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

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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Relationships between genetic polymorphisms of triggering receptor expressed on myeloid cells-1 and septic shock in a Chinese Han population

World Journal of Emergency Medicine ◽

10.5847/wjem.j.1920-8642.2015.02.007 ◽

2015 ◽

Vol 6 (2) ◽

pp. 123 ◽

Cited By ~ 7

Author(s):

Liang-shan Peng ◽

Juan Li ◽

Gao-sheng Zhou ◽

Lie-hua Deng ◽

Hua-guo Yao

Keyword(s):

Septic Shock ◽

Genetic Polymorphisms ◽

Myeloid Cells ◽

Chinese Han Population ◽

Chinese Han ◽

Han Population

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Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Inhibits Steroidogenesis in Adrenocortical Cell by Macrophage-derived Exosomes in Lipopolysaccharide-induced Septic Shock

10.21203/rs.3.rs-57909/v1 ◽

2020 ◽

Author(s):

Hui Ye ◽

Pinhao Li ◽

Qian Zhai ◽

Ping Fang ◽

Shiyue Yang ◽

...

Keyword(s):

Septic Shock ◽

Ex Vivo ◽

Early Stage ◽

Myeloid Cells ◽

Wild Type ◽

Steroidogenic Enzymes ◽

Adrenocortical Cells ◽

Steroid Synthesis ◽

Knock Out

Abstract Background: Endogenously produced glucocorticoids exhibit immunomodulating properties and are of pivotal importance for sepsis outcome. Uncontrolled activation of the immune-adrenal crosstalk increases the risk of sepsis-related death. Triggering receptor expressed on myeloid cells-2 (TREM2) is richly expressed on macrophages and has been demonstrated to improve outcome of sepsis by enhancing elimination of pathogens. However, the role and mode of action of macrophage TREM2 on adrenocortical steroidogenesis remains unclear in septic shock.Methods: The acute septic shock model was established by intraperitoneally challenging wild-type (WT) and TREM2 knock-out (Trem2-/-) mice with lipopolysaccharide (30 mg/kg). The mice were assessed for TREM2 expression and local inflammation in adrenal gland and synthesis of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) in vivo. Bone marrow-derived macrophages or macrophage-derived exosomes were isolated from WT and Trem2-/- mice and co-cultured with adrenocortical cells. The expression of steroidogenic enzymes and corticosterone production were assessed.Results: Genetic deficiency of TREM2 caused significantly higher corticosterone levels (326.6 ± 73.0 ng/ml in Trem2-/- mice vs. 151.1 ± 58.9 ng/ml in WT mice; p < 0.001) at the early stage of LPS-induced septic shock. While TREM2 deficiency neither increased CRH and ACTH, nor exacerbated the inflammation in adrenocortical tissue during septic shock. Ex vivo study revealed that Trem2-/- macrophages significantly promoted the expression of steroidogenic enzymes and increased production of corticosterone (27.73 ± 1.78 ng/ml in Trem2-/- mice vs. 22.96 ± 1.94 ng/ml in W T mice; p < 0.01). Furthermore, Trem2-/- macrophage-derived exosomes were able to mimic Trem2-/- macrophages in enhancing adrenocortical steroidogenesis. Conclusions: At the early stage of lipopolysaccharide-induced septic shock, macrophage TREM2 inhibited the steroid synthesis and corticosterone production in adrenocortical cells, which may be partially associated with macrophage-derived exosomes.

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IMMATURE GRANULOCYTES, IMMATURE MYELOID CELLS AND ERYTHROBLASTS PREDICT OUTCOME IN SEPSIS AND SEPTIC SHOCK

Shock ◽

10.1097/00024382-200403001-00399 ◽

2004 ◽

Vol 21 (Supplement) ◽

pp. 100

Author(s):

A Nierhaus ◽

B Montag ◽

D Frings ◽

A Heydorn ◽

J Schulte Esch

Keyword(s):

Septic Shock ◽

Myeloid Cells ◽

Immature Myeloid Cells ◽

Sepsis And Septic Shock

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Targeted endothelial gene deletion of triggering receptor expressed on myeloid cells-1 protects mice during septic shock

Cardiovascular Research ◽

10.1093/cvr/cvy018 ◽

2018 ◽

Vol 114 (6) ◽

pp. 907-918 ◽

Cited By ~ 11

Author(s):

Lucie Jolly ◽

Kevin Carrasco ◽

Marc Derive ◽

Jérémie Lemarié ◽

Amir Boufenzer ◽

...

Keyword(s):

Septic Shock ◽

Gene Deletion ◽

Myeloid Cells

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High Levels of Soluble Triggering Receptor Expressed on Myeloid Cells–Like Transcript (TLT)-1 Are Associated With Acute Respiratory Distress Syndrome

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029618774149 ◽

2018 ◽

Vol 24 (7) ◽

pp. 1122-1127 ◽

Cited By ~ 3

Author(s):

Jessica Morales-Ortíz ◽

Matthew T. Rondina ◽

Samuel M. Brown ◽

Colin Grissom ◽

A. Valance Washington

Keyword(s):

Septic Shock ◽

Acute Respiratory Distress Syndrome ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Plasma Levels ◽

Distress Syndrome ◽

White Blood Cells ◽

Myeloid Cells ◽

Control Group ◽

Healthy Controls

We have previously demonstrated that elevated levels of soluble triggering receptor expressed on myeloid cells–like transcript 1 (sTLT-1) modulate sepsis-induced inflammation and positively correlate with disseminated intravascular coagulation (DIC). Here, we evaluate the clinical implications of plasma sTLT-1 in acute respiratory distress syndrome (ARDS), which is common in sepsis patients. Soluble TLT-1 levels in the plasma of ARDS patients (n = 20) were determined by slot blot analysis and were compared with clinical parameters to identify significant associations. For comparisons to ARDS, we also measured sTLT-1 levels in matched healthy controls (n = 20). Of the 20 plasma samples evaluated from patients with ARDS, 60% were diagnosed with sepsis and 40% were diagnosed with septic shock. The white blood cells (WBCs) of patients with ARDS were found to be significantly elevated over healthy controls with a mean of 13 k/µL over 6.2 k/µL, respectively. The mean plasma levels of sTLT-1 were 148.4 pg/mL ± 16.52 in the patient cohort and 92.45 pg/mL ± 17.12 in the control group ( P = .02). No statistically significant correlations were found between plasma levels of sTLT-1 and WBCs, sepsis, septic shock or acute physiologic, and chronic health evaluation II scores. A statistically significant inverse correlation (r2 = .25, P < .05) was found between plasma sTLT-1 and peripheral platelet counts in patients with ARDS. Increased levels of sTLT-1 in ARDS patients suggest that TLT-1 may mediate the pathobiology of ARDS. Moreover, our data are the first to demonstrate a specific platelet marker in the development of ARDS due to sepsis.

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Diagnostic effectiveness of soluble triggering receptor expressed on myeloid cells-1 in sepsis, severe sepsis and septic shock

Archives of Medical Science ◽

10.5114/aoms.2018.73090 ◽

2019 ◽

Vol 15 (3) ◽

pp. 713-721 ◽

Cited By ~ 2

Author(s):

Monika Jedynak ◽

Andrzej Siemiątkowski ◽

Robert Milewski ◽

Barbara Mroczko ◽

Maciej Szmitkowski

Keyword(s):

Septic Shock ◽

Severe Sepsis ◽

Myeloid Cells ◽

Sepsis And Septic Shock

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PDK1/mTOR Signaling in Myeloid Cells Differentially Regulates the Early and Late Stages of Sepsis

Mediators of Inflammation ◽

10.1155/2020/5437175 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Juan Du ◽

Guoli Li ◽

Mingxi Hua ◽

Junyan Han ◽

Yu Hao ◽

...

Keyword(s):

Septic Shock ◽

Knockout Mice ◽

Late Stage ◽

Gold Standard ◽

Cecal Ligation ◽

Myeloid Cells ◽

Metabolic Signaling ◽

Important Regulator ◽

Late Stages ◽

Stimulation Of

The cecal ligation and perforation (CLP) model is the gold standard for the polymicrobial sepsis. In the CLP mice, the myeloid cells play an important role in septic shock. The phenotypes and the activation state of the macrophage and neutrophil correlate with their metabolism. In the present study, we generated the specific myeloid deletion of PDK1 and mTOR mice, which was the important regulator of metabolic signaling. We found that the deletion of PDK1 in the myeloid cells could aggravate the early septic shock in the CLP mice, as well as the deletion of mTORC1 and mTORC2. Moreover, PDK1 deletion attenuated the inflammation induced by LPS in the late stage on CLP mice, which was exacerbated in mTORC1 and mTORC2 knockout mice. Both PDK1 and mTORC1/2 could not only regulate the cellular metabolism but also play important roles on the myeloid cells in the secondary stimulation of sepsis. The present study will provide a theoretical prospect for the therapy of the septic shock in different stages.

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