Early serum levels of soluble triggering receptor expressed on myeloid cells–1 in septic patients: Correlation with monocyte gene expression

doi:10.1016/j.jcrc.2011.06.013

Journal of Critical Care

Volume 27, Issue 3, June 2012, Pages 294-300

https://doi.org/10.1016/j.jcrc.2011.06.013 Get rights and content

Abstract

Purpose

To define early kinetics of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and of TREM-1 monocyte gene expression in critically ill patients with sepsis.

Methods

Blood was sampled at regular time intervals from 105 patients with sepsis. Concentrations of tumour necrosis factor α (TNFα), interleukin (IL)–6, IL-8 and IL-10 and IL-12p70 and sTREM-1 were measured by an enzyme immunoassay. Blood mononuclear cells were isolated on day 0 from 20 patients and 10 healthy volunteers; RNA was extracted and gene expression of TREM-1 and TNFα were assessed by reverse transcriptase polymerase chain reaction.

Results

Early serum concentrations of sTREM-1 were greater among patients with severe sepsis/shock than among patients with sepsis; those of TNFα, IL-6, IL-8 and IL-10 were pronounced among patients with septic shock. Gene transcripts of TNFα were lower among patients with severe sepsis/shock than among patients with sepsis; that was not the case for TREM-1. Early serum levels of sTREM-1 greater than 180 pg/mL were predictors of shorter duration of mechanical ventilation.

Conclusions

Although serum levels of sTREM-1 are increased early upon advent of severe sepsis/shock, gene expression of TREM-1 on monocytes in severe sepsis/shock is not increased. These findings add considerably to our knowledge on the pathophysiology of sepsis.

Introduction

Triggering receptor expressed on myeloid cells–1 (TREM-1) is a receptor engaged on cell membranes of neutrophils and blood monocytes. Triggering receptor expressed on myeloid cells–1 plays a considerable role in the innate immune response against invading microorganisms. Triggering receptor expressed on myeloid cells–1 consists of 3 domains: one ectodomain where the agonist is bound, one transmembrane domain composed by leukine rich repeats, and one intracellular domain. After stimulation by a yet undefined ligand, the intracellular domain activates the adaptor molecule AP-12, which eventually leads to activation of nuclear factor-kappa B. Finally, the intracellular production and subsequent extracellular release of tumor necrosis factor–alpha (TNFα) and of interleukin (IL)-8 ensues [1].

Expression of TREM-1 is highly up-regulated in the event of septic phenomena, mainly of septic shock. Then, some of the amount of membranic TREM-1 is shed into the systemic circulation through the activation of metalloproteinases [2]. This shed molecule, also known as soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), circulates at significantly elevated concentrations in patients with septic shock, and it has been hypothesized that sTREM-1 might be a mediator conducting transition from sepsis and severe sepsis into septic shock [3].

It is thought that sepsis ensues in 2 phases: the first phase is characterized by intense inflammatory phenomena due to the production of pro-inflammatory mediators by blood monocytes and tissue macrophages after stimulation from the invading microorganisms; in the second phase, blood monocytes and tissue macrophages fail to release pro-inflammatory mediators after stimulation participating that to a hypo-inflammatory state of the host known as immunoparalysis [4]. The exact time frames of these 2 phases and their relationships with the clinical phenomena of sepsis have not been settled. Furthermore whether the pro-inflammatory receptor TREM-1 is down-regulated in this phase of immunoparalysis or not remains to be investigated.

In the present study serum kinetics of sTREM-1 were investigated in patients with early septic phenomena and their relationship with the physical course of patients. Results were also correlated with other cytokines and with gene expression of TREM-1 in circulating monocytes.

Section snippets

Study design

This prospective study included 105 mechanically ventilated septic patients hospitalized in the intensive care unit of ATTIKON University Hospital during the period December 2005-June 2007. The protocol was approved by the ethics committee of the hospital; written informed consent was provided by first-degree relatives.

Inclusion criteria were the concomitant presence of (a) age of 18 years and above and (b) sepsis or severe sepsis or septic shock presented within the last 24 hours. Exclusion

Results

Demographic characteristics of enrolled patients according to the clinical stages of the septic syndrome are shown in Table 1. Mortality from septic shock was greater than by sepsis and severe sepsis (P = .023).

Thirty-seven of the enrolled healthy controls were men, and six, women; their mean ± SD age was 49.1 ± 6.1 years.

Concentrations of the estimated cytokines upon advent of signs of sepsis are shown in Fig. 1. Concentrations of TNFα, IL-6, IL-8, and IL-10 were greater among patients with

Discussion

The present study aimed to define the kinetics of the concentrations of sTREM-1 and other cytokines in the serum of critically ill patients early upon advent of signs of sepsis and to correlate these changes with gene transcripts of TREM-1 and of TNFα in monocytes of patients.

Results revealed that early, that is, within less than 24 hours upon diagnosis, serum levels of sTREM-1 are increased in parallel with disease severity so that concentrations of patients with severe sepsis and septic shock

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Cited by (28)

The characteristics and pivotal roles of triggering receptor expressed on myeloid cells-1 in autoimmune diseases
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In addition to myeloid cells, TREM-1 is also expressed on non-myeloid cell types including epithelial and endothelial cells (ECs) [18–20]. TREM-1 expression is significantly increased in infectious diseases [21,22] and non-infectious inflammatory diseases such as acute pancreatitis, inflammatory bowel diseases, gout and rheumatoid arthritis [23–25]. Therefore, TREM-1 expression is probably an important mediator of inflammation (Table 1).
Triggering receptor expressed on myeloid cells-1 (TREM-1) engagement can directly trigger inflammation or amplify an inflammatory response by synergizing with TLRs or NLRs. Autoimmune diseases are a family of chronic systemic inflammatory disorders. The pivotal role of TREM-1 in inflammation makes it important to explore its immunological effects in autoimmune diseases. In this review, we summarize the structural and functional characteristics of TREM-1. Particularly, we discuss recent findings on TREM-1 pathway regulation in various autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type 1 diabetes (T1D), and psoriasis. This receptor may potentially be manipulated to alter the inflammatory response to chronic inflammation and possible therapies are explored in this review.
Endocan and Soluble Triggering Receptor Expressed on Myeloid Cells-1 as Novel Markers for Neonatal Sepsis
2015, Pediatrics and Neonatology
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Nonetheless, it was shown that increased sTREM-1 levels were not specific for infection and could also increase markedly in acute inflammation without infection. In another study it was shown that within < 24 hours after diagnosis serum levels of sTREM-1 were increased in parallel with sepsis severity, being higher in severe sepsis and septic shock.22 In a study conducted in mechanically ventilated patients with pneumonia, Gibot et al21 found higher levels of sTREM-1 in bronchoalveolar lavage fluid samples taken from patients with a diagnosis of community-acquired pneumonia and ventilator-associated pneumonia than from those who did not have pneumonia.
Neonatal sepsis is an important cause of neonatal morbidity and mortality in the neonatal intensive care unit. Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) has been evaluated in sepsis and septic shock, and it was found to be valuable in distinguishing septic cases from nonseptic cases. Endocan is constitutively expressed by endothelial cells, and high levels of endocan may be of relevance for the promotion of systemic inflammation. The aim of this study was to investigate whether the levels of sTREM-1 and endocan were increased in late-onset neonatal sepsis.
Patients were classified into septic and nonseptic groups. Blood was collected from a peripheral vein of all septic newborns and healthy newborns at the time of initial laboratory evaluation before any treatment, and within 48–72 hours after initiation of treatment. Serum sTREM-1 and endocan measurements were performed when the study was finished.
The study population comprised of 50 neonates: 20 nonseptic neonates and 30 septic neonates. The groups were similar with regards to baseline characteristics. The initial measurements of interleukin-6 (IL-6), sTREM-1, endocan, and immature/total neutrophil ratio (I/T ratio) were significantly higher in septic neonates in comparison with nonseptic neonates. Receiver operating characteristic (ROC) curve analyses revealed that IL-6, sTREM-1, endocan, and I/T ratio resulted in significant areas under the curve (AUC) with respect to early identification of septic neonates. Soluble TREM-1 and IL-6 performed best to distinguish septic neonates from nonseptic neonates. Univariate logistic regression analysis showed that increased IL-6 and sTREM-1 were strong predictors of neonatal late-onset sepsis.
Serum sTREM-1, IL-6, endocan levels, and I/T ratio increased in septic neonates. However, the diagnostic accuracy of circulating sTREM-1 seemed to be better than endocan and I/T ratio, but lower than IL-6.
Immune responses in relation to the type and time of thermal injury: An experimental study
2015, Injury
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Nevertheless, most of animal models have studied circulating cytokines mainly within the first hours after injury. Importantly, our findings indicate TNFα as the only down-regulated cytokine in contrast to the phenomenon of sepsis-induced immunoparalysis, in which a generally impaired cytokine production by monocytes has been reported [16–18]. In this context, the study of Th1, Th2 and Th17 responses characterized by IFNγ, IL-10, and IL-17 production, respectively, were studied [19].
Thermal injuries are followed by a complex immune response, but the relationship between the severity of burn injury and the time exposure to the thermal injury on the extent of the immune response is still not known.
This study focuses on characterising the effect of temperature and time exposure on the post-burn immune response.
We used 120 C57BL/6 male mice divided equally in 5 burn groups and one sham operated group (groups A–E and sham). Ten mice per group were sacrificed at 24 and 48 h after burn injury and whole blood was collected; specimens of liver, lung, spleen, kidney and bowel were excised. Apoptosis and TREM-1 expression on circulating blood cells were measured. Splenocytes were isolated and stimulated for cytokine production; the rate of apoptosis of splenocytes was also measured.
Production of IL-17 from splenocytes of mice group D was enhanced. Considerable effects were shown on the apoptosis of circulating lymphocytes and of spleen cells. The apoptotic rates varied between groups and also evolved after 24 and 48 h. To examine the origin of this differential response, quantitative bacterial cultures of liver, lung and kidney were made but no differences were observed compared with sham-operated animals.
This study was based on an experimental murine model.
There is a unique response for each type of injury depending on the temperature of the thermal source and the exposure time.
Clinical significance of soluble-triggering receptor expressed on myeloid cells-1 (sTREM-1) in patients with rheumatoid arthritis
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Triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified molecule involved in monocytic activation and inflammatory response. It is expressed mainly on monocytes and neutrophils, and plays an important role in amplifying inflammatory response in acute and chronic inflammatory conditions [5,6]. TREM-1 expression is increased by various Toll-like receptor (TLR) ligands during acute inflammation [5].
To assess serum concentrations of triggering receptor expressed on myeloid cells-1 (sTREM-1) in rheumatoid arthritis (RA) patients, and correlate them with the main clinical, serological, radiological features and functional capacity of RA patients.
Sera from 61 RA patients, and 30 healthy controls were assayed for sTREM-1 by Enzyme Linked Immunosorbant Assay. RA disease activity was assessed using 28-joint disease activity score (DAS-28). Assessment of patient’s functional capacity was done using modified health assessment questionnaire (mHAQ). Standardized X-rays were done to all RA participants and evaluated according to Larsen score
Serum levels of sTREM-1 were significantly higher in RA patients vs healthy controls (57.61 ± 28.87 and 43.72 ± 10.64 ng/ml; p = 0.027). These levels were higher in patients with severe disease activity (68.27 ± 36.14 ng/ml) than those with mild and moderate disease activity (43.50 ± 6.49 ng/ml and 47.52 ± 12.26 ng/ml, respectively; p = 0.008). On the contrary, no significant difference was found in levels of sTREM-1 in patients with extra-articular involvement or positive RF than those without. Levels of sTREM-1 showed a highly significant positive correlation with DAS-28 (P = 0.001), ESR (P = 0.02) and mHAQ (p = 0.003).There were no significant correlations between sTREM-1 level with age, disease duration, morning stiffness, nor radiological narrowing and erosion scores.
Levels of sTREM-1 were elevated in RA patients and correlated significantly with clinical and laboratory markers of disease activity as well as functional disability (as determined by mHAQ). To confirm our results we propose that larger scale, multicenter studies with longer evaluation periods are needed.
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^☆: Conflict of interest: The authors declare that they have no competing interests.

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SepsisEarly serum levels of soluble triggering receptor expressed on myeloid cells–1 in septic patients: Correlation with monocyte gene expression☆

Abstract

Purpose

Methods

Results

Conclusions

Introduction

Section snippets

Study design

Results

Discussion

Immunol Lett

Immunobiology

Chest

Cytokine

Does soluble triggering receptor expressed on myeloid cells-1 play any role in the pathogenesis of septic shock?

Clin Exp Immunol

Harmful molecular mechanisms in sepsis

Nat Immunol

Ventilator-associated pneumonia

Am J Respir Crit Care Med

The International Sepsis Forum Consensus definitions of infections in the intensive care unit

Crit Care Med

2001 SCCM / ESICM / ACCP / ATS / SIS international sepsis definitions conference

Crit Care Med

Time-course of sTREM (soluble triggering receptor expressed on myeloid cells)-1, procalcitonin, and C-reactive protein plasma concentrations during sepsis

Crit Care Med

Sepsis
Early serum levels of soluble triggering receptor expressed on myeloid cells–1 in septic patients: Correlation with monocyte gene expression☆