TREM-1 multimerization is essential for its activation on monocytes and neutrophils

Carrasco, Kévin; Boufenzer, Amir; Jolly, Lucie; Cordier, Hélène; Wang, Guanbo; Heck, Albert J. R.; Cerwenka, Adelheid; Vinolo, Emilie; Nazabal, Alexis; Kriznik, Alexandre; Launay, Pierre; Gibot, Sébastien; Derive, Marc

doi:10.1038/s41423-018-0003-5

Cited by 66 publications

(71 citation statements)

References 43 publications

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“…Monocytes also express TREM‐1, the level of which increases upon stimulation with LPS . LR12 dose‐dependently reduced TG supported by monocytes, in both unstimulated and stimulated cells (Figure A‐C).…”

Section: Resultsmentioning

confidence: 79%

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

Pillo

Carrasco²,

Brustolin

et al. 2020

Journal of Thrombosis and Haemostasis

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Background:New evidence has shown the link between inflammation and thrombosis. Triggering receptor expressed on myeloid cells-1 (TREM-1) is an immunoreceptor expressed mostly on neutrophils and monocytes/macrophages. TREM-1 acts as an amplifier of the inflammatory response, and its pharmacological inhibition displays protective effects in various models of inflammatory disorders, in particular by dampening coagulation abnormalities and thrombocytopenia observed during acute inflammation.Objectives: We aimed to decipher the role of TREM-1 in fostering thrombin generation. Methods:We measured thrombin generation (TG) by the use of calibrated automated thrombography with whole blood, and isolated primary human neutrophils and monocytes upon stimulation with lipopolysaccharide (LPS). Tissue factor (TF) expression was measured by flow cytometry and its activity by ELISA. Phosphatidylserine (PtdSer) exposure was determined by flow cytometry. A dodecapeptide (LR12) was used as a specific inhibitor of TREM-1. Results: LPS increased TG, TF expression, and activity, as well as the exposure of PtdSer on the surface of monocytes. LR12 dampened TF activity through the decrease of PtdSer exposure, leading to a reduction of thrombin generation. Conclusions: TREM-1 inhibition decreases thrombin generation and could be an interesting target for the development of new inhibitors of leukocyte-associated thrombotic activity. K E Y W O R D S monocytes, thrombin generation, TREM-1 | 455 di PiLLO et aL.

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Section: Resultsmentioning

confidence: 79%

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

Pillo

Carrasco²,

Brustolin

et al. 2020

Journal of Thrombosis and Haemostasis

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“…However, myricetin treatment abrogated the increase levels of TREM-1 gene and protein expression (Figures 7A-D). Activation of TREM-1 has been shown to trigger and aggravate inflammation, especially through synergism with TLRs signaling (13)(14)(15)(16); therefore, we further assessed the effects of myricetin on the mRNA expression of TLR2, TLR4, and its adapter protein MyD88. As expected, our result confirmed that myricetin treatment significantly inhibited TLR2/4-MyD88 signaling expression in livers from NASH mice.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The triggering receptor expressed on myeloid cells (TREM)-1 is a kind of immunoglobulin superfamily activation receptors express on neutrophils and monocyte macrophages (13,14). Upon activation, TREM-1 can trigger and augment inflammatory reaction, especially through synergism with toll-like receptors (TLRs) signaling in macrophages (13)(14)(15)(16). Moreover, several studies have already revealed that TREM-1 play an important role in regulating the activation of Kupffer cell and is associated with macrophages polarization, which amplifies acute and chronic inflammatory responses in diseases (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

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Myricetin Modulates Macrophage Polarization and Mitigates Liver Inflammation and Fibrosis in a Murine Model of Nonalcoholic Steatohepatitis

Yao

et al. 2020

Front. Med.

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This study aimed to investigate the beneficial effects of myricetin in a diet-induced nonalcoholic steatohepatitis (NASH) model and the underlying mechanism. C57BL/6J mice were fed a standard chow or the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 8 weeks with the treatment of myricetin (100 mg/kg) or vehicle by daily gavage. Hepatic inflammation, steatosis, fibrosis, and hepatic stellate cells (HSC) activation were assessed. We also analyzed M1 and M2 macrophages and its related markers in livers from NASH mice and in RAW264.7 macrophages stimulated by lipopolysaccharide (LPS) or interleukin 4 (IL-4) in vitro. Furthermore, we determined the effect of myricetin on the triggering receptor expressed on myeloid cells-1 (TREM-1), toll like receptor (TLR) 2 and 4, and myeloid differentiation factor 88 (MyD88) signaling both in livers from mice and in RAW264.7 cells stimulated by LPS. Our results revealed that myricetin remarkably ameliorated hepatic steatosis, inflammation, and inhibited hepatic macrophage infiltration in CDAHFD-fed mice. Myricetin-treated to CDAHFD-fed mice also inhibited liver fibrosis and HSC activation when compared with vehicle-treated to those mice. Moreover, myricetin inhibited M1 macrophage polarization and its relative markers in livers of NASH mice while induced M2 polarization. Similarly, in vitro study, myricetin inhibited the LPS-induced mRNA expression of M1 macrophages marker genes and induced IL-4-induced M2 macrophage marker genes in RAW264.7 macrophages. Mechanically, myricetin inhibited the expression of TREM-1 and TLR2/4-MyD88 signaling molecules in livers from NASH mice and in RAW264.7 macrophages stimulated by LPS in vitro. Additionally, myricetin inhibited the activation of nuclear factor (NF)-κB signaling and the phosphorylation of the signal transducer and activation of transcription 3 (STAT3) in LPS-stimulated RAW264.7 macrophages. Taken together, our data indicated that myricetin modulated the polarization of macrophages via inhibiting the TREM-1-TLR2/4-MyD88 signaling molecules in macrophages and therefore mitigated NASH and hepatic fibrosis in the CDAHFD-diet-induced NASH model in mice.

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“…LR-12 is shown to block TREM-1 and reduces its activation of monocyte/macrophage to form foam cells in atherosclerosis pathogenesis 67,95 . Furthermore, recently been found the multimerization of TREM-1 that causes its activation is inhibited by LR12 96 . Also, curcumin extracted from yellow pigment of turmeric has been shown to inhibit TREM-1 down streaming signaling.…”

Section: Therapeutics Of Cardiovascular Diseases Targeting Trem1 Pathwaymentioning

confidence: 99%

TREM-1; is It a Pivotal Target for Cardiovascular Diseases?

Kouassi

Gunasekar

Agrawal

et al. 2018

Preprint

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Cardiovascular Diseases (CVDs) are still menacing and killing adults worldwide, notwithstanding the tremendous effort, to decrease their related mortality and morbidity. Lately, a growing body of evidences indicated that inflammation plays a pivotal role in the pathogenesis and complications of CVDs. A receptor of the immunoglobulin superfamily, triggering receptor expressed on myeloid cells -1 (TREM-1) was shown to induce and to amplify the inflammation in both acute and chronic diseases pathogenesis and progression and hence it is one of the important factors that complicates CVDs. Thus, studies endeavored to investigate the role played by TREM-1 in CVDs with respect to their etiologies, complications and possible therapeutics. We examined here, for the first time, the most relevant studies regarding TREM-1 involvement in CVDs. We summarized the finding after critically analyzing them and made some suggestions for furtherance of the investigations with the aim to utilize TREM-1 and its pathways for diagnostic, management and prognosis of CVDs. Overall, TREM-1 was found to be involved in the pathogenesis of acute and chronic cardiovascular conditions like Acute myocardial infraction (AMI) and atherosclerosis as well. Although most therapeutic approaches are yet to be elucidated, present research outcome displays a promising future to utilize TREM-1 pathway as potential target to understand and manage CVDs.

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TREM-1 multimerization is essential for its activation on monocytes and neutrophils

Cited by 66 publications

References 43 publications

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

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

Myricetin Modulates Macrophage Polarization and Mitigates Liver Inflammation and Fibrosis in a Murine Model of Nonalcoholic Steatohepatitis

TREM-1; is It a Pivotal Target for Cardiovascular Diseases?

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