Myeloid Cells-1 Research Articles

Diagnostic and prognostic predictive values of triggering receptor expressed on myeloid cell-1 expression in neonatal sepsis: A meta-analysis and systematic review

ObjectiveThe purpose of this systematic review was to explore the value of the expression level of the triggering receptor expressed on myeloid cell-1 (TREM-1) in the diagnosis and prognosis of neonatal sepsis.MethodsA comprehensive search was performed to identify the diagnostic and prognostic predictive values of the TREM-1 expression level in neonatal sepsis. Based on the retrieval strategy, Cochrane Library, Embase, Ovid, ProQuest, PubMed, Scopus, and Web of Science databases were searched from inception to February 2022. Studies were included if they assessed the accuracy of TREM-1 expression in the diagnosis of neonatal sepsis and distinguished survival and death in neonatal sepsis. Two authors independently evaluated the study and extracted the data, including the first author of the literature, country, total study population, basic population characteristics of the study group and the control group, study design (observational studies), type of sample, sepsis onset, type of biomarker, assay method, cut-off, sensitivity, specificity, true positives (TP), false positives (FP), false negatives (FN), and true negatives (TN). A third party will be consulted if disputed. The accuracy of TREM-1 expression in the diagnosis and prognostic prediction of neonatal sepsis was evaluated by a bivariate mixed-effects model. The source of heterogeneity was explored through meta-regression analysis.ResultsThirteen articles that met the research criteria were included in qualitative analysis, and 11 of them were included in quantitative analysis. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the summary receiver operator characteristic (SROC) curve of soluble TREM-1 (sTREM-1) were 0.94 (95% CI: 0.82, 0.98), 0.87 (95% CI: 0.70, 0.95), 7.36 (95% CI: 2.75, 19.74), 0.07 (95% CI: 0.02, 0.24), 111.71 (95% CI: 13.24, 942.92), and 0.96 (95% CI: 0.94, 0.98), respectively. Meta-regression and subgroup analysis were used to investigate the heterogeneity, owing to non-threshold effects caused by types of test sample and research design. sTREM-1 as a biomarker for distinguishing survival and death in neonates with sepsis had pooled sensitivity, specificity, area under the SROC curve, PLR, NLR, and DOR of 0.95 (95% CI: 0.83, 0.99), 0.98 (95% CI: 0.68, 1.00), 0.99 (95% CI: 0.97, 0.99), 39.28 (95% CI: 2.13, 723.99), 0.05 (95% CI: 0.01, 0.19), and 789.61 (95% CI: 17.53, 35,560.72), respectively.ConclusionThe study showed that TREM-1 was a potential biomarker for the diagnosis and prognosis of neonatal sepsis. The biggest advantage of this study is that it is the first to comprehensively explore the role of TREM-1 expression in the diagnosis and prognosis of neonatal sepsis. However, there are some limitations in this study, such as the reduced number of clinical studies on TREM-1 expression as a biomarker of neonatal sepsis, regional bias, and differences in detection methods. Hence, more large-scale and high-quality studies are needed to improve diagnostic accuracy.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022338041.

SerpinB3 as a Pro-Inflammatory Mediator in the Progression of Experimental Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide. In 20-30% of patients, NAFLD can progress into non-alcoholic steatohepatitis (NASH), eventually leading to fibrosis, cirrhosis and hepatocellular carcinoma development. SerpinB3 (SB3), a hypoxia-inducible factor-2α dependent cysteine protease inhibitor, is up-regulated in hepatocytes during progressive NAFLD and proposed to contribute to disease progression. In this study we investigated the pro-inflammatory role of SB3 by employing phorbol-myristate acetate-differentiated human THP-1 macrophages exposed in vitro to human recombinant SB3 (hrSB3) along with mice overexpressing SB3 in hepatocytes (TG/SB3) or knockout for SB3 (KO/SB3) in which NASH was induced by feeding methionine/choline deficient (MCD) or a choline-deficient, L-amino acid defined (CDAA) diets. In vivo experiments showed that the induction of NASH in TG/SB3 mice was characterized by an impressive increase of liver infiltrating macrophages that formed crown-like aggregates and by an up-regulation of hepatic transcript levels of pro-inflammatory cytokines. All these parameters and the extent of liver damage were significantly blunted in KO/SB3 mice. In vitro experiments confirmed that hrSB3 stimulated macrophage production of M1-cytokines such as TNFα and IL-1β and reactive oxygen species along with that of TGFβ and VEGF through the activation of the NF-kB transcription factor. The opposite changes in liver macrophage activation observed in TG/SB3 or KO/SB3 mice with NASH were associated with a parallel modulation in the expression of triggering receptor expressed on myeloid cells-2 (TREM2), CD9 and galectin-3 markers, recently detected in NASH-associated macrophages. From these results we propose that SB3, produced by activated/injured hepatocytes, may operate as a pro-inflammatory mediator in NASH contributing to the disease progression.

Biological correlates of elevated soluble TREM2 in cerebrospinal fluid

Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells-2 (sTREM2) is an emerging biomarker of neuroinflammation in Alzheimer's disease (AD). Yet, sTREM2 expression has not been systematically evaluated in relation to concomitant drivers of neuroinflammation. While associations between sTREM2 and tau in CSF are established, we sought to determine additional biological correlates of CSF sTREM2 during the prodromal stages of AD by evaluating CSF Aβ species (Aβx-40), a fluid biomarker of blood-brain barrier integrity (CSF/plasma albumin ratio), and CSF biomarkers of neurodegeneration measured in 155 participants from the Vanderbilt Memory and Aging Project. A novel association between high CSF levels of both sTREM2 and Aβx-40 was observed and replicated in an independent dataset. Aβx-40 levels, as well as the CSF/plasma albumin ratio, explained additional and unique variance in sTREM2 levels above and beyond that of CSF biomarkers of neurodegeneration. The component of sTREM2 levels correlated with Aβx-40 levels best predicted future cognitive performance. We highlight potential contributions of Aβ homeostasis and blood-brain barrier integrity to elevated CSF sTREM2, underscoring novel biomarker associations relevant to disease progression and clinical outcome measures.

Lipocalin-2 Deficiency Reduces Hepatic and Hippocampal Triggering Receptor Expressed on Myeloid Cells-2 Expressions in High-Fat Diet/Streptozotocin-Induced Diabetic Mice.

Background: Lipocalin-2 (LCN2) is an acute-phase protein that has been linked to insulin resistance, diabetes, and neuroinflammatory diseases. Triggering receptor expressed on myeloid cells-2 (TREM2) has been also implicated in microglia-mediated neuroinflammation. However, the potential role of LCN2 on TREM2 in diabetic mouse models is not fully understood. Methods: We investigated hepatic and hippocampal TREM2 expressions in high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic LCN2 knockout (KO) mice. Results: In addition to increased serum LCN2 level, diabetic wild-type (WT) mice had insulin resistance and hepatic steatosis. However, LCN2 deletion attenuated these metabolic parameters in diabetic mice. We also found that LCN2 deletion reduced hepatic inflammation and microglial activation in diabetic mice. In particular, diabetic LCN2 KO mice had a reduction in hepatic and hippocampal TREM2 expressions compared with diabetic WT mice. Furthermore, we found that many TREM2-positive Kupffer cells and microglia in diabetic WT mice were reduced through LCN2 deletion. Conclusions: These findings indicate that LCN2 may promote hepatic inflammation and microglial activation via upregulation of TREM2 in diabetic mice.

Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and other inflammatory mediators in malaria by Plasmodium vivax during enteroparasites coinfection.

Malaria is a major health issue with more than 200 million cases occurring annually. Moreover, in Malaria endemic area are frequently observed Malaria-enteroparasite co-infections associated with the modulation of inflammatory response. In this aspect, biomarkers play an important role in the disease prognosis. This study aimed to evaluate inflammatory mediators in malaria during coinfection with enteroparasites. A subset of serum samples already collected was analyzed and divided into four groups: Malaria (n = 34), Co-infected (n = 116), Enteroparasite (n = 120) and Control (n = 95). The serum levels of sTREM-1 and IL-6 were measured by ELISA. TNF-α, and IL-10 levels were previously carried out by flow cytometry. Higher serum levels of sTREM-1 and IL-6 were showed in malaria patients compared to healthy controls. In co-infected malarial patients sTREM-1 serum levels were similar to control group. Interestingly, co-infected malaria patients showed IL-6 serum levels decreased compared to individuals only infected with P. vivax. However, in Malaria patients and co-infected there was a positive correlation between the IL-6 and IL-10 levels (P < 0.0001). This is the first report of sTREM-1 levels in P. vivax infected. Moreover, the results revealing a divergent effect of co-infection with the increased balance between pro-and anti-inflammatory cytokines and reduced IL-6 levels but increases the anemia occurrence. The results also highlight the potential use of IL-6 as a biomarker for P. vivax and enteroparasites coinfection.

Sulfavant A as the first synthetic TREM2 ligand discloses a homeostatic response of dendritic cells after receptor engagement

ObjectiveThe immune response arises from a fine balance of mechanisms that provide for surveillance, tolerance, and elimination of dangers. Sulfavant A (SULF A) is a sulfolipid with a promising adjuvant activity. Here we studied the mechanism of action of SULF A and addressed the identification of its molecular target in human dendritic cells (hDCs).MethodsAdjuvant effect and immunological response to SULF A were assessed on DCs derived from human donors. In addition to testing various reporter cells, target identification and downstream signalling was supported by a reverse pharmacology approach based on antibody blocking and gene silencing, crosstalk with TLR pathways, use of human allogeneic mixed lymphocyte reaction.ResultsSULF A binds to the Triggering Receptor Expressed on Myeloid cells-2 (TREM2) and initiates an unconventional maturation of hDCs leading to enhanced migration activity and up-regulation of MHC and co-stimulatory molecules without release of conventional cytokines. This response involves the SYK-NFAT axis and is compromised by blockade or gene silencing of TREM2. Activation by SULF A preserved the DC functions to excite the allogeneic T cell response, and increased interleukin-10 release after lipopolysaccharide stimulation.ConclusionSULF A is the first synthetic small molecule that binds to TREM2. The receptor engagement drives differentiation of an unprecedented DC phenotype (homeDCs) that contributes to immune homeostasis without compromising lymphocyte activation and immunogenic response. This mechanism fully supports the adjuvant and immunoregulatory activity of SULF A. We also propose that the biological properties of SULF A can be of interest in various physiopathological mechanisms and therapies involving TREM2.

TREM-1 Modulation Strategies for Sepsis.

The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor, which can be upregulated in inflammatory diseases as an amplifier of immune responses. Once activated, TREM-1 induces the production and release of pro-inflammatory cytokines and chemokines, in addition to increasing its own expression and circulating levels of the cleaved soluble extracellular portion of TREM-1 (sTREM-1). This amplification of the inflammatory response by TREM-1 has now been considered as a critical contributor to the dysregulated immune responses in sepsis. Studies have shown that in septic patients there is an elevated expression of TREM-1 on immune cells and increased circulating levels of sTREM-1, associated with increased mortality. As a result, a considerable effort has been made towards identifying endogenous ligands of TREM-1 and developing TREM-1 inhibitory peptides to attenuate the exacerbated inflammatory response in sepsis. TREM-1 modulation has proven a promising strategy for the development of therapeutic agents to treat sepsis. Therefore, this review encompasses the ligands investigated as activators of TREM-1 thus far and highlights the development and efficacy of novel inhibitors for the treatment of sepsis and septic shock.

Role of soluble triggering receptors expressed on myeloid cells-1 and 25-hydroxy vitamin D as early diagnostic markers of neonatal Ventilator-associated pneumonia: A prospective cohort study.

Ventilator-associated pneumonia (VAP) is one of the most common causes of nosocomial pneumonia in ventilated neonates. Nevertheless, its diagnosis is challenging due to the nonspecific clinical parameters and the lack of sensitive biomarkers. The main objective of this study was to compare soluble triggering receptors expressed on myeloid cells-1 (sTREM-1) and 25-hydroxy vitamin D as early predictors of neonatal VAP. This prospective cohort study included 85 ventilated neonates divided into the VAP group (n = 33) and the non-VAP group (n = 52). sTREM-1 levels in the endotracheal aspirate (ETA) and serum 25-hydroxy vitamin D levels were measured on the third and seventh days following mechanical ventilation. The Ethical and Research Committee approved the study at Tanta University Hospitals, Egypt (with the Approval code: 32751/12/18). The sTREM-1 cutoff value of >0.46 and >0.44 ng/ml at 3 and 7 days had a sensitivity of 93.94% and 96.97%, a specificity of 92.31% and 100%, and an area under the receiver operating characteristic curve (AUC) of 0.963 and 0.993, respectively, to predict the development of neonatal VAP. A serum 25-hydroxy vitamin D cutoff value of ≤17.5 ng/ml at 3 and 7 days had a sensitivity of 90.91% and 81.82%, a specificity of 75% and 78.85%, and area under the curve of 0.877 and 0.939, respectively. Both sTREM-1 in ETA and serum 25-hydroxy vitamin D could be used as early predictors of neonatal VAP, but sTREM-1 appears more useful.

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

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.

Abstract 195: Transcriptional Regulation Of Transcriptional Regulation Of Triggering Receptor Expressed On Myeloid Cells-1 By Low Shear Stress In A Three-dimensional Co-culture Of Coronary Artery Smooth Muscle Cells, Endothelial Cells, And Monocytes

Objectives: To identify transcriptional factors involved in the expression of Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) in response to low shear stress in an in-vitro model of coronary artery atherosclerosis. Methods: Human coronary artery smooth muscle cells were mixed with neutralized type I collagen solution and plated on glass coverslips. The human coronary artery endothelial cells (HCAECs) were then plated on top of the collagen gels followed by plating monocytes (THP-1 cells) on top of the HCAECs. After 48 h, the co-culture was treated with or without low shear stress (LSS, 5±3 dyne/cm 2 ) using the Flexcell Streamer for 30 min. Protein and mRNA of TREM-1 expression was assessed by immunofluorescence staining and real time RT-PCR. The expression of transcriptional factors involved in the expression of TREM-1 was assessed by ChIP assay. Results: LSS significantly stimulated TREM-1 expression as evidenced by IF staining and mRNA expression (fold increase vs control: 43.2 ± 9.7, Fig 1A and 1B ). ChIP assay demonstrated that, under control condition (no flow), NF-κB (p65), PU.1 and activation transcription factor 2 (ATF2) bound to TREM-1 promoter region 2, but not to region 1 ( Fig 2A ). In response to LSS for 30 min, however, binding of the NF-κB (p65), PU.1 and ATF2 to TREM-1 promoter region 2 was significantly enhanced; furthermore, LSS treatment induced binding of NF-κB (p65), PU.1 and ATF2 to TREM-1 promoter region 1 ( Fig 2B) . Conclusions: Transcriptional factors NF-κB (p65), PU.1 and ATF2 are critically involved in the TREM-1 expression in response to LSS stimulation in an in-vitro model of human coronary artery atherosclerosis.

STREM-1 promotes the phagocytic function of microglia to induce hippocampus damage via the PI3K\u2013AKT signaling pathway

Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a soluble form of TREM-1 released during inflammation. Elevated sTREM-1 levels have been found in neuropsychiatric systemic lupus erythematosus (NPSLE) patients; yet, the exact mechanisms remain unclear. This study investigated the role of sTREM-1 in brain damage and its underlying mechanism. The sTREM-1 recombinant protein (2.5 μg/3 μL) was injected into the lateral ventricle of C57BL/6 female mice. After intracerebroventricular (ICV) injection, the damage in hippocampal neurons increased, and the loss of neuronal synapses and activation of microglia increased compared to the control mice (treated with saline). In vitro. after sTREM-1 stimulation, the apoptosis of BV2 cells decreased, the polarization of BV2 cells shifted to the M1 phenotype, the phagocytic function of BV2 cells significantly improved, while the PI3K–AKT signal pathway was activated in vivo and in vitro. PI3K–AKT pathway inhibitor LY294002 reversed the excessive activation and phagocytosis of microglia caused by sTREM-1 in vivo and in vitro, which in turn improved the hippocampus damage. These results indicated that sTREM-1 activated the microglial by the PI3K–AKT signal pathway, and promoted its excessive phagocytosis of the neuronal synapse, thus inducing hippocampal damage. sTREM-1 might be a potential target for inducing brain lesions.

Paeoniflorin Attenuated TREM-1-Mediated Inflammation in THP-1 Cells.

Sepsis is caused by bacterial infections or viral infections. Clinically, there exist confirmed or highly suspected infection foci. Mortality caused by septic shock remains in a high rate even though antibiotic treatment works effectively. In this study, we treat THP-1 cells with 1 ug/mL LPS (lipopolysaccharide) and add paeoniflorin or LR-12 inhibitor. TREM-1 (triggering receptor expressed on myeloid cells-1), IL-6, IL-1β, and TNF-α (tumour necrosis factor alpha (a)-cachectin) were detected by ELISA and qRT-PCR, and western blotting is performed to detect related proteins in the NF-κB signaling pathway. As a result, paeoniflorin can significantly reduce the production of LPS-stimulated TREM-1 as well as inflammatory factors and attenuate the phosphorylation of NF-κB signaling pathway-related factors, such as p65 and IκBα. At the same time, the combined effect of paeoniflorin and LR-12 is more significant. The results of this study solidly prove that paeoniflorin plays a role in inhibiting TREM-1-mediated inflammation and the NF-κB pathway could be a potential mechanism of action.

Foam Cells in Atherosclerosis: Novel Insights Into Its Origins, Consequences, and Molecular Mechanisms.

Foam cells play a vital role in the initiation and development of atherosclerosis. This review aims to summarize the novel insights into the origins, consequences, and molecular mechanisms of foam cells in atherosclerotic plaques. Foam cells are originated from monocytes as well as from vascular smooth muscle cells (VSMC), stem/progenitor cells, and endothelium cells. Novel technologies including lineage tracing and single-cell RNA sequencing (scRNA-seq) have revolutionized our understanding of subtypes of monocyte- and VSMC-derived foam cells. By using scRNA-seq, three main clusters including resident-like, inflammatory, and triggering receptor expressed on myeloid cells-2 (Trem2hi) are identified as the major subtypes of monocyte-derived foam cells in atherosclerotic plaques. Foam cells undergo diverse pathways of programmed cell death including apoptosis, autophagy, necroptosis, and pyroptosis, contributing to the necrotic cores of atherosclerotic plaques. The formation of foam cells is affected by cholesterol uptake, efflux, and esterification. Novel mechanisms including nuclear receptors, non-coding RNAs, and gut microbiota have been discovered and investigated. Although the heterogeneity of monocytes and the complexity of non-coding RNAs make obstacles for targeting foam cells, further in-depth research and therapeutic exploration are needed for the better management of atherosclerosis.

Urine soluble triggering receptor expressed on myeloid cells-1 is a novel biomarker for active lupus nephritis: a case-control study.

To determine the value of plasma and urine sTREM-1 levels as a biomarker of lupus nephritis (LN) as well as extra-renal systemic lupus erythematosus (SLE). Consecutive adult patients with SLE attending a tertiary lupus clinic in 2016-2018 were prospectively divided into 3 groups according to SLEDAI-2K and renal-SLEDAI scores: active renal lupus (ARL), active non-renal lupus (ANL), and inactive lupus (IL). Blood and spot urine samples from each group and matched healthy subjects were analysed by means of ELISA for plasma and urine sTREM-1 levels. The cohort included 59 patients (mean age 41.5+2.9 years, 85% female) with SLE: 15 ARL, 14 ANL, and 30 IL. The ARL group had higher scores on the SLEDAI-2K and renal-SLEDAI, and higher urine protein/creatinine ratio than the other patient groups (p=0.0001 for all). Plasma sTREM-1 level was highest in the ANL group (p=0.0085). Urine sTREM-1 level was higher in the whole SLE cohort than the healthy controls (p=0.0249), and higher in the ARL group than the others (p=0.0044). Neither plasma nor urine sTREM-1 level was associated with non-renal SLE features. On Spearman correlation analysis, urine sTREM-1 level, but not plasma sTREM-1 level, was correlated positively with renal-SLEDAI score (r=0.34, p=0.018), inversely with serum C3 and C4 levels (r=-0.42, p=0.0027 and r=-0.28, p=0.056, respectively), and positively with proteinuria (UPCR: r=0.32, p=0.0305). Urine sTREM-1 might serve as a potential biomarker of active renal SLE.

Comparison of CRP, Procalcitonin, Neutrophil Counts, Eosinophil Counts, sTREM-1, and OPN between Pneumonic and Nonpneumonic Exacerbations in COPD Patients.

Introduction The patients with community-acquired pneumonia (CAP) and acute exacerbations of COPD (AECOPD) could have a higher risk of acute and severe respiratory illness than those without CAP in AECOPD. Consequently, early identification of pneumonia in AECOPD is quite important. Methods. 52 subjects with AECOPD + CAP and 93 subjects with AECOPD from two clinical centers were enrolled in this prospective observational study. The values of osteopontin (OPN), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), C-reactive protein (CRP), procalcitonin (PCT), eosinophil (EOS) counts, and neutrophil (Neu) counts in blood on the first day of admission and clinical symptoms were compared in AECOPD and AECOPD + CAP. In addition, subgroup analyses of biomarker difference were conducted based on the current use of inhaled glucocorticoids (ICS) or systemic corticosteroids (SCS). Results Patients with AECOPD + CAP had increased sputum volume, sputum purulence, diabetes mellitus, and longer hospital stays than AECOPD patients (p < 0.05). A clinical logistic regression model showed among the common clinical symptoms, purulent sputum can independently predict pneumonia in AECOPD patients after adjusting for a history of diabetes. At day 1, AECOPD + CAP patients had higher values of Neu, CRP, PCT, and OPN, while serum sTREM-1 levels and EOS counts were similar in the two groups. CRP fared best at predicting AECOPD with CAP (p < 0.05 for the test of difference), while OPN had similar accuracy with Neu, PCT, and purulent sputum (p > 0.05 for the test of difference). Multivariate analysis, including clinical symptoms and biomarkers, suggested that CRP ≥15.8 mg/dL at day 1 was a only promising predictor of pneumonia in AECOPD. CRP and OPN were not affected by ICS or SCS. Conclusions CRP ≥15.8 mg/dL is an ideal promising predictor of pneumonia in AECOPD, and its plasma level is not affected by ICS or SCS. The diagnostic performance of CRP is not significantly improved when combined with clinical symptoms or other markers (OPN, PCT, and Neu).

Role of triggering receptor expressed on myeloid cells-1 (TREM-1) in COVID-19 and other viral pneumonias: a systematic review and meta-analysis of clinical studies.

BackgroundTriggering receptor expressed on myeloid cells-1 (TREM-1) has emerged as an important inflammatory marker of immune response associated with severity and mortality outcomes in infection diseases, including viral pneumonias.Aim(1) To evaluate the expression of TREM-1 in patients with COVID-19 and other viral pneumonias compared to healthy individuals; and (2) to analyze the levels of these biomarkers according to disease severity.Materials and methodsThis review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Searches were performed in PubMed, Scopus, Embase, and Google Scholar. Studies were considered eligible if they were observational studies that provided data on the levels of TREM-1 in humans with viral pneumonia compared to healthy controls. The results of the meta-analysis were expressed as standardized mean difference (SMD) and an effect size of 0.8 was considered a large effect. A subgroup analysis was performed according to the disease severity.ResultsSeven studies were included in this systematic review. Four studies included patients with COVID-19 and three analyzed patients with different viruses. The meta-analysis was performed only with patients with COVID-19, which showed increased levels of soluble form of TREM-1 (sTREM-1) among patients with COVID-19 compared to healthy controls (SMD 1.53; 95% CI 0.53–2.52; p < 0.01). No differences were found between patients with mild-to-moderate COVID-19 and healthy controls, but higher levels of sTREM-1 were shown among patients with severe COVID-19 (SMD 1.83; 95% CI 0.77–2.88; p < 0.01). All three studies including patients with other viral pneumonias showed that TREM-1 levels were significantly elevated in infected patients compared with controls.ConclusionThese findings may provide evidence on the pro-inflammatory role of TREM-1 in these infections, contributing to the inflammatory profile and disease progression.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10787-022-00972-6.

TREM-1 Expression on the Surface of Neutrophils in Patients With Visceral Leishmaniasis Is Associated With Immunopathogenesis.

Visceral leishmaniasis (VL) is a systemic chronic and potentially fatal disease for humans. Mechanisms related to the dysregulation of the inflammatory response may be involved in both the pathogenesis and prognosis of VL. Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) is a receptor constitutively expressed on neutrophils and monocyte subsets. The protein serves to regulate and amplify inflammatory responses. This study aimed to evaluate the expression profile of TREM-1 on the surface of neutrophils from patients with VL at varying time points during leishmanicidal treatment. For this purpose, neutrophils were isolated from the peripheral blood of patients with VL at different stages of treatment, which include 0, 7, and 30 days after treatment. Surface TREM-1 expression was assessed by immunophenotyping neutrophil populations. In addition, the association of TREM-1 expression on the surface of neutrophils with clinical and laboratory parameters and serum levels of inflammatory mediators was also evaluated. Results demonstrate a lower surface expression of TREM-1 in VL patients in the absence of treatment. However, increased levels of TREM-1 expression were observed 7 and 30 days after the start of treatment, with levels similar to those of healthy controls. TREM-1 expression was directly correlated with lymphocyte and erythrocyte count and indirectly correlated with spleen and liver size. Furthermore, elevated levels of TREM-1 expression were also correlated with lower serum levels of interleukin (IL)-22. Taken together, these results suggest that infection by Leishmania infantum leads to depressed TREM-1 expression on the neutrophil surface and may contribute to the inflammatory imbalance that characterizes active VL disease.

A novel eCIRP/TREM-1 pathway inhibitor attenuates acute kidney injury

BackgroundExtracellular cold-inducible RNA-binding protein aggravates acute kidney injury after renal ischemia/reperfusion. Although extracellular cold-inducible RNA-binding protein activates triggering receptor expressed on myeloid cells-1, how this receptor and its antagonism with a novel peptide M3 affects acute kidney injury is poorly understood. We, therefore, hypothesize that inhibiting the extracellular cold-inducible RNA-binding protein/triggering receptor expressed on myeloid cells-1 pathway with M3 attenuates acute kidney injury. MethodsWild-type and triggering receptor expressed on myeloid cells-1-/- mice were subjected to bilateral 30-minute renal hilum clamping followed by reperfusion or sham. After 4 hours, wild-type mice received M3 (10 mg/kg BW) or normal saline intraperitoneally. After 24 hours, renal tissue and serum were collected for analysis. Additionally, wild-type mice were subjected to bilateral renal ischemia for 34 minutes and treated with M3 at 10 mg/kg BW or vehicle at the time of reperfusion. Survival was monitored for 10 days. ResultsAfter renal ischemia/reperfusion, triggering receptor expressed on myeloid cells-1 messenger ribonucleic acid expression increased by 9-fold in wild-type mice compared to sham mice. Wild-type mice also demonstrated significant increases in serum blood urea nitrogen, creatinine, and interleukin-6 and renal tissue levels of interleukin-6 and neutrophil gelatinase-associated lipocalin after renal ischemia/reperfusion compared to sham mice. Triggering receptor expressed on myeloid cells-1-/- mice demonstrated significant reductions in serum blood urea nitrogen, creatinine, and interleukin-6 compared to wild-type mice after renal ischemia/reperfusion. Levels of renal interleukin-6 and neutrophil gelatinase-associated lipocalin were also significantly decreased in the kidneys of triggering receptor expressed on myeloid cells-1-/- mice. Furthermore, treatment with M3 in wild-type mice significantly decreased serum and renal levels of interleukin-6 after renal ischemia/reperfusion. M3 treatment demonstrated significant reductions in renal messenger ribonucleic acid and protein levels of neutrophil gelatinase-associated lipocalin, serum blood urea nitrogen and creatinine, and histologic structural damage as well as apoptosis. Treatment with M3 also increased survival from 35% to 65% in mice with acute kidney injury. ConclusionTriggering receptor expressed on myeloid cells-1 mediates the deleterious effects of extracellular cold-inducible RNA-binding protein in acute kidney injury after renal ischemia/reperfusion. The novel extracellular cold-inducible RNA-binding protein/triggering receptor expressed on myeloid cells-1 pathway antagonist, M3, attenuates acute kidney injury and has the potential to be developed as a therapeutic agent for acute kidney injury.

Construction of Durvalumab/carbon nanotube/PEI/aptamer-siRNA chimera for the immunotherapy of hepatocellular carcinoma

Immunotherapy is the most promising treatment for hepatocellular carcinoma (HCC). However, the immunosuppressive microenvironment and necrosis limit its therapeutic effectiveness. Carbon nanotubes (CNTs) have good tissue permeability and can penetrate tumor necrosis area. Here we constructed a Durvalumab/CNT/PEI/aptamer-siRNA chimera (chimera/Durmab/CNT) nanoparticles for the immunotherapy of HCC. In vivo and in vitro experiments showed that aptamer-siRNA chimeras could specifically bind HCC cells and inhibit the triggering receptor expressed on myeloid cells-2 (Trem2) expression, but had no effect on Trem2 expression in normal liver and lung. Transmission electron microscope results showed that the CNT/PEI nanoparticles were 20–30 nm in diameter and 200–350 nm in length. Dense PEI attachment can be observed on CNTs. CNT/PEI nanoparticles could control the sustained release of Durvalumab for 48 h. In vitro experimental results showed that chimera/Durmab/CNT could increase the proportion of T cells and CD8 + T cells, and then promote the apoptosis of HepG2 cells, and the therapeutic effect was superior to aptamer/Durmab/CNT and Durmab/CNT. We constructed a tumor-bearing mouse model, and the results showed that chimera/Durmab/CNT significantly inhibited the growth of transplanted tumor, and the volume and proliferation was further reduced in the chimera/Durmab/CNT group compared with the aptamer/Durmab/CNT group. T cells and CD8 + T cells infiltration, and HCC cell apoptosis were significantly increased in the chimera/Durmab/CNT group. In conclusion, we constructed a Durvalumab/CNT/PEI/chimera, which can effectively treat HCC by activating anti-tumor immunity.

Construction of Durvalumab/carbon nanotube/PEI/aptamer-siRNA chimera for the immunotherapy of hepatocellular carcinoma.

Immunotherapy is the most promising treatment for hepatocellular carcinoma (HCC). However, the immunosuppressive microenvironment and necrosis limit its therapeutic effectiveness. Carbon nanotubes (CNTs) have good tissue permeability and can penetrate tumor necrosis area. Here we constructed a Durvalumab/CNT/PEI/ aptamer-siRNA chimera (chimera/Durmab/CNT) nanoparticles for the immunotherapy of HCC. In vivo and in vitro experiments showed that aptamer-siRNA chimeras could specifically bind HCC cells and inhibit the triggering receptor expressed on myeloid cells-2 (Trem2) expression, but had no effect on Trem2 expression in normal liver and lung. Transmission electron microscope (TEM) results showed that the CNT/PEI nanoparticles were 20-30 nm in diameter and 200-350nm in length. Dense PEI attachment can be observed on CNTs. CNT/PEI nanoparticles could control the sustained release of Durvalumab for 48 hours. In vitro experimental results showed that chimera/Durmab/CNT could increase the proportion of T cells and CD8+T cells, and then promote the apoptosis of HepG2 cells, and the therapeutic effect was superior to aptamer/Durmab/CNT and Durmab/CNT. We constructed a tumor-bearing mouse model, and the results showed that chimera/Durmab/CNT significantly inhibited the growth of transplanted tumor, and the volume and proliferation was further reduced in the chimera/Durmab/CNT group compared with the aptamer/Durmab/CNT group. T cells and CD8+T cells infiltration, and HCC cell apoptosis were significantly increased in the chimera/Durmab/CNT group. In conclusion, we constructed a Durvalumab/CNT/PEI/chimera, which can effectively treat HCC by activating anti-tumor immunity.