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

Boufenzer, Amir; Carrasco, Kévin; Jolly, Lucie; Brustolin, Benjamin; Di-Pillo, Elisa; Derive, Marc; Gibot, Sébastien

doi:10.1038/s41423-020-00591-7

Cited by 42 publications

(33 citation statements)

References 60 publications

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“…Therefore, our study highlights the excessive activation of stress-responsive pathways and TLR signaling in SMCs at the onset of TAAD. It is also noteworthy that TREM1 signaling in macrophages partners with TLR signaling 53 . Medical therapies targeting DAMPs and TLR signaling may also serve as a promising way to mitigate the progression of TAAD.…”

Section: Discussionmentioning

confidence: 99%

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Single-cell RNA sequencing identifies an Il1rn+/Trem1+ macrophage subpopulation as a cellular target for mitigating the progression of thoracic aortic aneurysm and dissection

et al. 2022

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Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition characterized by medial layer degeneration of the thoracic aorta. A thorough understanding of the regulator changes during pathogenesis is essential for medical therapy development. To delineate the cellular and molecular changes during the development of TAAD, we performed single-cell RNA sequencing of thoracic aortic cells from β-aminopropionitrile-induced TAAD mouse models at three time points that spanned from the early to the advanced stages of the disease. Comparative analyses were performed to delineate the temporal dynamics of changes in cellular composition, lineage-specific regulation, and cell–cell communications. Excessive activation of stress-responsive and Toll-like receptor signaling pathways contributed to the smooth muscle cell senescence at the early stage. Three subpopulations of aortic macrophages were identified, i.e., Lyve1+ resident-like, Cd74high antigen-presenting, and Il1rn+/Trem1+ pro-inflammatory macrophages. In both mice and humans, the pro-inflammatory macrophage subpopulation was found to represent the predominant source of most detrimental molecules. Suppression of macrophage accumulation in the aorta with Ki20227 could significantly decrease the incidence of TAAD and aortic rupture in mice. Targeting the Il1rn+/Trem1+ macrophage subpopulation via blockade of Trem1 using mLR12 could significantly decrease the aortic rupture rate in mice. We present the first comprehensive analysis of the cellular and molecular changes during the development of TAAD at single-cell resolution. Our results highlight the importance of anti-inflammation therapy in TAAD, and pinpoint the macrophage subpopulation as the predominant source of detrimental molecules for TAAD. Targeting the IL1RN+/TREM1+ macrophage subpopulation via blockade of TREM1 may represent a promising medical treatment.

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Section: Discussionmentioning

confidence: 99%

“…To pharmacologically inhibit Trem1, a dodecapeptide, murine LR12 (LQEEDTGEYGCV; mLR12) 53 was chemically synthesized (SBS Genetech, China), and COOH terminally amidated. Following purification, the purity was above 98%, which was determined by high-performance liquid chromatography and mass spectrometry.…”

Section: Methodsmentioning

confidence: 99%

Single-cell RNA sequencing identifies an Il1rn+/Trem1+ macrophage subpopulation as a cellular target for mitigating the progression of thoracic aortic aneurysm and dissection

et al. 2022

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“…Histones can also act as stimulators to TLR signaling pathways which drive the production of pro-inflammatory cytokines (Xu et al, 2009;Allam et al, 2012). Recently, the triggering receptor expressed on myeloid cell-1 (TREM-1) has been identified to potentiate NETosis and impair vascular activity (Murao et al, 2020;Boufenzer et al, 2021). Other components of NETs such as DNA and granule proteins have also been discovered to play a procoagulant role in sepsis (Kannemeier et al, 2007;Massberg et al, 2010;Iba et al, 2014).…”

Section: Detrimental Role Of Nets In Sepsismentioning

confidence: 99%

Targeting Neutrophils in Sepsis: From Mechanism to Translation

et al. 2021

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Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Although our understanding in the pathophysiological features of sepsis has increased significantly during the past decades, there is still lack of specific treatment for sepsis. Neutrophils are important regulators against invading pathogens, and their role during sepsis has been studied extensively. It has been suggested that the migration, the antimicrobial activity, and the function of neutrophil extracellular traps (NETs) have all been impaired during sepsis, which results in an inappropriate response to primary infection and potentially increase the susceptibility to secondary infection. On the other hand, accumulating evidence has shown that the reversal or restoration of neutrophil function can promote bacterial clearance and improve sepsis outcome, supporting the idea that targeting neutrophils may be a promising strategy for sepsis treatment. In this review, we will give an overview of the role of neutrophils during sepsis and discuss the potential therapeutic strategy targeting neutrophils.

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“…TREM-1 (triggering receptor expressed on myeloid cells-1) is a transmembrane receptor expressed by innate immune cells, including endothelial cells and platelets. TREM-1 is a crucial mediator of septic shock that acts by synergizing with Toll-like receptors (TLRs) to amplify the inflammatory responses to pathogens, thus promoting sepsis-induced immune dysregulation and organ dysfunction [ 1 – 3 ].…”

mentioning

confidence: 99%