TREM-1 Modulation Strategies for Sepsis

Siskind, Sara; Wang, Ping

doi:10.3389/fimmu.2022.907387

Cited by 28 publications

(44 citation statements)

References 99 publications

(196 reference statements)

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“…Macrophages, which are radioresistant compared to neutrophils, potentially play a crucial role as innate immune cells for infections after radiation injury ( 5 ). TREM-1, a receptor expressed in myeloid cells, including macrophages, is upregulated in inflammatory diseases such as sepsis and its upregulation dysregulates the innate immune system, resulting in tissue injuries and poor prognosis ( 6 ). Therefore, we focused on TREM-1 expression on macrophages after radiation exposure and investigated the association between TREM-1 and prognosis in radiation injury.…”

Section: Discussionmentioning

confidence: 99%

“…The triggering receptor expressed on myeloid cells-1 (TREM-1) can be expressed on monocytes, macrophages, neutrophils, and dendritic cells. TREM-1 has been identified as a critical amplifier of inflammation to dysregulate immune response in various diseases ( 6 ). In septic patients, TREM-1 is upregulated on monocytes ( 7 ) and neutrophils ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

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Radiation upregulates macrophage TREM-1 expression to exacerbate injury in mice

Yamaga

Murao

et al. 2023

Front. Immunol.

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IntroductionExposure to high-dose ionizing radiation causes tissue injury, infections and even death due to immune dysfunction. The triggering receptor expressed on myeloid cells-1 (TREM-1) has been demonstrated to critically amplify and dysregulate immune responses. However, the role of TREM-1 in radiation injury remains unknown. Extracellular cold-inducible RNA-binding protein (eCIRP), a new damage-associated molecular pattern, is released from activated or stressed cells during inflammation. We hypothesized that ionizing radiation upregulates TREM-1 expression via eCIRP release to worsen survivalMethodsRAW264.7 cells and peritoneal macrophages collected from C57BL/6 wild-type (WT) mice were exposed to 5- and 10-Gray (Gy) radiation. C57BL/6 WT and CIRP-/- mice underwent 10-Gy total body irradiation (TBI). TREM-1 expression on RAW264.7 cells and peritoneal macrophages in vitro and in vivo were evaluated by flow cytometry. eCIRP levels in cell culture supernatants and in peritoneal lavage isolated from irradiated mice were evaluated by Western blotting. We also evaluated 30-day survival in C57BL/6 WT, CIRP-/- and TREM-1-/- mice after 6.5-Gy TBI.ResultsThe surface protein and mRNA levels of TREM-1 in RAW264.7 cells were significantly increased at 24 h after 5- and 10-Gy radiation exposure. TREM-1 expression on peritoneal macrophages was significantly increased after radiation exposure in vitro and in vivo. eCIRP levels were significantly increased after radiation exposure in cell culture supernatants of peritoneal macrophages in vitro and in peritoneal lavage in vivo. Moreover, CIRP-/- mice exhibited increased survival after 6.5-Gy TBI compared to WT mice. Interestingly, TREM-1 expression on peritoneal macrophages in CIRP-/- mice was significantly decreased compared to that in WT mice at 24 h after 10-Gy TBI. Furthermore, 30-day survival in TREM-1-/- mice was significantly increased to 64% compared to 20% in WT mice after 6.5-Gy TBI.ConclusionOur data indicate that ionizing radiation increases TREM-1 expression in macrophages via the release of eCIRP, and TREM-1 contributes to worse survival after total body irradiation. Thus, targeting TREM-1 could have the potential to be developed as a novel medical countermeasure for radiation injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Radiation upregulates macrophage TREM-1 expression to exacerbate injury in mice

Yamaga

Murao

et al. 2023

Front. Immunol.

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“…Several of these genes have been linked to ARDS and inflammation and consequently, cytokine storms, as highlighted in the table. Of particular interest is TREM-1, which has been previously reported to accentuate lung injury during ARDS and has shown promise as an inflammatory biomarker and as therapeutic target for sepsis and septic shock [ 26 , 27 ]. It has been reported to function in regulating T-cell proliferation and activation of antigen presenting cells during the antiviral immune response by amplifying toll-like receptor (TLR)-initiated responses against microbial challenges [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Drug Repurposing Using Gene Co-Expression and Module Preservation Analysis in Acute Respiratory Distress Syndrome (ARDS), Systemic Inflammatory Response Syndrome (SIRS), Sepsis, and COVID-19

Mailem

Tayo

2022

Biology

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SARS-CoV-2 infections are highly correlated with the overexpression of pro-inflammatory cytokines in what is known as a cytokine storm, leading to high fatality rates. Such infections are accompanied by SIRS, ARDS, and sepsis, suggesting a potential link between the three phenotypes. Currently, little is known about the transcriptional similarity between these conditions. Herein, weighted gene co-expression network analysis (WGCNA) clustering was applied to RNA-seq datasets (GSE147902, GSE66890, GSE74224, GSE177477) to identify modules of highly co-expressed and correlated genes, cross referenced with dataset GSE160163, across the samples. To assess the transcriptome similarities between the conditions, module preservation analysis was performed and functional enrichment was analyzed in DAVID webserver. The hub genes of significantly preserved modules were identified, classified into upregulated or downregulated, and used to screen candidate drugs using Connectivity Map (CMap) to identify repurposed drugs. Results show that several immune pathways (chemokine signaling, NOD-like signaling, and Th1 and Th2 cell differentiation) are conserved across the four diseases. Hub genes screened using intramodular connectivity show significant relevance with the pathogenesis of cytokine storms. Transcriptomic-driven drug repurposing identified seven candidate drugs (SB-202190, eicosatetraenoic-acid, loratadine, TPCA-1, pinocembrin, mepacrine, and CAY-10470) that targeted several immune-related processes. These identified drugs warrant further study into their efficacy for treating cytokine storms, and in vitro and in vivo experiments are recommended to confirm the findings of this study.

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“…In an AD model, TREM-1 facilitated microglial phagocytosis of amyloid beta (Aβ) [ 54 ]. Numerous preclinical experiments have demonstrated that TREM-1 inhibition can inhibit macrophage and microglia activation, thereby attenuating the inflammatory response [ 55 ]. The above studies suggest that microglial activation interacts with TREM-1 expression and that this action is at least partially dependent on NF-κB signaling.…”

Section: Introductionmentioning

confidence: 99%

The role of triggering receptor expressed on myeloid cells-1 (TREM-1) in central nervous system diseases

Kan

Zhang

et al. 2022

Mol Brain

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Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily and is mainly expressed on the surface of myeloid cells such as monocytes, macrophages, and neutrophils. It plays an important role in the triggering and amplification of inflammatory responses, and it is involved in the development of various infectious and non-infectious diseases, autoimmune diseases, and cancers. In recent years, TREM-1 has also been found to participate in the pathological processes of several central nervous system (CNS) diseases. Targeting TREM-1 may be a promising strategy for treating these diseases. This paper aims to characterize TREM-1 in terms of its structure, signaling pathway, expression, regulation, ligands and pathophysiological role in CNS diseases.

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TREM-1 Modulation Strategies for Sepsis

Cited by 28 publications

References 99 publications

Radiation upregulates macrophage TREM-1 expression to exacerbate injury in mice

Radiation upregulates macrophage TREM-1 expression to exacerbate injury in mice

Drug Repurposing Using Gene Co-Expression and Module Preservation Analysis in Acute Respiratory Distress Syndrome (ARDS), Systemic Inflammatory Response Syndrome (SIRS), Sepsis, and COVID-19

The role of triggering receptor expressed on myeloid cells-1 (TREM-1) in central nervous system diseases

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