOFA score from baseline to day 5 in the low-dose and high-dose groups compared with placebo, in the predefined high sTREM-1 (≥ 400 pg/mL) population, and in the overall modified intention-to-treat population. All-cause 28-day mortality, safety, pharmacokinetics, and evaluation of the relationship between TREM-1 activation and treatment response were included in the secondary endpoints. Seventy-one percent of patients were in the a priori–defined high sTREM-1 population [2]. Even though the primary endpoint did not reach significance, this trial revealed promising results. In the high sTREM-1 population, the difference in the SOFA score at day 5 between the high-dose and placebo groups revealed a positive trend, but it was not significant (p = 0.104). The same effect could be seen in the overall population (p = 0.108). Interestingly, the exploratory analyses revealed clinically relevant benefits and significantly different results among patients with baseline sTREM-1 concentrations > 532 pg/mL (p < 0.05). These treatment benefits at increasing sTREM-1 thresholds were seen across all six SOFA subscores [2]. In an exploratory descriptive analysis, the change in the IL-6 levels from baseline to day 2 presented a pattern consistent with the observed clinical effect of a greater reduction at sTREM-1 cut-off values > 500 pg/ml. The study was not powered to detect a significant effect on mortality. The low-dose group had a numerically higher mortality rate, but the authors justified this outcome based on imbalances in the population at baseline [2] (Table 1).

Table 1 Important preclinical-, animal developments and clinical trials concerning TREM-1 and TREM-1 inhibitors in infectious diseases, sepsis, and septic shock
Full size table

Summary and perspectives

TREM-1 is a PRR involved in many inflammatory reactions and contributes to various diseases that are aggravated through an inadequate immune response. Cytokine release leading to the often-described fatal cytokine storm seems to be an important driver in the pathogenesis of septic shock. This life-threatening condition is responsible for an estimated 11 million deaths each year throughout the world [79] and lead to a high personal and financial costs for health care systems [80]. This underlines the importance of developing new therapeutic strategies to improve morbidity and mortality. Currently, except for angiotensin-II and enibarcimab there are no septic shock–specific treatments, of which only angiotensin-II has Food and Drug Administration approval. The current therapeutic options are focused on organ support and control of the infection source [81] Furthermore, the current state of research shows that there are no specific treatment strategies that apply to all septic patients. Immune and non-immune profiling, as well as the use of artificial intelligence, could enable the development of patient-specific therapies in the coming years and improve outcome of patients significantly.

TREM-1 seems to play an important role in the pathogenesis of sepsis and septic shock, and studies concerning sTREM-1 plasma levels have revealed promising results for sTREM-1 as a biomarker for outcome prediction. sTREM-1 also appears to be relevant to other conditions with an inappropriate immune response, including other infectious and non-infectious disease states. François et al. [2, 14, 82] have investigated nangibotide, a TREM-1 inhibitor in phase 2a and 2b trials in patients with septic shock. Although these studies did not reach the primary endpoint, the authors demonstrated beneficial effects, and there were no adverse events related to treatment. In a subgroup of patients with high plasma sTREM-1 levels, nangibotide treatment led to a significantly better SOFA score at day 5 after septic shock onset, favoring high-dose nangibotide treatment [2, 14]. The change in the SOFA score is a soft outcome parameter: Some authors have described the clinical importance of this change as uncertain [83]. Nevertheless, the authors did provide evidence to support the potential benefit of nangibotide, the treatment appears to be safe, and the early clinical data suggest efficacy. Therefore, nangibotide is an interesting candidate for being tested in a phase 3 trial. However, future studies focusing on the best sTREM-1 cut-off value and the subset of patients with septic shock who might benefit most from nangibotide treatment could be executed before conducting a phase 3 trial. The study could be simplified by using rapid sTREM-1 assays, such as the "near-patient" 1-h assay used by Van Singer et al. [55]. Point-of-care testing could improve early identification of patients at high risk for adverse outcomes and facilitate the judicious use of TREM-1 inhibitors such as nangibotide in the future (Fig. 2).

Fig. 2
figure 2

Future principle of personalized and biomarker-driven therapy in sepsis. The sepsis cascade is a complex process that begins with a suspected infection and leads to a potentially fatal outcome for patients. sTREM-1 might help to detect suitable patients for nangibotide treatment, resulting in a targeted therapy to stop the excessive cytokine release and thereby halt organ dysfunction. Therefore, defining robust cut-off values for sTREM-1 is crucial. Abbreviations: ELISA = enzyme-linked immunosorbent assay; sTREM-1 = soluble triggering receptor expressed on myeloid cells-1; TREM-1 = triggering receptor expressed on myeloid cells-1

Full size image

Although various studies have shown an increase in TREM-1 ligands in septic patients [84,85,86], to our knowledge there is no data on their change during sepsis. Characterizing this in more detail could help to better coordinate the use of TREM-1 inhibitors during sepsis in clinical practice and improve their beneficial effect in therapeutic strategies.

In addition to clinical research on nagibotide, the other TREM-1 inhibitors should also be further developed and, if possible, brought into the clinical study phase. As it is becoming increasingly clear in current sepsis research that there are different endotypes in septic patients, different adjunctive and targeted therapies are necessary in order to treat patients according to their profile.

Conclusion

In summary, both sTREM-1 as a biomarker and TREM-1 inhibitors deserve further attention. sTREM-1 as an indicator of TREM-1 activation alongside markedly increased cytokine release could select those patients who would benefit the most from targeted anti-inflammatory or cytokine-reducing therapy—not only in sepsis, but also in other diseases. This view is supported by the growing evidence that IL-6 metabolism can also be positively influenced by TREM-1 inhibitors, like nangibotide. Nevertheless, additional studies to characterize patients more likely to benefit from this adjunctive therapy remain necessary. In addition, despite the exciting results of nangibotide, the other TREM-1 inhibitors should also be further developed and brought into clinical trial phase in order to test and develop other substances beside nangibotide in the treatment of sepsis and septic shock.

Availability of data and materials

Not applicable.

Abbreviations

ALT:

Alanine aminotransferase

APACHE:

Acute physiology and chronic health evaluation

ARDS:

Acute respiratory distress syndrome

AST:

Aspartate aminotransferase

CD:

Cluster of differentiation

CLP:

Cecal ligation and puncture

DAP12:

DNAX-activating protein of 12 kDa protein

DAMPs:

Damage-associated molecular patterns

eCIRP:

Extracellular cold-inducible RNA binding protein

ELISA:

Enzyme-linked immunosorbent assay

FiO2:

Fraction of inspired oxygen

IL:

Interleukin

IF:

Interferon

ITIM:

Immunoreceptor tyrosine-based inhibition motif

HMGB1:

High mobility group box 1

Hsp 70:

Heat shock protein 70

LPS:

Lipopolysaccharide

MAMPs:

Microbial-associated molecular patterns

MCP:

Monocyte chemoattractant protein

MIP:

Macrophage inflammatory protein

MMPs:

Metalloproteinases

mRNA:

Messenger RNA

PaO2:

Partial pressure of arterial oxygen

PGLYRP1:

Peptidoglycan receptor protein 1

PRRs:

Pattern recognition receptors

RAGE:

Receptor for advanced glycation endproducts

rCIRP:

Recombinant CIRP

rmTREM-1:

Recombinant murine TREM-1

rTREM-1:

Recombinant TREM-1

SLC-TREM-1:

TREM-1 sneaking ligand construct

SOFA:

Sequential organ failure assessment

sTLT:

Soluble TREM-like-transcript

sTREM-1:

Soluble triggering receptor expressed on myeloid cells-1

Syk:

Spleen tyrosine kinase

TLRs:

Toll-like receptors

TLT:

TREM-like-transcripts

TNF:

Tumor necrosis factor

TREM-1:

Triggering receptor expressed on myeloid cells-1

TREM-1/FC:

TREM-1 Fc fusion protein

References

  1. Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes1. J Immunol. 2000;164(10):4991–5.

    Article  PubMed  CAS  Google Scholar 

  2. François B, Lambden S, Fivez T, Gibot S, Derive M, Grouin JM, et al. Prospective evaluation of the efficacy, safety, and optimal biomarker enrichment strategy for nangibotide, a TREM-1 inhibitor, in patients with septic shock (ASTONISH): a double-blind, randomised, controlled, phase 2b trial. Lancet Respir Med. 2023.

  3. Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature. 2001;410(6832):1103–7.

    Article  PubMed  CAS  Google Scholar 

  4. Roe K, Gibot S, Verma S. Triggering receptor expressed on myeloid cells-1 (TREM-1): a new player in antiviral immunity? Front Microbiol. 2014;5:627.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Tammaro A, Derive M, Gibot S, Leemans JC, Florquin S, Dessing MC. TREM-1 and its potential ligands in non-infectious diseases: from biology to clinical perspectives. Pharmacol Ther. 2017;177:81–95.

    Article  PubMed  CAS  Google Scholar 

  6. Gulati A, Kaur D, Krishna Prasad GVR, Mukhopadhaya A. PRR function of innate immune receptors in recognition of bacteria or bacterial ligands. In: Chattopadhyay K, Basu SC, editors. Biochemical and biophysical roles of cell surface molecules. Singapore: Springer; 2018. p. 255–80.

    Chapter  Google Scholar 

  7. Tammaro A, Kers J, Emal D, Stroo I, Teske GJD, Butter LM, et al. Effect of TREM-1 blockade and single nucleotide variants in experimental renal injury and kidney transplantation. Sci Rep. 2016;6(1):38275.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Colonna M. The biology of TREM receptors. Nat Rev Immunol. 2023;23:580–94.

    Article  PubMed  CAS  Google Scholar 

  9. Dantas P, Matos AO, da Silva FE, Silva-Sales M, Sales-Campos H. Triggering receptor expressed on myeloid cells-1 (TREM-1) as a therapeutic target in infectious and noninfectious disease: a critical review. Int Rev Immunol. 2020;39(4):188–202.

    Article  PubMed  CAS  Google Scholar 

  10. Gibot S. Clinical review: role of triggering receptor expressed on myeloid cells-1 during sepsis. Crit Care. 2005;9(5):485–9.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Gibot S, Massin F, Le Renard P, Béné MC, Faure GC, Bollaert PE, et al. Surface and soluble triggering receptor expressed on myeloid cells-1: expression patterns in murine sepsis. Crit Care Med. 2005;33(8):1787–93.

    Article  PubMed  CAS  Google Scholar 

  12. Siskind S, Brenner M, Wang P. TREM-1 modulation strategies for sepsis. Front Immunol. 2022;13: 907387.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Weber B, Schuster S, Zysset D, Rihs S, Dickgreber N, Schürch C, et al. TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. PLoS Pathog. 2014;10(1): e1003900.

    Article  PubMed  PubMed Central  Google Scholar 

  14. François B, Wittebole X, Ferrer R, Mira JP, Dugernier T, Gibot S, et al. Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial. Intensive Care Med. 2020;46(7):1425–37.

    Article  PubMed  Google Scholar 

  15. Kelker MS, Foss TR, Peti W, Teyton L, Kelly JW, Wüthrich K, et al. Crystal structure of human triggering receptor expressed on myeloid Cells 1 (TREM-1) at 1.47Å. J Mol Biol. 2004;342(4):1237–48.

    Article  PubMed  CAS  Google Scholar 

  16. Radaev S, Kattah M, Rostro B, Colonna M, Sun PD. Crystal structure of the human myeloid cell activating receptor TREM-1. Structure. 2003;11(12):1527–35.

    Article  PubMed  CAS  Google Scholar 

  17. Allcock RJN, Barrow AD, Forbes S, Beck S, Trowsdale J. The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44. Eur J Immunol. 2003;33(2):567–77.

    Article  PubMed  CAS  Google Scholar 

  18. Gibot S, Massin F. Soluble form of the triggering receptor expressed on myeloid cells 1: an anti-inflammatory mediator? Intensive Care Med. 2006;32(2):185–7.

    Article  PubMed  CAS  Google Scholar 

  19. Tessarz AS, Cerwenka A. The TREM-1/DAP12 pathway. Immunol Lett. 2008;116(2):111–6.

    Article  PubMed  CAS  Google Scholar 

  20. Lanier LL. DAP10- and DAP12-associated receptors in innate immunity. Immunol Rev. 2009;227(1):150–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Arts RJ, Joosten LA, van der Meer JW, Netea MG. TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors. J Leukoc Biol. 2013;93(2):209–15.

    Article  PubMed  CAS  Google Scholar 

  22. Derive M, Bouazza Y, Sennoun N, Marchionni S, Quigley L, Washington V, et al. Soluble TREM-like transcript-1 regulates leukocyte activation and controls microbial sepsis. J Immunol. 2012;188(11):5585–92.

    Article  PubMed  CAS  Google Scholar 

  23. Read CB, Kuijper JL, Hjorth SA, Heipel MD, Tang X, Fleetwood AJ, et al. Cutting edge: identification of neutrophil PGLYRP1 as a ligand for TREM-1. J Immunol. 2015;194(4):1417–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Kashyap DR, Wang M, Liu LH, Boons GJ, Gupta D, Dziarski R. Peptidoglycan recognition proteins kill bacteria by activating protein-sensing two-component systems. Nat Med. 2011;17(6):676–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Sharapova TN, Romanova EA, Ivanova OK, Sashchenko LP, Yashin DV. Cytokines TNFα, IFNγ and IL-2 are responsible for signal transmission from the innate immunity protein Tag7 (PGLYRP1) to cytotoxic effector lymphocytes. Cells. 2020;9(12):2602.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Sharapova TN, Ivanova OK, Soshnikova NV, Romanova EA, Sashchenko LP, Yashin DV. Innate immunity protein Tag7 induces 3 distinct populations of cytotoxic cells that use different mechanisms to exhibit their antitumor activity on human leukocyte antigen-deficient cancer cells. J Innate Immun. 2017;9(6):598–608.

    Article  PubMed  CAS  Google Scholar 

  27. Singh H, Rai V, Nooti SK, Agrawal DK. Novel ligands and modulators of triggering receptor expressed on myeloid cells receptor family: 2015–2020 updates. Expert Opin Ther Pat. 2021;31(6):549–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Bustin M. Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins. Mol Cell Biol. 1999;19(8):5237–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Yang H, Antoine DJ, Andersson U, Tracey KJ. The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol. 2013;93(6):865–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Weigand MA, Hörner C, Bardenheuer HJ, Bouchon A. The systemic inflammatory response syndrome. Best Pract Res Clin Anaesthesiol. 2004;18(3):455–75.

    Article  PubMed  CAS  Google Scholar 

  31. Dong H, Zhang Y, Huang Y, Deng H. Pathophysiology of RAGE in inflammatory diseases. Frontiers Immunol. 2022;13:931473.

    Article  CAS  Google Scholar 

  32. Wu J, Li J, Salcedo R, Mivechi NF, Trinchieri G, Horuzsko A. The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res. 2012;72(16):3977–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Wang X, Xiang L, Li H, Chen P, Feng Y, Zhang J, et al. The role of HMGB1 signaling pathway in the development and progression of hepatocellular carcinoma: a review. Int J Mol Sci. 2015;16(9):22527–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Rosenzweig R, Nillegoda NB, Mayer MP, Bukau B. The Hsp70 chaperone network. Nat Rev Mol Cell Biol. 2019;20(11):665–80.

    Article  PubMed  CAS  Google Scholar 

  35. El Mezayen R, El Gazzar M, Seeds MC, McCall CE, Dreskin SC, Nicolls MR. Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin. Immunol Lett. 2007;111(1):36–44.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med. 2000;6(4):435–42.

    Article  PubMed  CAS  Google Scholar 

  37. Sharapova TN, Romanova EA, Ivanova OK, Yashin DV, Sashchenko LP. Hsp70 interacts with the TREM-1 receptor expressed on monocytes and thereby stimulates generation of cytotoxic lymphocytes active against mhc-negative tumor cells. Int J Mol Sci. 2021;22(13):6889.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Sudakov NP, Klimenkov IV, Byvaltsev VA, Nikiforov SB, Konstantinov YM. Extracellular actin in health and disease. Biochemistry (Mosc). 2017;82(1):1–12.

    Article  PubMed  CAS  Google Scholar 

  39. Haselmayer P, Grosse-Hovest L, von Landenberg P, Schild H, Radsak MP. TREM-1 ligand expression on platelets enhances neutrophil activation. Blood. 2007;110(3):1029–35.

    Article  PubMed  CAS  Google Scholar 

  40. Fu L, Han L, Xie C, Li W, Lin L, Pan S, et al. Identification of Extracellular Actin As a Ligand for Triggering Receptor Expressed on Myeloid Cells-1 Signaling. Front Immunol. 2017;8:917.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Gibot S, Kolopp-Sarda MN, Béné MC, Bollaert PE, Lozniewski A, Mory F, et al. A soluble form of the triggering receptor expressed on myeloid cells-1 modulates the inflammatory response in murine sepsis. J Exp Med. 2004;200(11):1419–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Qiang X, Yang WL, Wu R, Zhou M, Jacob A, Dong W, et al. Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med. 2013;19(11):1489–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Denning NL, Aziz M, Murao A, Gurien SD, Ochani M, Prince JM, et al. Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis. JCI Insight. 2020;5(5):e134172.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Gómez-Piña V, Soares-Schanoski A, Rodríguez-Rojas A, del Fresno C, García F, Vallejo-Cremades MaT, et al. Metalloproteinases Shed TREM-1 ectodomain from lipopolysaccharide-stimulated human monocytes1. J Immunol. 2007;179(6):4065–73.

    Article  PubMed  Google Scholar 

  45. Gibot S, Cravoisy A, Kolopp-Sarda MN, Béné MC, Faure G, Bollaert PE, et al. Time-course of sTREM (soluble triggering receptor expressed on myeloid cells)-1, procalcitonin, and C-reactive protein plasma concentrations during sepsis. Crit Care Med. 2005;33(4):792–6.

    Article  PubMed  CAS  Google Scholar 

  46. Brenner T, Uhle F, Fleming T, Wieland M, Schmoch T, Schmitt F, et al. Soluble TREM-1 as a diagnostic and prognostic biomarker in patients with septic shock: an observational clinical study. Biomarkers. 2017;22(1):63–9.

    Article  PubMed  CAS  Google Scholar 

  47. Rogier M, Determann Julian L, Sébastien M, Gibot Johanna C, Korevaar Margreeth B, Tom V, van der Poll Christopher S, Garrard Marcus J, Schultz (2005) Serial changes in soluble triggering receptor expressed on myeloid cells in the lung during development of ventilator-associated pneumonia. Intens Care Med 31(11):1495-1500. https://0-doi-org.brum.beds.ac.uk/10.1007/s00134-005-2818-7

  48. Klesney-tait J, Turnbull I, Colonna M. The TREM receptor family and signal integration. Nat Immunol. 2007;7:1266–73.

    Article  Google Scholar 

  49. Ríos-Toro JJ, Márquez-Coello M, García-Álvarez JM, Martín-Aspas A, Rivera-Fernández R, Sáez de Benito A, et al. Soluble membrane receptors, interleukin 6, procalcitonin and C reactive protein as prognostic markers in patients with severe sepsis and septic shock. PLoS One. 2017;12(4):e0175254.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Su L, Liu D, Chai W, Liu D, Long Y. Role of sTREM-1 in predicting mortality of infection: a systematic review and meta-analysis. BMJ Open. 2016;6(5): e010314.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Charles PE, Noel R, Massin F, Guy J, Bollaert PE, Quenot JP, et al. Significance of soluble triggering receptor expressed on myeloid cells-1 elevation in patients admitted to the intensive care unit with sepsis. BMC Infect Dis. 2016;16(1):559.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637–45.

  53. Neto PVdS, Carvalho JCSd, Pimentel VE, Pérez MM, Carmona-Garcia I, Neto NT, et al. Prognostic value of sTREM-1 in COVID-19 patients: a biomarker for disease severity and mortality. medRxiv. 2020:2020.09.22.20199703.

  54. da Silva-Neto PV, de Carvalho JCS, Pimentel VE, Pérez MM, Toro DM, Fraga-Silva TFC, et al. sTREM-1 Predicts Disease Severity and Mortality in COVID-19 Patients: involvement of peripheral blood leukocytes and MMP-8 Activity. Viruses. 2021;13(12):2521.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Van Singer M, Brahier T, Ngai M, Wright J, Weckman AM, Erice C, et al. COVID-19 risk stratification algorithms based on sTREM-1 and IL-6 in emergency department. J Allergy Clin Immunol. 2021;147(1):99-106.e4.

    Article  PubMed  Google Scholar 

  56. de Nooijer AH, Grondman I, Lambden S, Kooistra EJ, Janssen NAF, Kox M, et al. Increased sTREM-1 plasma concentrations are associated with poor clinical outcomes in patients with COVID-19. Biosci Rep. 2021;41(7):BSR2021090.

    Article  Google Scholar 

  57. Chen CY, Yang KY, Chen MY, Chen HY, Lin MT, Lee YC, et al. Decoy receptor 3 levels in peripheral blood predict outcomes of acute respiratory distress syndrome. Am J Respir Crit Care Med. 2009;180(8):751–60.

    Article  PubMed  CAS  Google Scholar 

  58. Lin MT, Wei YF, Ku SC, Lin CA, Ho CC, Yu CJ. Serum soluble triggering receptor expressed on myeloid cells-1 in acute respiratory distress syndrome: a prospective observational cohort study. J Formos Med Assoc. 2010;109(11):800–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Wang YK, Tang JN, Shen YL, Hu B, Zhang CY, Li MH, et al. Prognostic utility of soluble TREM-1 in predicting mortality and cardiovascular events in patients with acute myocardial infarction. J Am Heart Assoc. 2018;7(12):e008985.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Jedynak M, Siemiatkowski A, Mroczko B, Groblewska M, Milewski R, Szmitkowski M. Soluble TREM-1 serum level can early predict mortality of patients with sepsis, severe sepsis and septic shock. Arch Immunol Ther Exp (Warsz). 2018;66(4):299–306.

    Article  PubMed  Google Scholar 

  61. Jolly L, Carrasco K, Salcedo-Magguilli M, Garaud JJ, Lambden S, van der Poll T, et al. sTREM-1 is a specific biomarker of TREM-1 pathway activation. Cell Mol Immunol. 2021;18(8):2054–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Li H, Guo S, Yan L, Meng C, Hu Y, He K, et al. Expression and purification of a functional porcine soluble triggering receptor expressed on myeloid cells 1. Anim Biotechnol. 2017;28(4):237–41.

    Article  PubMed  CAS  Google Scholar 

  63. Yang C, Chen B, Zhao J, Lin L, Han L, Pan S, et al. TREM-1 signaling promotes host defense during the early stage of infection with highly pathogenic Streptococcus suis. Infect Immun. 2015;83(8):3293–301.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Yang C, Zhao J, Lin L, Pan S, Fu L, Han L, et al. Targeting TREM-1 signaling in the presence of antibiotics is effective against streptococcal toxic-shock-like syndrome (STSLS) caused by streptococcus suis. Front Cell Infect Microbiol. 2015;5:79.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Leong K, Gaglani B, Khanna AK, McCurdy MT. Novel diagnostics and therapeutics in sepsis. Biomedicines. 2021;9(3):311.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Derive M, Boufenzer A, Bouazza Y, Groubatch F, Alauzet C, Barraud D, et al. Effects of a TREM-like transcript 1–derived peptide during hypodynamic septic shock in pigs. Shock. 2013;39(2):176–82.

    Article  PubMed  CAS  Google Scholar 

  67. Derive M, Boufenzer A, Gibot S. Attenuation of responses to endotoxin by the triggering receptor expressed on myeloid cells-1 inhibitor LR12 in nonhuman primate. Anesthesiology. 2014;120(4):935–42.

    Article  PubMed  CAS  Google Scholar 

  68. Boufenzer A, Lemarié J, Simon T, Derive M, Bouazza Y, Tran N, et al. TREM-1 mediates inflammatory injury and cardiac remodeling following myocardial infarction. Circ Res. 2015;116(11):1772–82.

    Article  PubMed  CAS  Google Scholar 

  69. Horst SA, Linnér A, Beineke A, Lehne S, Höltje C, Hecht A, et al. Prognostic value and therapeutic potential of TREM-1 in Streptococcus pyogenes- induced sepsis. J Innate Immun. 2013;5(6):581–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Gibot S, Buonsanti C, Massin F, Romano M, Kolopp-Sarda MN, Benigni F, et al. Modulation of the triggering receptor expressed on the myeloid cell type 1 pathway in murine septic shock. Infect Immun. 2006;74(5):2823–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Qian L, Weng XW, Chen W, Sun CH, Wu J. TREM-1 as a potential therapeutic target in neonatal sepsis. Int J Clin Exp Med. 2014;7(7):1650–8.

    PubMed  PubMed Central  Google Scholar 

  72. Wang F, Liu S, Wu S, Zhu Q, Ou G, Liu C, et al. Blocking TREM-1 signaling prolongs survival of mice with Pseudomonas aeruginosa induced sepsis. Cell Immunol. 2012;272(2):251–8.

    Article  PubMed  CAS  Google Scholar 

  73. Sharapova TN, Romanova EA, Chernov AS, Minakov AN, Kazakov VA, Kudriaeva AA, et al. Protein PGLYRP1/Tag7 peptides decrease the proinflammatory response in human blood cells and mouse model of diffuse alveolar damage of lung through blockage of the TREM-1 and TNFR1 receptors. Int J Mol Sci. 2021;22(20):11213.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Sigalov AB. School of nature: ligand-independent immunomodulatory peptides. Drug Discov Today. 2020;25(8):1298–306.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Sigalov AB. A novel ligand-independent peptide inhibitor of TREM-1 suppresses tumor growth in human lung cancer xenografts and prolongs survival of mice with lipopolysaccharide-induced septic shock. Int Immunopharmacol. 2014;21(1):208–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Gibot S, Jolly L, Lemarié J, Carrasco K, Derive M, Boufenzer A. Triggering receptor expressed on myeloid cells-1 inhibitor targeted to endothelium decreases cell activation. Front Immunol. 2019;10:2314.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Gattis JL, Washington AV, Chisholm MM, Quigley L, Szyk A, McVicar DW, et al. The structure of the extracellular domain of triggering receptor expressed on myeloid cells like transcript-1 and evidence for a naturally occurring soluble fragment. J Biol Chem. 2006;281(19):13396–403.

    Article  PubMed  CAS  Google Scholar 

  78. Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, et al. A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition. Br J Clin Pharmacol. 2018;84(10):2270–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200–11.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Dugani S, Veillard J, Kissoon N. Reducing the global burden of sepsis. CMAJ. 2017;189(1):E2-e3.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486–552.

    Article  PubMed  Google Scholar 

  82. François B, Lambden S, Garaud JJ, Derive M, Grouin JM, Asfar P, et al. Evaluation of the efficacy and safety of TREM-1 inhibition with nangibotide in patients with COVID-19 receiving respiratory support: the ESSENTIAL randomised, double-blind trial. EClinicalMedicine. 2023;60: 102013.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Neupane M, Kadri SS. Nangibotide for precision immunomodulation in septic shock and COVID-19. The Lancet Respiratory Med. 2023. https://0-doi-org.brum.beds.ac.uk/10.1016/S2213-2600(23)00220-5.

    Article  Google Scholar 

  84. Kustán P, Horváth-Szalai Z, Mühl D. Nonconventional markers of sepsis. Ejifcc. 2017;28(2):122–33.

    PubMed  PubMed Central  Google Scholar 

  85. Yoo H, Im Y, Ko R-E, Lee JY, Park J, Jeon K. Association of plasma level of high-mobility group box-1 with necroptosis and sepsis outcomes. Sci Rep. 2021;11(1):9512.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Delogu G, Lo Bosco L, Marandola M, Famularo G, Lenti L, Ippoliti F, et al. Heat shock protein (HSP70) expression in septic patients. J Crit Care. 1997;12(4):188–92.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Not applicable

Funding

Open Access funding enabled and organized by Projekt DEAL.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 672, 69120, Heidelberg, Germany

    Vivienne Theobald, Felix Carl Fabian Schmitt, Chiara Simone Middel, Lena Gaissmaier & Markus Alexander Weigand

  2. Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    Thorsten Brenner

Authors
  1. Vivienne Theobald
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Felix Carl Fabian Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chiara Simone Middel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lena Gaissmaier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thorsten Brenner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Markus Alexander Weigand
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: VT and MW; writing—original draft preparation: VT, MW; writing—review and editing: FCFS, CSM, LG, TB, MW; visualization: VT, LG; supervision: FCFS, MW; funding acquisition: MW. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Markus Alexander Weigand.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

VT, FSCS, CSM and LG have no conflicts of interest. MW received grants from Köhler Chemie, DFG and BMBF, consulting fees from B. Braun, Gilead, Mundipharma and Boehringer Ingelheim, and payment or honoraria for lectures, presentations, or educational events from MSD, Gilead, Shionogi, Pfizer and Beckman Coulter. Dr Weigand is also a patent owner (EP17185036.5 and EP17198330.7), has participated on advisory boards for MSD, Gilead, Shionogi, Biotest, Pfizer, Eumedica, SOBI and Beckman Coulter, is the vice-head of the German Sepsis Society and member of the scientific advisory council of PEG, and is cofounder of Delta Theragnostics. TB received scientific grants from Deutsche Forschungsgemeinschaft (DFG), Innovation Fund of the Federal Joint Committee (G-BA), Dietmar Hopp Stiftung, Heidelberg Foundation of Surgery as well as Stiftung Universitätsmedizin Essen. Moreover, he received honoraria for lectures as well as advisory board participation from Baxter Deutschland GmbH, Schöchl medical education GmbH, Boehringer Ingelheim Pharma GmbH, CSL Behring GmbH, Astellas Pharma GmbH, B. Braun Melsungen AG, MSD Sharp & Dohme GmbH, BRAHMS GmbH, Lücke Kongresse GmbH, Georg Thieme Verlag GmbH as well as Akademie für Infektionsmedizin e.V.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Theobald, V., Schmitt, F.C.F., Middel, C.S. et al. Triggering receptor expressed on myeloid cells-1 in sepsis, and current insights into clinical studies. Crit Care 28, 17 (2024). https://0-doi-org.brum.beds.ac.uk/10.1186/s13054-024-04798-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://0-doi-org.brum.beds.ac.uk/10.1186/s13054-024-04798-2

Keywords

Critical Care

ISSN: 1364-8535