Triggering receptor expressed on myeloid cells-1 deletion in mice attenuates high-fat diet-induced obesity.

Introduction: The low-grade inflammatory state present in obesity leads to the development and perpetuation of comorbidities associated with obesity. Our laboratory has been working for several years on an amplification loop of the inflammatory response mediated by TREM-1 (Triggering Receptor of Expressed on Myeloid Cells-1). It is implicated in many acute (septic shock) and chronic (IBD) inflammatory diseases. Previously, TREM-1 has been shown to be overexpressed in adipose and liver tissue in obese and diabetic patients, but its impact has never been characterized in these pathologies. Methods: Our hypothesis is that TREM-1 plays a major role in the generation and perpetuation of inflammation during obesity and its associated complication (Insulin resistance and cardiac dysfunction). We assessed TREM-1 protein expression by western blot and immunofluorescence in omental and subcutaneous (pre-)adipocyte. Moreover, we submitted mice to a high-fat diet and investigated the effects of the genetic Trem1 deletion (trem1 KO mice). Results: We showed, for the first time, that TREM-1 is expressed and is functional in subcutaneous and omental (pre-)adipocytes. In the mouse model of high-fat diet-induced obesity, we found that Trem1 suppression limited weight gain, insulin resistance and inflammation in white adipose tissue and liver. Discussion/conclusion: Our results reveal the trem1 KO model can be viewed as a preventive model and that TREM-1 seems to play an important role in the development of obesity and its associated complication. It could therefore be a new therapeutic target in this context.

Potentiation of NETs release is novel characteristic of TREM-1 activation and the pharmacological inhibition of TREM-1 could prevent from the deleterious consequences of NETs release in sepsis.

During sepsis, neutrophil activation induces endothelial cell (EC) dysfunction partly through neutrophil extracellular trap (NET) release. The triggering receptor expressed on myeloid cell-1 (TREM-1) is an orphan immune receptor that amplifies the inflammatory response mediated by Toll-like receptor-4 (TLR4) engagement. Although the key role of TLR4 signaling in NETosis is known, the role of TREM-1 in this process has not yet been investigated. Here, we report that TREM-1 potentiates NET release by human and murine neutrophils and is a component of the NET structure. In contrast, pharmacologic inhibition or genetic ablation of TREM-1 decreased NETosis in vitro and during experimental septic shock in vivo. Moreover, isolated NETs were able to activate ECs and impair vascular reactivity, and these deleterious effects were dampened by TREM-1 inhibition. TREM-1 may, therefore, constitute a new therapeutic target to prevent NETosis and associated endothelial dysfunction.

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

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.