Soluble Form of the Triggering Receptor Expressed on Myeloid Cells-1 as a Marker of Microbial Infection

Abstract Background. The triggering receptor expressed on myeloid cells-1 (TREM-1) mediates fatal septic shock in murine models, but studies linking the soluble form of TREM-1 (sTREM-1) to mortality in clinical sepsis are inconclusive, and few have examined its relationship to organ dysfunction. We sought to identify associations between circulating sTREM-1 and both mortality and organ dysfunction among a broad cohort of critically ill medical, post-surgical and trauma patients. Methods. We enrolled a prospective cohort of patients who met two or more criteria for the systemic inflammatory response syndrome (SIRS) within 24 hours of intensive care unit (ICU) admission at a large academic medical center. sTREM-1 concentrations were measured at study enrollment. We used relative risk regression, adjusted for age, sex, and Charlson comorbidity index, to determine associations between sTREM-1 and the primary outcome of 28-day mortality. We also examined secondary outcomes of prevalent organ dysfunction on enrollment, and composites of persistent organ dysfunction or death at day 7. Results. Among 231 critically ill patients, non-survivors (n=19, 8%) had a higher proportion of pre-existing comorbidities, mechanical ventilation (79% vs. 44%) and shock (58% vs. 28%) compared to survivors. At study enrollment, increasing sTREM-1 was associated with a higher risk of severe acute kidney injury (AKI), shock, and acute hypoxemic respiratory failure requiring mechanical ventilation. sTREM-1 was higher among non-survivors than survivors (885 vs 336 pg/mL); each doubling of sTREM-1 concentration was associated with a 2.41-fold higher risk of 28-day mortality (95% CI 1.57, 3.72). Among 92 patients with shock on enrollment, doubling of sTREM-1 was associated with a 3.89-fold higher risk of persistent shock or death by day 7 (95% CI 1.85, 8.17). Higher sTREM-1 was also associated with a higher risk of both persistent AKI and persistent hypoxemic respiratory failure or death. Conclusions. Elevated plasma sTREM-1 is highly associated with 28-day mortality and organ dysfunction across a diverse critically ill population. These data support that early activation of the innate immune system plays a role in the development of organ dysfunction and death. Further studies should address whether modulation of the TREM-1 pathway might be beneficial in critically ill patients.

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CD93 Is Rapidly Shed from the Surface of Human Myeloid Cells and the Soluble Form Is Detected in Human Plasma

The Journal of Immunology ◽

10.4049/jimmunol.175.2.1239 ◽

2005 ◽

Vol 175 (2) ◽

pp. 1239-1247 ◽

Cited By ~ 49

Author(s):

Suzanne S. Bohlson ◽

Richard Silva ◽

Maria I. Fonseca ◽

Andrea J. Tenner

Keyword(s):

Human Plasma ◽

Myeloid Cells ◽

Soluble Form

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The DC-SIGN–related lectin LSECtin mediates antigen capture and pathogen binding by human myeloid cells

Blood ◽

10.1182/blood-2006-09-048058 ◽

2007 ◽

Vol 109 (12) ◽

pp. 5337-5345 ◽

Cited By ~ 55

Author(s):

Angeles Dominguez-Soto ◽

Laura Aragoneses-Fenoll ◽

Enrique Martin-Gayo ◽

Lorena Martinez-Prats ◽

Maria Colmenares ◽

...

Keyword(s):

Dendritic Cells ◽

Lymph Node ◽

Adhesion Molecule ◽

Myeloid Cells ◽

Intercellular Adhesion ◽

Leukemic Cells ◽

Intercellular Adhesion Molecule ◽

Soluble Form ◽

Binding Studies ◽

Antigen Uptake

AbstractLiver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin [CLEC4G]) is a C-type lectin encoded within the liver/lymph node–specific intercellular adhesion molecule-3–grabbing nonintegrin (L-SIGN)/dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN)/CD23 gene cluster. LSECtin expression has been previously described as restricted to sinusoidal endothelial cells of the liver and lymph node. We now report LSECtin expression in human peripheral blood and thymic dendritic cells isolated ex vivo. LSECtin is also detected in monocyte-derived macrophages and dendritic cells at the RNA and protein level. In vitro, interleukin-4 (IL-4) induces the expression of 3 LSECtin alternatively spliced isoforms, including a potentially soluble form (Δ2 isoform) and a shorter version of the prototypic molecule (Δ3/4 isoform). LSECtin functions as a pathogen receptor, because its expression confers Ebola virus–binding capacity to leukemic cells. Sugar-binding studies indicate that LSECtin specifically recognizes N-acetyl-glucosamine, whereas no LSECtin binding to Mannan- or N-acetyl-galactosamine–containing matrices are observed. Antibody or ligand-mediated engagement triggers a rapid internalization of LSECtin,which is dependent on tyrosine and diglutamic-containing motifs within the cytoplasmic tail. Therefore, LSECtin is a pathogen-associated molecular pattern receptor in human myeloid cells. In addition, our results suggest that LSECtin participates in antigen uptake and internalization, and might be a suitable target molecule in vaccination strategies.

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A Soluble Form of the Triggering Receptor Expressed on Myeloid Cells-1 Modulates the Inflammatory Response in Murine Sepsis

Journal of Experimental Medicine ◽

10.1084/jem.20040708 ◽

2004 ◽

Vol 200 (11) ◽

pp. 1419-1426 ◽

Cited By ~ 241

Author(s):

Sébastien Gibot ◽

Marie-Nathalie Kolopp-Sarda ◽

Marie-C. Béné ◽

Pierre-Edouard Bollaert ◽

Alain Lozniewski ◽

...

Keyword(s):

Septic Shock ◽

Proinflammatory Cytokines ◽

Myeloid Cells ◽

Soluble Form ◽

Therapeutic Tool ◽

Serum Samples ◽

Conserved Domain ◽

Microbial Products

The triggering receptor expressed on myeloid cells (TREM)-1 is a recently discovered receptor expressed on the surface of neutrophils and a subset of monocytes. Engagement of TREM-1 has been reported to trigger the synthesis of proinflammatory cytokines in the presence of microbial products. Previously, we have identified a soluble form of TREM-1 (sTREM-1) and observed significant levels in serum samples from septic shock patients but not controls. Here, we investigated its putative role in the modulation of inflammation during sepsis. We observed that sTREM-1 was secreted by monocytes activated in vitro by LPS and in the serum of animals involved in an experimental model of septic shock. Both in vitro and in vivo, a synthetic peptide mimicking a short highly conserved domain of sTREM-1 appeared to attenuate cytokine production by human monocytes and protect septic animals from hyper-responsiveness and death. This peptide seemed to be efficient not only in preventing but also in down-modulating the deleterious effects of proinflammatory cytokines. These data suggest that in vivo modulation of TREM-1 by sTREM peptide might be a suitable therapeutic tool for the treatment of sepsis.

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Synthesis and release of B-lymphocyte stimulator from myeloid cells

Blood ◽

10.1182/blood.v97.1.198 ◽

2001 ◽

Vol 97 (1) ◽

pp. 198-204 ◽

Cited By ~ 406

Author(s):

Bernardetta Nardelli ◽

Ornella Belvedere ◽

Viktor Roschke ◽

Paul A. Moore ◽

Henrik S. Olsen ◽

...

Keyword(s):

Dendritic Cells ◽

B Cell ◽

Culture Medium ◽

B Lymphocyte ◽

Myeloid Cells ◽

Interleukin 10 ◽

Soluble Form ◽

Blood Monocytes ◽

B Lymphocyte Stimulator ◽

Ifn Γ

Abstract B-lymphocyte stimulator (BLyS) is a recently identified novel member of the tumor necrosis factor ligand superfamily shown to exist in a membrane-bound and soluble form. BLyS was found to be specifically expressed on cells of myeloid lineage and to selectively stimulate B-lymphocyte proliferation and immunoglobulin production. The expression of a cytokine involved in potentiation of humoral immune responses, such as BLyS, is expected to be strictly controlled. The goal of the present study was to examine regulation of BLyS levels in monocytic cells in response to cytokines and during their differentiation to macrophages and dendritic cells. The presence of BLyS on the cell surface and in the culture medium of both normal blood monocytes and on tumor cells of myelomonocytic origin was demonstrated. BLyS gene expression and levels of membrane-associated and soluble BLyS were found to be regulated by cytokines, in particular interferon (IFN)-γ and to a lesser extent interleukin-10 (IL-10). The expression of BLyS on monocyte membranes was retained following differentiation into macrophages, but detection on the surface of monocyte-derived dendritic cells required stimulation with IFN-γ. Both IFN-γ and IL-10 enhanced the release of soluble BLyS that was active in B-cell proliferation assays. Cells transfected with BLyS complementary DNA mutated in a predicted cleavage site failed to release BLyS into the culture medium, thereby suggesting that soluble BLyS was derived from the membrane form. These results provide further support for an important role for BLyS expressed in myeloid cells in B-cell expansion and antibody responses.

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Production of Soluble Triggering Receptor Expressed on Myeloid Cells by Lipopolysaccharide-Stimulated Human Neutrophils Involves De Novo Protein Synthesis

Clinical and Vaccine Immunology ◽

10.1128/cvi.13.4.492-495.2006 ◽

2006 ◽

Vol 13 (4) ◽

pp. 492-495 ◽

Cited By ~ 20

Author(s):

Amr M. Mahdy ◽

Damon A. Lowes ◽

Helen F. Galley ◽

Jane E. Bruce ◽

Nigel R. Webster

Keyword(s):

Protein Synthesis ◽

De Novo ◽

Myeloid Cells ◽

Surface Expression ◽

Soluble Form ◽

Human Neutrophils ◽

Lps Challenge ◽

Alternatively Spliced ◽

Culture Supernatants ◽

De Novo Protein Synthesis

ABSTRACT The triggering receptor expressed on myeloid cells (TREM-1) is a recently identified receptor expressed on neutrophils and monocytes. Activation of the receptor induces neutrophils to release the enzyme myeloperoxidase and inflammatory cytokines such as interleukin-8. TREM-1 has an alternatively spliced variant that lacks the transmembrane region, resulting in the receptor being secreted in a soluble form (sTREM-1). Soluble TREM-1 has been detected in plasma during experimental and clinical sepsis and has been advocated as a diagnostic marker of infection for pneumonia and as a prognostic marker for patients with septic shock. We studied TREM-1 surface expression, using flow cytometry, and simultaneously measured sTREM-1 concentrations in culture supernatants of lipopolysaccharide (LPS)-stimulated neutrophils. TREM-1 surface expression was constitutive and was not upregulated upon LPS stimulation. However, sTREM-1 release from neutrophils was significantly upregulated by LPS stimulation (P < 0.0001), an effect that was abrogated by cycloheximide. Soluble TREM-1 is therefore secreted by human neutrophils in response to LPS challenge in a process involving de novo protein synthesis that is not accompanied by an upregulation of the TREM-1 receptor on the surfaces of the cells.

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Amniotic Fluid-Soluble Form of Triggering Receptors Expressed on Myeloid Cells: A Physiologic Constituent at Term

Gynecologic and Obstetric Investigation ◽

10.1159/000446943 ◽

2016 ◽

Vol 82 (2) ◽

pp. 131-136

Author(s):

Natália Prearo Moço ◽

Laura Fernandes Martin ◽

Bruna Ribeiro de Andrade Ramos ◽

Rodrigo Paupério Soares de Camargo ◽

Stephanno Gomes Pereira Sarmento ◽

...

Keyword(s):

Amniotic Fluid ◽

Myeloid Cells ◽

Soluble Form

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CD38 binding to human myeloid cells is mediated by mouse and human CD31

Biochemical Journal ◽

10.1042/bj3301129 ◽

1998 ◽

Vol 330 (3) ◽

pp. 1129-1135 ◽

Cited By ~ 27

Author(s):

L. Alberto HORENSTEIN ◽

Hannes STOCKINGER ◽

A. Beat IMHOF ◽

Fabio MALAVASI

Keyword(s):

Tertiary Structure ◽

Peptide Mapping ◽

Myeloid Cells ◽

Binding Domain ◽

Membrane Receptors ◽

Soluble Form ◽

Cross Linking ◽

Αvβ3 Integrin ◽

Intact Cells ◽

Cd38 Antigen

Soluble forms of membrane receptors are emerging candidates as physiological regulators of leukocyte trafficking. In the present study, we found that the soluble form of the CD38 antigen (sCD38) bears a binding domain of low affinity for a cellular receptor on U937 cells. Cross-linking and peptide-mapping studies confirmed the physical association and the identification of the U937 receptor as a 130 kDa protein. The binding of sCD38 to the receptor was differentially inhibited by several monoclonal antibodies against the CD31 cell-adhesion molecule. Thus the interaction was analysed through direct association of soluble and membrane CD38 with soluble recombinant murine CD31 with three N-terminal and with all six extracellular Ig domains. Cross-linking experiments on U937 intact cells, and ligand blot assays of the immunoprecipitated CD38 molecule, indicated that (i) the recognized epitope is determined by the tertiary structure of the molecule, and that (ii) the binding domain involved resides in the ectocellular portion of the CD31 molecule, more precisely in the first three N-terminal domains. A comparative functional activity between murine and human CD31 was also explored. The data presented suggest that (i) human CD31 bears a highly functional similarity with its murine counterpart, as it is a receptor in myeloid cells with more than one ligand (the αvβ3 integrin and the CD38 molecule), and that (ii) the activity of sCD38 as decoy molecule for CD31 may play an important role in cell-cell interactions in physiological and pathological conditions.

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Soluble form of the triggering receptor expressed on myeloid cells 1: An anti-inflammatory mediator?

Intensive Care Medicine ◽

10.1007/s00134-005-0018-0 ◽

2006 ◽

Vol 32 (2) ◽

pp. 185-187 ◽

Cited By ~ 17

Author(s):

Sébastien Gibot ◽

Frederic Massin

Keyword(s):

Inflammatory Mediator ◽

Myeloid Cells ◽

Soluble Form ◽

Anti Inflammatory

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Siglec-15: a potential regulator of osteoporosis, cancer, and infectious diseases

Journal of Biomedical Science ◽

10.1186/s12929-019-0610-1 ◽

2020 ◽

Vol 27 (1) ◽

Cited By ~ 7

Author(s):

Takashi Angata

Keyword(s):

Infectious Diseases ◽

Therapeutic Target ◽

Chemical Biology ◽

Osteoclast Differentiation ◽

Myeloid Cells ◽

Exact Nature ◽

Cancer Microenvironment ◽

Microbial Infection ◽

Potential Therapeutic Target ◽

Biological Context

AbstractSiglec-15 is a member of the Siglec family of glycan-recognition proteins, primarily expressed on a subset of myeloid cells. Siglec-15 has been known to be involved in osteoclast differentiation, and is considered to be a potential therapeutic target for osteoporosis. Recent studies revealed unexpected roles of Siglec-15 in microbial infection and the cancer microenvironment, expanding the potential pathophysiological roles of Siglec-15. Chemical biology has advanced our understanding of the nature of Siglec-15 ligands, but the exact nature of Siglec-15 ligand depends on the biological context, leaving plenty of room for further exploration.

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