TREM-1 Research Articles

N6-methyladenosine-mediated overexpression of TREM-1 is associated with periodontal disease.

Periodontitis, a prevalent inflammatory disease, involves the destruction of tooth-supporting tissues. N6-methyladenosine (m6A) is a type of post-transcriptional modification that significantly influences gene and protein expression. It is involved in the regulation of various diseases, including those with an inflammatory component. This study investigates the potential role of m6A-mediated TREM-1 expression in the development of periodontitis. Clinical features and TREM-1 expression were assessed in periodontitis patients and healthy controls. LPS-stimulated human gingival fibroblasts (HGFs) were used to investigate m6A levels, m6A regulator METTL3, TREM-1, and inflammatory gene expression. In silico functional analysis explored TREM-1 interactions and functionalities. Periodontitis patients showed significantly elevated TREM-1 expression at both mRNA and protein levels. Predicted m6A motifs were present within the TREM-1 transcript. LPS stimulation of HGFs increased m6A content, METTL3, and TREM-1 expression, suggesting a potential link between m6A modification and TREM-1 regulation. Bioinformatic analysis revealed TREM-1 interaction with genes associated with periodontitis and its association with inflammatory pathways. This study suggests a potential role for METTL3-mediated m6A modification in regulating TREM-1 expression in periodontitis. Further investigation is needed to solidify this link and translate findings into clinical applications for improved periodontal health.

Analysis of macrophage polarization and regulation characteristics in ovarian tissues of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) can lead to infertility and increase the risk of endometrial cancer. Analyzing the macrophage polarization characteristics in ovarian tissues of PCOS is crucial for clinical treatment. We obtained 13 PCOS and nine control ovarian samples from the CEO database and analyzed differentially expressed genes (DEGs). Macrophage polarization-related genes (MPRGs) were sourced from the GeneCards and MSigDB databases. Intersection of DEGs with MPRGs identified DEGs associated with macrophage polarization (MPRDEGs). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-protein interaction (PPI) Network analysis were conducted on MPRDEGs. Moreover, the top 10 genes from three algorithms were identified as the hub genes of MPRGs. In addition, miRNAs, transcription factors (TFs), and drugs were retrieved from relevant databases for regulatory network analysis of mRNA-miRNA, mRNA-TF, and mRNA-Drug interactions. Immune cell composition analysis between the PCOS and control groups was performed using the CIBERSORT algorithm to calculate correlations across 22 immune cell types. A total of 13 PCOS samples and nine control ovarian samples were obtained in this study. We identified 714 DEGs between the two groups, with 394 up-regulated and 320 down-regulated. Additionally, we identified 774 MPRGs, from which we derived 30 MPRDEGs by intersecting with DEGs, among which 21 exhibited interaction relationships. GO and KEGG analyses revealed the enrichment of MPRDEGs in five biological processes, five cell components, five molecular functions, and three biological pathways. Immune infiltration analysis indicated a strong positive correlation between activated nature killer (NK) cells and memory B cells, while neutrophils and monocytes showed the strongest negative correlation. Further investigation of MPRDEGs identified nine hub genes associated with 41 TFs, 82 miRNAs, and 44 drugs or molecular compounds. Additionally, qRT-PCR results demonstrated overexpression of the CD163, TREM1, and TREM2 genes in ovarian tissues from the PCOS group. This study elucidated the polarization status and regulatory characteristics of macrophages in ovarian tissues of the PCOS subjects, confirming significant overexpression of CD163, TREM1, and TREM2. These findings contribute to a deeper understanding of the pathogenesis of PCOS.

SNPs in splicing region and miRNA binding region of Bos taurus TREM-1 gene reveals its association with mastitis

Proper splicing is important for the functioning of a gene, and any interruption in splicing causes several deleterious events. Triggering receptors present on myeloid cells, TREM-1, are implicated in inflammation and act as amplifiers by mediating the release of proinflammatory chemokines and cytokines in response to fungal and bacterial infections. In bovines, mastitis is an inflammatory disease in which mammary gland inflammation is generally caused by bacteria. We found rs109937179 and rs208224995 SNPs in the splicing and miRNA binding region of TREM-1 gene in Chinese Holstein cows. The genotype distribution of the alleles for TREM-1 (rs109937179 and rs208224995) gene polymorphisms was investigated in 364 and 320 Chinese Holstein cows, respectively. We found that the GG genotype of the rs109937179 polymorphism and rs208224995 genotype of CA within the TREM-1 gene were associated with an increased risk of mastitis. Importantly, rs109937179 was found in the splicing region of TREM-1, and rs208224995 has a miRNA binding region for bta-miR- 2329-3p in the 3'UTR, which determines its effective roles in gene expression regulation.

Baseline TREM-1 Whole Blood Gene Expression Does Not Predict Response to Adalimumab Treatment in Patients with Ulcerative Colitis or Crohn's Disease in the SERENE Studies.

This study assessed whether baseline triggering receptor expressed on myeloid cells [TREM-1] whole blood gene expression predicts response to anti-tumour necrosis factor [anti-TNF] therapy in patients with ulcerative colitis [UC] or Crohn's disease [CD]. TREM-1 whole blood gene expression was analysed by RNA sequencing in patients with moderately to severely active UC or CD treated with adalimumab in the Phase 3 SERENE-UC and SERENE-CD clinical trials. The predictive value of baseline TREM-1 expression was evaluated and compared according to endoscopic and clinical response vs non-response, and remission vs non-remission, at Weeks 8 and 52 [SERENE-UC], and Weeks 12 and 56 [SERENE-CD]. TREM-1 expression was analysed in 95 and 106 patients with UC and CD, respectively, receiving standard-dose adalimumab induction treatment. In SERENE-UC, baseline TREM-1 expression was not predictive of endoscopic response [p = 0.48], endoscopic remission [p = 0.53], clinical response [p = 0.58], or clinical remission [p = 0.79] at Week 8, or clinical response [p = 0.60] at Week 52. However, an association was observed with endoscopic response [p = 0.01], endoscopic remission [p = 0.048], and clinical remission [p = 0.04997] at Week 52. For SERENE-CD, baseline TREM-1 expression was not predictive of endoscopic response [p = 0.56], endoscopic remission [p = 0.33], clinical response [p = 0.07], or clinical remission [p = 0.65] at Week 12, or endoscopic response [p = 0.61], endoscopic remission [p = 0.51], clinical response [p = 0.62], or clinical remission [p = 0.97] at Week 56. Baseline TREM-1 gene expression did not uniformly predict adalimumab response in SERENE clinical trials. Further research is needed to identify potential blood-based biomarkers predictive of response to anti-TNF therapy in patients with inflammatory bowel disease. NCT02065622; NCT02065570.

TREM1 КАК ВАЖНЫЙ УЧАСТНИК В РАЗВИТИИ КРИТИЧЕСКИХ ОСЛОЖНЕНИЙ У КАРДИОХИРУРГИЧЕСКИХ ПАЦИЕНТОВ

Introduction: It is known that the variability of immune response genes and the corresponding immune profile modulate the risk of a number of pathologies. Understanding the role of the immunogenetic status based on the variability of innate immunity receptors in the dynamics of the systemic inflammatory response of non-infectious genesis in open cardiac surgery, as well as the issues of objective assessment and possible correction of complications in the form of multiple organ failure (MOF), remain relevant. Objective: To determine those alleles of the TREM1 gene that are associated with the risk of developing POF in patients after coronary artery bypass grafting and which levels of sTREM1 may be of diagnostic significance. Materials and methods: A comprehensive examination of 680 patients with atherosclerosis of the coronary arteries was performed on the basis of the Federal State Budgetary Scientific Institution "NII KPSSZ" in the preoperative and early postoperative periods of coronary artery bypass grafting. Two groups were retrospectively formed, differing in the presence/absence of MOF in the early postoperative period. Based on clinical and laboratory data, the first group included 30 patients (4.4%) with MOF established in the early postoperative period (SOFA score over 4 points, combined dysfunction of 2 or more systems with further progression of organ disorders) and 650 patients (95.6%) were included in the second group - with an uncomplicated course of the postoperative period (score on the SOFA scale less than 4 points, disorders of 1-2 organ systems that occur with minor clinical manifestations and do not require long-term correction and support). Serum concentrations were determined by ELISA twice - before surgery and 24 hours (1 day) after surgery. Genotyping of 8 TREM1 polymorphic variants (rs1817537, rs3804277, rs6910730, rs7768162, rs2234246, rs4711668, rs9471535, rs2234237) was performed according to the protocol of the TagMan probe manufacturer by PCR with real-time detection of amplification products. Statistical data processing was carried out using SNPstats and GraphPad Prism 8 software. Results: It was found that in individuals with the T rs2234246 allele (p=0.0076), the G rs1817537 allele (p=0.019) and the T rs3804277 allele (p=0.019) of TREM1, the risk of developing POF after coronary artery bypass grafting increases. Carrying a homozygous genotype for a rare allele in these polymorphic variants is associated with a high concentration of sTREM1 at the preoperative stage (p=0.0005). It was also found that the most pronounced increase in the concentration of sTREM1 in the preoperative and early postoperative periods was observed in critically ill patients. Differences in sTREM1 concentrations between groups were significant throughout the intraoperative period (p<0.0001 and p<0.0001, respectively). Conclusion: It has been established that the concentration of sTREM and the carriage of rare alleles in certain polymorphic sites of the TREM1 gene (T rs2234246 allele, G rs1817537 allele and T rs3804277 allele), as well as their relationship with the level of circulating sTREM, demonstrate their significance in the development of MOF in patients with coronary artery disease after undergoing coronary artery bypass grafting.

Pathogenetic significance of polymorphic variants in the <i>TREM-1</i> gene in the multiple organ failure risk after cardiac surgery

Introduction. Searching of highly specific, sensitive and easy-to-use markers of multiple organ failure (MOF) that will help to the early prognosis of this unfavorable condition, prevent complications and reduce mortality in the early postoperative period is very urgent for the modern medicine.Aim: To study the pathogenetic significance of the TREM-1 gene polymorphism in MOF in patients with coronary artery disease (CAD) in the early postoperative period.Material and methods. 592 CAD patients (564 patients with uncomplicated postoperative period and 28 MOF patients) were selected for the presented study. Genotyping polymorphic variants rs1817537, rs3804277, rs6910730, rs7768162, rs2234246, rs4711668, rs9471535 and rs2234237 in the TREM-1 gene was carried out by polymerase chain reaction.Results. It was found that the allele T (rs2234246), the allele G (rs1817537) and the allele T (rs3804277) in the TREM-1 gene were associated with an increased MOF risk after elective surgery according to the dominant inheritance model. TREM-1 polymorphic loci rs7768162 and rs4711668 were associated with a decreased MOF risk according to the additive inheritance model. We found no significant associations between polymorphic variants rs2234237, rs6910730, rs9471535, as well as inherited haplotype and MOF risk. Using the MDR analysis, three most significant models of gene-gene interactions of TREM-1 polymorphic loci associated with MOF risk in patients after cardiac surgery were identified.Conclusion. The obtained results demonstrate a significant contribution of polymorphic variants in the TREM-1 gene to the development of MOF in patients undergoing cardiac surgery.

Influence of trem-1 gene polymorphisms on cytokine levels during malaria by Plasmodium vivax in a frontier area of the Brazilian Amazon

BackgroundThe immunopathology during malaria depends on the level of inflammatory response generated. In this scenario, the TREM-1 has been associated with the severity of infectious diseases and could play an important role in the inflammatory course of malaria. We aimed to describe the allelic and genotypic frequency of four polymorphisms in the trem-1 gene in Plasmodium vivax-infected patients and to verify the association of these polymorphisms with clinical and immunological factors in a frontier area of the Brazilian Amazon. MethodsWe included 76 individuals infected with P. vivax and 144 healthy controls living in the municipality of Oiapoque, Amapá, Brazil. The levels of TNF-α, IL-10, IL-2, IL-4, IL-5, and IFN-γ were measured by flow cytometry, while IL-6, sTREM-1, and antibodies against PvMSP-119 were evaluated by ELISA. The SNPs were genotyped by qPCR technique. Polymorphisms analysis, allelic and genotype, frequencies, and HWE calculation were determined by x2 test in R Software. The association between the parasitemia, gametocytes, antibodies, cytokines, and sTREM-1 with the genotypes of malaria and control groups was performed using the Kruskal-Wallis test, these analyzes were conducted in SPSS Software, at 5% significance level. ResultsAll SNPs were successfully genotyped. Allelic and genotypic distribution was in Hardy-Weinberg Equilibrium. Furthermore, several associations were identified between malaria and control groups, with increased levels of IL-5, IL-6, IL-10, TNF-α, and IFN-γ in the infected individuals with rs6910730A, rs2234237T, rs2234246T, rs4711668C alleles compared to the homozygous wild-type and heterozygous genotypes of the controls (p-value < 0.05). No association was found for these SNPs and the levels of IL-2, and sTREM-1. ConclusionsThe SNPs on the trem-1 gene are associated with the effector molecules of the innate immunity and may contribute to the identification and effective participation of trem-1 in the modulation of the immune response. This association may be essential for the establishment of immunization strategies against malaria.

TREM-1 as a Marker of Multiple Organ Failure in Cardiac Surgery

ABSTRACT Systemic inflammatory response syndrome (SIRS) frequently accompanies early postoperative period after cardiac surgery and in some cases is complicated by multiple organ failure (MOF). Inherited variation in the innate immune response genes (e.g., TREM1) is among the major factors determining the development of SIRS and the risk of MOF. This research was aimed to study whether the polymorphisms within the TREM1 gene are associated with MOF after the coronary artery bypass graft (CABG) surgery. Here we enrolled 592 patients who underwent CABG surgery in the Research Institute for Complex Issues of Cardiovascular Diseases (Kemerovo, Russia) and documented 28 cases of MOF. Genotyping was performed by allele-specific PCR using TaqMan probes. In addition, we measured serum soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) using enzyme-linked immunosorbent assay. Five polymorphisms (rs1817537, rs2234246, rs3804277, rs7768162 andrs4711668) within the TREM1 gene were significantly associated with MOF. Patients with MOF had higher serum sTREM-1 as compared with those without MOF at both pre- and post-intervention stages. Serum sTREM-1 was associated with the rs1817537,rs2234246 and rs3804277 polymorphisms within the TREM1 gene. Minor alleles within the TREM1 gene define the level of serum sTREM-1 and are associated with MOF after CABG surgery.

Association between genetic variants in TREM1, CXCL10, IL4, CXCL8 and TLR7 genes with the occurrence of congenital Zika syndrome and severe microcephaly

Congenital Zika syndrome (CZS) is a cluster of malformations induced by Zika virus (ZIKV) infection and the underline mechanisms involved in its occurrence are yet not fully understood. Along with epidemiological and environmental factors, the genetic host factors are suggested as important to the CZS occurrence and development, however, few studies have evaluated this. This study enrolled a total of 245 individuals in a case–control association study compound a cohort of high specific interest constituted by 75 mothers who had delivered CZS infants, their 76 infants, and 47 mothers that had delivered healthy infants, and their 47 infants. Sixteen single-nucleotide polymorphisms on TREM1, CXCL10, IL4, CXCL8, TLR3, TLR7, IFNR1, CXCR1, IL10, CCR2 and CCR5 genes were genotyped to investigate their association as risk factors to CZS. The results show an association between C allele at TREM1 rs2234246 and C allele at IL4 rs224325 in mothers infected with ZIKV during pregnancy, with the increased susceptibility to CZS occurrence in their infants and the SNP CXCL8 rs4073 and the G allele at CXCL10 rs4508917 with presence of CZS microcephaly in the infants. Furthermore, the T allele at CXCL8 rs4073 and TRL7 rs179008 SNPs were associated with the severity of microcephaly in children with CZS. These results suggest that these polymorphisms in genes of innate immune responses addressed here are associated to increased risk of occurrence and severity of CZS in pregnant mothers infected with ZIKV and their CZS infants.

Association of rs2062323 in the TREM1 gene with Alzheimer's disease and cerebrospinal fluid-soluble TREM2.

Genetic variations play a significant role in determining an individual's AD susceptibility. Research on the connection between AD and TREM1 gene polymorphisms (SNPs) remained lacking. We sought to examine the associations between TREM1 SNPs and AD. Based on the 1000 Genomes Project data, linkage disequilibrium (LD) analyses were utilized to screen for candidate SNPs in the TREM1 gene. AD cases (1081) and healthy control subjects (870) were collected and genotyped, and the associations between candidate SNPs and AD risk were analyzed. We explored the associations between target SNP and AD biomarkers. Moreover, 842 individuals from ADNI were selected to verify these results. Linear mixed models were used to estimate associations between the target SNP and longitudinal cognitive changes. The rs2062323 was identified to be associated with AD risk in the Han population, and rs2062323T carriers had a lower AD risk (co-dominant model: OR, 0.67, 95% CI, 0.51-0.88, p=0.0037; additive model: OR, 0.82, 95% CI, 0.72-0.94, p=0.0032). Cerebrospinal fluid (CSF) sTREM2 levels were significantly increased in middle-aged rs2062323T carriers (additive model: β=0.18, p=0.0348). We also found significantly elevated levels of CSF sTREM2 in the ADNI. The rate of cognitive decline slowed down in rs2062323T carriers. This study is the first to identify significant associations between TREM1 rs2062323 and AD risk. The rs2062323T may be involved in AD by regulating the expression of TREM1, TREML1, TREM2, and sTREM2. The TREM family is expected to be a potential therapeutic target for AD.

Muscone Inhibits the Excessive Inflammatory Response in Myocardial Infarction by Targeting TREM-1.

The inhibitory effect of muscone on the hyperinflammatory response after myocardial ischemia reperfusion injury (MIRI) was investigated, and the target and signal pathways of muscone were explored. The levels of inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor alpha were detected through qRT-PCR and ELISA. The expression levels of p38 and NF-κB signaling pathway-related proteins were detected through Western blot. TREM-1 siRNA was transfected into macrophages in vitro. The rat model of myocardial ischemia was established and used in studying the inhibitory effect of muscone on the inflammatory response and its protective effect muscone on myocardial apoptosis. The expression of TREM-1 was upregulated during myocardial ischemia. Knocking down TREM-1 decreased the increase in inflammatory cytokines in the supernatant of macrophages induced by rmHMGB1 (1 μg/mL) and rmHSP60 (1 mol/mL). In addition, knocking down TREM-1 decreased p38 and NF-κB signaling activation. Muscone can protect myocardial cells by inhibiting the expression of TREM-1 and the inflammatory response after myocardial infarction. Further study showed that muscone inhibited the production of DAM-triggered (damage-associated molecular pattern trigger) inflammatory cytokines. In addition, muscone inhibited the activation of p38 and NF-κB signals under DAM-induced conditions. Muscone and TREM-1 gene knockout reduced cell apoptosis and provided protection against MIRI by inhibiting p38 and NF-κB signaling activation. Mechanism studies showed that muscone inhibited the production and release of inflammatory cytokines by inhibiting TREM-1, and thereby reducing the inflammatory response and providing protection against MIRI.

Persistent DNA damage and oncogenic stress-induced Trem1 promotes leukemia in mice.

The immune receptor TREM1 (Triggering receptor expressed on myeloid cells 1) is a master regulator of inflammatory response. Compelling evidence suggests important pathological roles for TREM1 in various types of solid tumors. However, the role of TREM1 in hematologic malignancies is not known. Our previous study demonstrated that TREM1 cooperates with diminished DNA damage response to induce expansion of pre-leukemic hematopoietic stem cells (HSC) in mice deficient for the Fanconi anemia gene Fanca. Here we investigated TREM1 in leukemogenesis using mouse models of the DNA repair-deficient Fanca-/- and the oncogenic MLL-AF9 or KrasG12D. We found that Trem1 was highly expressed in preleukemic HSC and leukemia stem cells (LSC). By selective deletion of the Trem1 gene in the hematopoietic compartment, we showed that ablation of Trem1 reduced leukemogenic activity of the pre-leukemic HSC and LSC in mice. Trem1 was required for the proliferation of the pre-leukemic HSC and LSC. Further analysis revealed that Trem1 expression in preleukemic HSC and LSC was associated with persistent DNA damage, prolonged oncogenic stress, and a strong inflammatory signature. Targeting several top Trem1 inflammatory signatures inhibited the proliferation of pre-leukemic HSC and LSC. Collectively, our observations uncover previously unknown expression and function of TREM1 in malignant stem cells, and identify TREM1 as a driver of leukemogenesis.

DOP81 Baseline whole-blood gene expression of TREM1 does not predict clinical or endoscopic outcomes following adalimumab treatment in patients with Ulcerative Colitis or Crohn’s Disease in the SERENE studies

Abstract Background Conflicting evidence exists regarding whether low baseline Triggering Receptor Expressed on Myeloid cells (TREM)1 whole-blood gene expression predicts response or non-response to anti-tumour necrosis factor agents in patients with Ulcerative Colitis (UC) or Crohn’s Disease (CD). This study investigated whether baseline TREM1 expression predicted outcomes following adalimumab treatment in patients with UC or CD in the SERENE Phase 3 studies. Methods The SERENE studies (SERENE-UC, NCT02065622; and SERENE-CD, NCT02065570) compared a higher adalimumab induction dosing regimen versus the standard regimen in patients with UC or CD. Whole-blood TREM1 expression was analysed by RNA sequencing in patients who received standard-dose adalimumab and had clinical and endoscopic outcomes at Week 8 or 52 in SERENE-UC (n=95 for Week 8 and n=70 for Week 52 outcomes), or Week 12 or 56 in SERENE-CD (n=106 for all Week 12 outcomes; n=48 for clinical and n=50 for endoscopic outcomes at Week 56). Outcome definitions are summarised in Table 1. A 2-sample t-test was used to compare baseline TREM1 gene expression (log2 counts per million) in clinical or endoscopic remitters or responders versus non-remitters or non-responders at Weeks 8 and 52 (SERENE-UC) or Weeks 12 and 56 (SERENE-CD). Results In SERENE-UC, baseline TREM1 expression did not predict clinical remission at Week 8 (Figure 1a; p=0.7942) and was only weakly predictive of clinical remission at Week 52 (Figure 1b; p=0.04997). Further, it was not predictive of clinical response at Week 8 or Week 52, nor of endoscopic remission or endoscopic response (Figure 1c) at Week 8 (p&amp;gt;0.05 in all cases), although a weak correlation was observed with both endoscopic remission (p=0.0484) and endoscopic response (p=0.01162; Figure 1d) at Week 52. In SERENE-CD, baseline TREM1 expression was not linked to endoscopic or clinical outcomes at either Week 12 or Week 56 (p&amp;gt;0.05 in all cases; Figure 2a–d). Stratification by adalimumab quartiles did not increase the ability of baseline TREM1 expression to predict clinical outcomes in either study. Of note, a highly positive correlation was observed between baseline TREM1 expression and neutrophils in endoscopic responders and non-responders in both studies. Regardless of clinical or endoscopic response or non-response, TREM1 expression decreased over time following adalimumab treatment. All results obtained with standard-dose adalimumab were replicated with the higher dose (data not shown). Conclusion The findings of this study suggest that baseline whole-blood TREM1 gene expression is not a robust predictor of clinical or endoscopic outcomes following adalimumab treatment in patients with UC or CD.

CD16+CD163+ monocytes traffic to sites of inflammation during necrotizing enterocolitis in premature infants.

Necrotizing enterocolitis (NEC) is a severe gastrointestinal complication of prematurity. Using suspension and imaging mass cytometry coupled with single-cell RNA sequencing, we demonstrate severe inflammation in patients with NEC. NEC mucosa could be subtyped by an influx of three distinct neutrophil phenotypes (immature, newly emigrated, and aged). Furthermore, CD16+CD163+ monocytes/Mϕ, correlated with newly emigrated neutrophils, were specifically enriched in NEC mucosa, found adjacent to the blood vessels, and increased in circulation of infants with surgical NEC, suggesting trafficking from the periphery to areas of inflammation. NEC-specific monocytes/Mϕ transcribed inflammatory genes, including TREM1, IL1A, IL1B, and calprotectin, and neutrophil recruitment genes IL8, CXCL1, CXCL2, CXCL5 and had enrichment of gene sets in pathways involved in chemotaxis, migration, phagocytosis, and reactive oxygen species generation. In summary, we identify a novel subtype of inflammatory monocytes/Mϕ associated with NEC that should be further evaluated as a potential biomarker of surgical NEC and a target for the development of NEC-specific therapeutics.

TREM-1 orchestrates angiotensin II-induced monocyte trafficking and promotes experimental abdominal aortic aneurysm.

The triggering receptor expressed on myeloid cells 1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of angiotensin II-induced (AngII-induced) AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalized with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide, limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2, and Mmp9 mRNA expression, and led to a decreased macrophage content due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L upregulation and promoted proinflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII receptor type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared with patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in humans.

Identification of gene expression markers and development of evaluation method using cell-based and RT-PCR-based assay for skin sensitising potential of chemicals

Recently, alternatives to animal testing have been used to evaluate skin sensitisers in cosmetic products. However, testing is still complicated and expensive. To develop a simpler, cost-effective and more accurate evaluation method for the skin sensitising chemicals, we employed cell-based and RT-PCR-based assay. Representative sensitiser specific gene expression in THP-1 cells was analysed by microarray. Gene ontology (GO) analysis revealed that 26 genes induced by the sensitisers were associated with immune function. First, seven of the 26 genes were chosen arbitrarily as candidate markers for our sensitisation assay. Then, THP-1 cells were exposed to 13 reference chemicals with known sensitising potential, and real-time RT-PCR assays targeting the candidate marker genes were performed. Among them, six markers were able to properly evaluate the sensitisation potential by classifying the gene induction rates with appropriate criteria. Especially, the results of the assay using TREM1 and TNFRSF12A gene markers showed 100% sensitivity and specificity. An existing test method, h-CLAT, requires a flow cytometer and is complicated to operate. In contrast, our method is relatively simpler and more cost-effective. Therefore, our method is a promising one to evaluate sensitising chemicals.

Expression of triggering receptor expressed on myeloid cells in periventricular leukomalacia of neonatal rat model

Objective To investigate the expression of triggering receptor expressed on myeloid cells(TREMs)in periventricular leukomalacia(PVL) of the neonatal rat model. Methods Thirty-two 3-day-old neonatal rats were double-blinded randomly divided into Sham group and Model group.The PVL rat model was established by ligating right carotid artery and oxygen deprivation.Hematoxylin-eosin (HE) was adopted to compare pathological changes of brain tissue between the two groups, and immunofluorescence was adopted to detect the expression of myline basic protein (MBP) in the right hemisphere of the two groups.Western blot was performed to detect the expression of TREM1 and TREM2 in the right hemisphere of the two groups. Results The results of HE staining showed that the brain tissues of Model group were significantly damaged compared with that of Sham group, and the mean fluorescence intensity of MBP in Model group(26.629±2.317) was significantly lower than that in Sham group(33.579±2.824), with statistically significant differences(t=9.124, P<0.05). The expression of TREM1 in Model group(0.789 ±0.120) was higher than that in Sham group(0.567±0.093), with statistically significant differences(t=-3.891, P<0.05). The expression of TREM2 in Model group(0.544±0.133) was lower than that in Sham group(0.791±0.118), with statistically significant differences(t=3.667, P<0.05). Conclusion The expressions of TREM1 and TREM2 in the neonatal rat model of PVL change abnormally, suggesting that TREMs may be involved in the pathological process of preterm white matter injury. Key words: Periventricular leukomalacia; White matter injury; Brain injury; Triggering receptor expressed on myeloid cells; Rat

Effects and mechanism of TREM-1 on inflammatory response and lipid metabolism in mice with nonalcoholic fatty liver disease

Objective Analysis of the effect of triggering receptor-1 expressed on myeloid cells (TREM-1) in nonalcoholic fatty liver disease (NAFLD) and the mechanism. Methods The oleic acid-treated HepG2 cells were divided into model group, overexpression group, interference group A, interference group B and negative control group. The mouse model of NAFLD was generated and randomly divided into (nuclear factor-κB) NF-κB inhibition group, protein kinase B (AKT) inhibition group, knockout group A, knockout group B and control group. The expression of inflammatory factors and TREM-1 in liver tissue was detected by PCR, and fat accumulation was detected by oil red O staining. Western blotting was used to detect the expression of TREM-1 and signaling pathway proteins, and HE staining was used to detect liver tissue changes. Results TREM-1 was up-regulated in liver tissue of NAFLD mice [(0.936±0.127) vs. (0.432±0.105)] and in oleic acid-treated HepG2 cells. In oleic acid-treated HepG2 cells, overexpression of TREM-1 increased inflammatory factor expression and increased lipid droplets; inhibition of TREM-1 expression decreased inflammatory factor expression, and lipid droplets decreased. Knockout of TREM-1 and inhibition of NF-κB in NAFLD mice reduced hepatocyte inflammatory factor expression and reduced liver damage; knockout of TREM-1 and inhibition of AKT reduced liver tissue lipids and drops accumulate. Conclusions The overexpression of TREM-1 in NAFLD mice liver tissue can regulate inflammatory factor expression and lipid droplets through NF-κB and AKT signal pathway. TREM-1 might be a potential therapeutic target of NAFLD. Key words: Inflammation; Nonalcoholic fatty liver disease; Triggering receptor-1 expressed on myeloid cells; Lipid accumulation

The role of gene TREM-1 at children who have operation congenital heart diseases

Introduction. Congenital heart disease (CHD) is one of the most common fetal malformations resulting in high postnatal disability and mortality. Despite significant advances in the diagnosis and surgical correction of defects, the molecular genetic aspects of the pathogenesis of this disease are still not fully understood. TREM-1 key receptor for the innate immune response, inflammatory inducing and involved in the pathogenesis of acute and chronic diseases. Purpose. To determine genotype frequencies of the TREM-1 gene in children with congenital heart disease. Methods. 154 children with congenital heart disease were included in the study. Genomic DNA isolated from peripheral blood leukocytes was used as a material for the study. The genotyped were with RT-PCR by 8 loci (rs1817537, rs3804277, rs6910730, rs7768162, rs2234246, rs4711668, rs9471535, rs2234237). Results and conclusions. The C/C genotype of the rs2234246 polymorphism was more frequently found in the group of patients with ductus-independent CHD compared with the ductus-dependent CHD (38.2 % vs. 15.4 %, p = 0,006). The T/T genotype of the rs4711668 was more frequently detected in the ductus-independent CHD (24 % vs. 8 % p = 0.02). The study did not establish differences in the distribution of alleles and genotypes of the TREM-1 gene in patients with CHD and healthy children. At the same time, statistically significant differences in the distribution of genotypes of polymorphic rs2234246 and rs4711668 variants in groups of patients with ductus-dependent and ductus-independent blood circulation were obtained.

Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) and polymorphic variants of TREM-1 in the development of multiple organ dysfunction syndrome after coronary artery bypass grafting

The onset of critical complications (multiple organ dysfunction syndrome, MODS) after coronary artery bypass grafting is the result of severe stress response. The key etiopathological factor of the induction phase of the complex pathological process, which ultimately leads to dysfunction of organs and systems, is the dysfunction of the immune response. The characteristics of reactions of the immune system in a particular individual are genetically determined and realized through innate immunity activation. Aim. To determine the role of TREM-1 gene polymorphism through the changes of sTREM serum levels and their contribution to the development of multiple organ dysfunction syndrome after coronary artery bypass grafting.Materials and Methods. 132 patients with coronary atherosclerosis who had undergone coronary artery bypass grafting were included in the study. Of them, 30 patients had multiple organ dysfunction syndrome in the early postoperative period. sTREM serum levels were measured using enzyme immunoassay. Genotyping of polymorphic loci of the TREM-1 gene was performed with real-time allele-specific PCR using TaqMan system.Results. Significant differences in sTREM levels among patients with and without MODS were found. sTREM levels depend on the carriage of certain allelic variants in the three polymorphic loci of the TREM-1 gene (rs1817537, rs2234246, rs3804277)Conclusion. The relationships of the levels of the circulating soluble form of TREM-1 and the polymorphic variants of the coding TREM-1 gene with the severity of MODS were determined in coronary artery disease patients after coronary artery bypass grafting.