Inhibition of triggering receptor expressed on myeloid cells‐1 impairs thrombin generation

Pillo, Elisa Di; Carrasco, Kévin; Brustolin, Benjamin; Boufenzer, Amir; Jolly, Lucie; Derive, Marc; Lacolley, Patrick; Régnault, V.; Gibot, Sébastien

doi:10.1111/jth.14677

Cited by 9 publications

(5 citation statements)

References 38 publications

(48 reference statements)

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“…TREM-1 is an immunoreceptor expressed mostly on neutrophils and monocytes/macrophages, and interestingly, recently, it is identified that acts on endothelial cells and regulates thrombin generation [ 37 , 38 ]. Current evidence showed that TREM-1 appears to augment inflammatory responses in infectious diseases [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

TREM-1 Modulates Dendritic Cells Maturation and Dendritic Cell-Mediated T-Cell Activation Induced by ox-LDL

Wang

Huang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Atherosclerosis is a chronic inflammatory disease. The triggering receptor expressed on myeloid cells-1 (TREM-1) plays a crucial role in inflammatory diseases; recently, it was identified as a major upstream proatherogenic receptor, but its mechanism is still unclear. In this study, we explore the role of TREM-1 on dendritic cells maturation and inflammatory responses induced by ox-LDL and its possible mechanism. Human dendritic cells were differentiated from blood monocytes and treated with ox-LDL. Naive autologous T cells were cocultured with pretreated DCs or treated directly. The expression of TREM-1 and inflammatory factors were evaluated by real-time PCR, western blot, and ELISA methods. And the expression of immune factors to evaluate the DCs maturation and T-cell activation were determined by the FACS. Our study showed that ox-LDL induced TREM-1 expression, DC maturation, and T-cell activation. T cells exposed to ox-LDL-treated DCs produced interferon-γ and interleukin-17 (IL-17). Blocking TREM-1 suppressed the DC maturation, showing lower expression of CD1a, CD40, CD86, CD83, and HLA-DR, and limited their production of tumor necrosis factor-alpha (TNF-α), IL-1β, IL-6, and monocyte chemoattractant protein-1 (MCP-1), meanwhile increased transforming growth factor-β(TGF-β) and IL-10 production. Ox-LDL induced miR-155, miR-27, Let-7c, and miR-185 expression; however, TREM-1 inhibiting decreased miRNA-155 expression. Furthermore, silencing miRNA-155 restores SOCS1 repression induced by ox-LDL. Experiments with T cells derived from carotid atherosclerotic plaques or healthy individuals showed similar results. Our results uncover a new link between ox-LDL and TREM-1 and may provide insight into this interaction in the context of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

TREM-1 Modulates Dendritic Cells Maturation and Dendritic Cell-Mediated T-Cell Activation Induced by ox-LDL

Wang

Huang

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…An increased presence of inflammation, neointimal formation, medial thickening, and plaque formation in RAPAs treated with scrambled peptide compared to LR12-treated arteries in this study supports the potency of ox-LDL in inducing plaque formation and inflammatory cell recruitment and the beneficial effects of LR12 peptide in attenuating inflammation and plaque formation [ 15 , 17 , 18 ]. This difference may have been associated with the effects of LR12, which has previously been shown to dampen the pro-thrombogenesis effects of TREM-1 [ 19 ]. LR12 inhibits the expression of tissue factors on monocytes and may reduce their activity in leukocyte-associated thrombosis.…”

Section: Discussionmentioning

confidence: 99%

Targeting Oncostatin M Receptor to Attenuate Carotid Artery Plaque Vulnerability in Hypercholesterolemic Microswine

Trinh,,

Shin,,

Rai,

et al. 2024

Cardiol Cardiovasc Med

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Atherosclerosis is a chronic inflammatory disease that leads to acute embolism via the formation of atherosclerotic plaques. Plaque formation is first induced by fatty deposition along the arterial intima. Inflammation, bacterial infection, and the released endotoxins can lead to dysfunction and phenotypic changes of vascular smooth muscle cells (VSMCs), advancing the plaque from stable to unstable form and prone to rupture. Stable plaques are characterized by increased VSMCs and less inflammation while vulnerable plaques develop due to chronic inflammation and less VSMCs. Oncostatin M (OSM), an inflammatory cytokine, plays a role in endothelial cells and VSMC proliferation. This effect of OSM could be modulated by p27 KIP1 , a cyclin-dependent kinase (CDK) inhibitor. However, the role of OSM in plaque vulnerability has not been investigated. To better understand the role of OSM and its downstream signaling including p27 KIP1 in plaque vulnerability, we characterized the previously collected carotid arteries from hyperlipidemic Yucatan microswine using hematoxylin and eosin stain, Movat Pentachrome stain, and gene and protein expression of OSM and p27 KIP1 using immunostaining and real-time polymerase chain reaction. OSM and p27 KIP1 expression in carotid arteries with angioplasty and treatment with either scrambled peptide or LR12, an inhibitor of triggering receptor expressed on myeloid cell (TREM)-1, were compared between the experimental groups and with contralateral carotid artery. The results of this study elucidated the presence of OSM and p27 KIP1 in carotid arteries with plaque and their association with arterial plaque and vulnerability. The findings suggest that targeting OSM and p27 KIP1 axis regulating VSMC proliferation may have therapeutic significance to stabilize plaque.

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“…TREM1 accelerates thrombin generation by inducing TF secretion and is an interesting target for investigating novel inhibitors of thrombotic activity. [ 46 ] In addition, TREM1 intervention partially compensates for FOXJ2‐ and SLAMF8‐induced TF secretion. These results provide novel evidence that FOXJ2 activation contributes to the pathogenesis of APS by repressing SLAMF8/TREM1‐mediated autophagy and inducing related inflammation and thrombosis.…”

Section: Discussionmentioning

confidence: 99%

H3K4me3‐Mediated FOXJ2/SLAMF8 Axis Aggravates Thrombosis and Inflammation in β2GPI/Anti‐β2GPI‐Treated Monocytes

Tan,

Qiao,

Yang

et al. 2024

Advanced Science

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Antiphospholipid syndrome (APS) is characterized by thrombus formation, poor pregnancy outcomes, and a proinflammatory response. H3K4me3‐related monocytes activation are key regulators of APS pathogenesis. Therefore, H3K4me3 CUT&Tag and ATAC‐seq are performed to examine the epigenetic profiles. The results indicate that the H3K4me3 signal and chromatin accessibility at the FOXJ2 promoter are enhanced in an in vitro monocyte model by stimulation with β2GPI/anti‐β2GPI, which mimics APS, and decreases after OICR‐9429 administration. Furthermore, FOXJ2 is highly expressed in patients with primary APS (PAPS) and is the highest in patients with triple‐positive antiphospholipid antibodies (aPLs). Mechanistically, FOXJ2 directly binds to the SLAMF8 promoter and activates SLAMF8 transcription. SLAMF8 further interacts with TREM1 to stimulate TLR4/NF‐κB signaling and prohibit autophagy. Knockdown of FOXJ2, SLAMF8, or TREM1 blocks TLR4/NF‐κB and provokes autophagy, subsequently inhibiting the release of inflammatory and thrombotic indicators. A mouse model of vascular APS is established via β2GPI intraperitoneal injection, and the results suggest that OICR‐9429 administration attenuates the inflammatory response and thrombus formation by inactivating FOXJ2/SLAMF8/TREM1 signaling. These findings highlight the overexpression of H3K4me3‐mediated FOXJ2 in APS, which consequently accelerates APS pathogenesis by triggering inflammation and thrombosis via boosting the SLAMF8/TREM1 axis. Therefore, OICR‐9429 is a promising candidate drug for APS therapy.

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Inhibition of triggering receptor expressed on myeloid cells‐1 impairs thrombin generation

Cited by 9 publications

References 38 publications

TREM-1 Modulates Dendritic Cells Maturation and Dendritic Cell-Mediated T-Cell Activation Induced by ox-LDL

TREM-1 Modulates Dendritic Cells Maturation and Dendritic Cell-Mediated T-Cell Activation Induced by ox-LDL

Targeting Oncostatin M Receptor to Attenuate Carotid Artery Plaque Vulnerability in Hypercholesterolemic Microswine

H3K4me3‐Mediated FOXJ2/SLAMF8 Axis Aggravates Thrombosis and Inflammation in β2GPI/Anti‐β2GPI‐Treated Monocytes

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