Triggering receptor expressed in myeloid cells 1 (TREM1) as a potential prognostic biomarker and association with immune infiltration in oral squamous cell carcinoma.

OBJECTIVE: The objective of this study is to investigate the significance and impact of Triggering Receptor Expression on Myeloid Cells-1 (TREM-1) in the context of oral squamous cell carcinoma (OSCC). METHODS: This study involved 51 OSCC patients, 21 oral epithelial dysplasia patients (OED), and the TCGA-HNSCC dataset. TREM1 expression was analyzed using quantitative reverse transcription PCR (RT-qPCR), and Western blot. Furthermore, we assessed TREM1 expression for clinicopathological, prognosis, and immune infiltration correlations utilizing publicly available TCGA-HNSCC datasets through UALCAN, Protein Atlas, Kaplan-Meier plot, TIMER2.0, and TISIDB. We also conducted bioinformatic analyses for functional enrichment employing publicly accessible datasets. RESULTS: TREM1 was significantly upregulated in OSCC and OED when compared to normal tissues, confirmed through multiple methods. Analysis of clinicopathological features showed associations with disease stage, grade, nodal metastasis, HPV status, and TP53 mutation. High TREM1 expression correlated with poorer patient survival. TREM1 was linked to immune cell infiltration and immune-related pathways. CONCLUSION: TREM1 is significantly upregulated in OSCC and is associated with poor clinicopathological features and survival. It may hold promise as a therapeutic target and prognostic marker in OSCC. Further research is needed to understand its functional role in OSCC.

Hypoxia-induced TREM1 promotes mesenchymal-like states of glioma stem cells via alternatively activating tumor-associated macrophages.

The mesenchymal subtype of glioblastoma (GBM) cells characterized by aggressive invasion and therapeutic resistance is thought to be dependent on cell-intrinsic alteration and extrinsic cellular crosstalk. Tumor-associated macrophages (TAMs) are pivotal in tumor progression, chemo-resistance, angiogenesis, and stemness maintenance. However, the impact of TAMs on the shifts in glioma stem cells (GSCs) states remains largely uncovered. Herein, we showed that the triggering receptor expressed on myeloid cells-1 (TREM1) preferentially expressed by M2-like TAMs and induced GSCs into mesenchymal-like states by modulating the secretion of TGFß2, which activated the TGFßR/SMAD2/3 signaling in GSCs. Furthermore, we demonstrated that TREM1 was transcriptionally regulated by HIF1a under the hypoxic environment and thus promoted an immunosuppressive type of TAMs via activating the TLR2/AKT/mTOR/c-MYC axis. Collectively, this study reveals that cellular communication between TAMs and GSCs through the TREM1-mediated TGFß2/TGFßR axis is involved in the mesenchymal-like transitions of GSCs. Our study provides valuable insights into the regulatory mechanisms between the tumor immune microenvironment and the malignant characteristics of GBM, which can lead to potential novel strategies targeting TAMs for tumor control.

TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-ß42 oligomer-induced bioenergetic changes, suggesting that amyloid-ß42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.

Molecular and immunological features of TREM1 and its emergence as a prognostic indicator in glioma.

Triggering receptor expressed on myeloid cells 1 (TREM1), which belongs to the Ig-like superfamily expressed on myeloid cells, is reportedly involved in various diseases but has rarely been studied in glioma. In this study, the prognostic value and functional roles of TREM2 in glioma were analyzed. TERM1 was observed to be significantly upregulated in GBM compared to in other grade gliomas and was associated with poor prognosis. Increased TREM1 accompanied distinct mutation and amplification of driver oncogenes. Moreover, gene ontology and KEGG analyses showed that TREM1 might play a role in immunologic biological processes in glioma. TREM1 was also found to be tightly correlated with immune checkpoint molecules. xCell research revealed a link between TREM1 expression and multiple immune cell types, especially monocytes and macrophages. Single-cell analysis and immunofluorescence results showed that macrophages expressed TREM1. In vitro, inhibition of TREM1 signaling could result in a decrease in tumor-promoting effects of monocytes/TAMs. In summary, TREM1 may be a potential independent prognostic factor and immune target, which might provide new avenues to improve the efficacy of immunotherapy in glioma patients.

Activation of toll-like receptor 4/nuclear factor-kappa B signaling by triggering a receptor expressed on myeloid cells 1 promotes alveolar macrophage M1 polarization and exacerbates septic acute lung injury.

BACKGROUND: Septic acute lung injury (ALI) is a life-threatening condition commonly occurring in the intensive care unit. Inflammation is considered as the basic pathological response of septic ALI. Triggering receptor expressed on myeloid cells 1 (TREM1) is a member of the immunoglobulin superfamily receptors that regulates the inflammatory response. However, the role of TREM1 in septic ALI has not yet been reported. METHODS: Cell viability was tested using the MTT assay. TdT-mediated dUTP nick end labeling assay and flow cytometry were used for apoptosis. The level of protein was detected using western blot analysis. The levels of tumor necrosis factor-α and interleukin-1ß were assessed using enzyme-linked immunosorbent assay. The lactate dehydrogenase content was assessed using the assay kit. Myeloperoxidase activity was determined using an assay. Histology of lung tissue was further analyzed through hematoxylin-eosin staining. RESULTS: We found that TREM1 knockdown by transfection with si-TREM1 inhibited lipopolysaccharide (LPS)-induced cell apoptosis of alveolar macrophage cell line MH-S. The LPS stimulation caused M1 polarization of MH-S cells, which could be reversed by TREM1 knockdown. In vivo assays proved that si-TREM1 injection improved lung injury and inflammation of cecal ligation and puncture-induced ALI in mice. In addition, TREM1 knockdown suppressed the activation of toll-like receptor 4/nuclear factor-kappa B signaling, implying the involvement of TLR4 in the effects of TREM1 in response to LPS stimulation. CONCLUSIONS: This study examined the proinflammatory role of TREM1 in septic ALI and its regulatory effect on alveolar macrophage polarization. These results suggest that TREM1 could potentially serve as a therapeutic target in the prevention and treatment of ALI.

TREM1 as a novel prognostic biomarker and tumor immune microenvironment evaluator in glioma.

Glioma is the most malignant tumor in the central nervous system with a poor prognosis. The tumor immune microenvironment plays a crucial role in glioma formation and progress. TREM1, as a vital immune regulator, has not been investigated in glioma. This study aims to explore the role of TREM1 in prognosis and tumor immune microenvironment of glioma. The mRNA expression level of TREM1 was collected from TCGA and GEO databases. The correlations between the clinic-pathological features and TREM1 expression were analyzed using Cox regression analysis. Kaplan-Meier was used to evaluate the effect of TREM1 on OS. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes were performed to analyze the functional annotations and signaling pathways of the TREM1 coexpression genes. ESTIMATE and TIMER explored the correlations between TREM1 and immune cell infiltration. Spearman correlation analysis was conducted to examine the association between the TREM1 and immune checkpoint expression. The expression level of TREM1 was significantly increased in glioma. TREM1 overexpression was positively related to poor prognosis, higher World Health Organization grade, isocitrate dehydrogenase wildtype, and 1p/19q non-codeletion. TREM1 coexpression genes were mainly related to immunoregulation and inflammatory response. TREM1 participated in the initiation and progression of glioma by regulating immune cell infiltration and expression of immune checkpoints. TREM1 is an effective prognostic and diagnostic biomarker in glioma. It can be adopted as a novel predictor for clinical prognosis, pathological characteristics, and immune microenvironment in glioma patients.

MiR-206 may regulate mitochondrial ROS contribute to the progression of Myocardial infarction via TREM1.

Myocardial infarction (MI) is a leading cause of mortality. To better understand its molecular and cellular mechanisms, we used bioinformatic tools and molecular experiments to explore the pathogenesis and prognostic markers. Differential gene expression analysis was conducted using GSE60993 and GSE66360 datasets. Hub genes were identified through pathway enrichment analysis and PPI network construction, and four hub genes (AQP9, MMP9, FPR1, and TREM1) were evaluated for their predictive performance using AUC and qRT-PCR. miR-206 was identified as a potential regulator of TREM1. Finally, miR-206 was found to induce EC senescence and ER stress through upregulating mitochondrial ROS levels via TREM1. These findings may contribute to understanding the pathogenesis of MI and identifying potential prognostic markers.

Targeting TREM1 augments antitumor T cell immunity by inhibiting myeloid-derived suppressor cells and restraining anti-PD-1 resistance.

The triggering receptor expressed on myeloid cell 1 (TREM1) plays a critical role in development of chronic inflammatory disorders and the inflamed tumor microenvironment (TME) associated with most solid tumors. We examined whether loss of TREM1 signaling can abrogate the immunosuppressive TME and enhance cancer immunity. To investigate the therapeutic potential of TREM1 in cancer, we used mice deficient in Trem1 and developed a novel small molecule TREM1 inhibitor, VJDT. We demonstrated that genetic or pharmacological TREM1 silencing significantly delayed tumor growth in murine melanoma (B16F10) and fibrosarcoma (MCA205) models. Single-cell RNA-Seq combined with functional assays during TREM1 deficiency revealed decreased immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs) accompanied by expansion in cytotoxic CD8+ T cells and increased PD-1 expression. Furthermore, TREM1 inhibition enhanced the antitumorigenic effect of anti-PD-1 treatment, in part, by limiting MDSC frequency and abrogating T cell exhaustion. In patient-derived melanoma xenograft tumors, treatment with VJDT downregulated key oncogenic signaling pathways involved in cell proliferation, migration, and survival. Our work highlights the role of TREM1 in cancer progression, both intrinsically expressed in cancer cells and extrinsically in the TME. Thus, targeting TREM1 to modify an immunosuppressive TME and improve efficacy of immune checkpoint therapy represents what we believe to be a promising therapeutic approach to cancer.

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

BACKGROUND: The 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. METHODS: We 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. RESULTS: All 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. CONCLUSIONS: The 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.

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

Introduction: Exposure 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 survival. Methods: RAW264.7 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. Results: The 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. Conclusion: Our 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.

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

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.

INTRODUCTION AND AIMS: 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. METHODS: 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. RESULTS: 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: ß = 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. CONCLUSIONS: 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.

TREM-1 induces pyroptosis in cardiomyocytes by activating NLRP3 inflammasome through the SMC4/NEMO pathway.

Sepsis often causes cell death via pyroptosis and hence results in septic cardiomyopathy. Triggering receptors expressed in myeloid cells-1 (TREM-1) may initiate cellular cascade pathways and, in turn, induce cell death and vital organ dysfunction in sepsis, but the evidence is limited. We set to investigate the role of TREM-1 on nucleotide-binding oligomerization domain-like receptors with pyrin domain-3 (NLRP3) inflammasome activation and cardiomyocyte pyroptosis in sepsis models using cardiac cell line (HL-1) and mice. In this study, TREM-1 was found to be significantly increased in HL-1 cells challenged with lipopolysaccharide (LPS). Pyroptosis was also significantly increased in the HL-1 cells challenged with lipopolysaccharide and an NLRP3 inflammasome activator, nigericin. The close interaction between TREM-1 and structural maintenance of chromosome 4 (SMC4) was also identified. Furthermore, inhibition of TREM-1 or SMC4 prevented the upregulation of NLRP3 and decreased Gasdermin-D, IL-1ß and caspase-1 cleavage. In mice subjected to caecal ligation and puncture, the TREM-1 inhibitor LR12 decreased the expression of NLRP3 and attenuated cardiomyocyte pyroptosis, leading to improved cardiac function and prolonged survival of septic mice. Our work demonstrates that, under septic conditions, TREM-1 plays a critical role in cardiomyocyte pyroptosis. Targeting TREM-1 and its associated molecules may therefore lead to novel therapeutic treatments for septic cardiomyopathy.

Translocated HMGB3 is involved in papillary thyroid cancer progression by activating cytoplasmic TLR3 and transmembrane TREM1.

The family of high mobility group box (HMGB) proteins participates in various biological processes including immunity, inflammation, as well as cancer formation and progression. However, its role in thyroid cancer remains to be clarified. We performed quantitative RT-PCR (qRT-PCR), western blot, enzyme-linked immunosorbent, immunohistochemistry, and immunofluorescence assays to evaluate the expression level and subcellular location of HMGB3. The effects of HMGB3 knockdown on malignant biological behaviors of thyroid cancer were determined by cell proliferation assays, cell cycle and apoptosis assays, and transwell chamber migration and invasion assays. Differential expression genes (DEGs) altered by HMGB3 were analyzed using the Ingenuity Pathway Analysis (IPA) and TRRUST v2 database. HMGB3 correlated pathways predicted by bioinformatic analysis were then confirmed using western blot, co-immunoprecipitation, dual-luciferase reporter assay, and flow cytometry. We found that HMGB3 is overexpressed and its downregulation inhibits cell viability, promotes cell apoptosis and cell cycle arrest, and suppresses cell migration and invasion in thyroid cancer. In PTC, both tissue and serum levels of HMGB3 are elevated and are correlated with lymph node metastasis and advanced tumor stage. Mechanistically, we observed the translocation of HMGB3 in PTC, induced at least partially by hypoxia. Cytoplasmic HMGB3 activates nucleic-acid-mediated TLR3/NF-κB signaling and extracellular HMGB3 interacts with the transmembrane TREM1 receptor in PTC. This study demonstrates the oncogenic role of HMGB3 cytoplasmic and extracellular translocation in papillary thyroid cancers; we recommend its future use as a potential circulating biomarker and therapeutic target for PTC.

Comparative transcriptomics in human COPD reveals dysregulated genes uniquely expressed in ferrets.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease with poor treatment options. However, most mouse models of COPD produce a primarily emphysematous disease not recapitulating clinically meaningful COPD features like chronic bronchitis. METHODS: Wild-type ferrets (Mustela putorius furo) were divided randomly into two groups: whole body cigarette smoke exposure and air controls. Ferrets were exposed to smoke from 1R6F research cigarettes, twice daily for six months. RNA-sequencing was performed on RNA isolated from lung tissue. Comparative transcriptomics analyses of COPD in ferrets, mice, and humans were done to find the uniquely expressed genes. Further, Real-time PCR was performed to confirmed RNA-Seq data on multiple selected genes. RESULTS: RNA-sequence analysis identified 420 differentially expressed genes (DEGs) that were associated with the development of COPD in ferrets. By comparative analysis, we identified 25 DEGs that are uniquely expressed in ferrets and humans, but not mice. Among DEGs, a number were related to mucociliary clearance (NEK-6, HAS1, and KL), while others have been correlated with abnormal lung function (IL-18), inflammation (TREM1, CTSB), or oxidative stress (SRX1, AHRR). Multiple cellular pathways were aberrantly altered in the COPD ferret model, including pathways associated with COPD pathogenesis in humans. Validation of these selected unique DEGs using real-time PCR demonstrated > absolute 2-fold changes in mRNA versus air controls, consistent with RNA-seq analysis. CONCLUSION: Cigarette smoke-induced COPD in ferrets modulates gene expression consistent with human COPD and suggests that the ferret model may be uniquely well suited for the study of aspects of the disease.

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

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.

The associations between plasma soluble Trem1 and neurological diseases: a Mendelian randomization study.

BACKGROUND: Triggering receptor expressed on myeloid cell 1 (Trem1) is an important regulator of cellular inflammatory responses. Neuroinflammation is a common thread across various neurological diseases. Soluble Trem1 (sTrem1) in plasma is associated with the development of central nervous system disorders. However, the extent of any causative effects of plasma sTrem1 on the risk of these disorders is still unclear. METHOD: Genetic variants for plasma sTrem1 levels were selected as instrumental variables. Summary-level statistics of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), epilepsy, cerebrovascular diseases, and migraine were collected from genome-wide association studies (GWASs). Whether plasma sTrem1 was causally associated with neurological disorders was assessed using a two-sample Mendelian randomization (MR) analysis, with false discovery rate (FDR)-adjusted methods applied. RESULTS: We inferred suggestive association of higher plasma sTrem1 with the risk of AD (odds ratio [OR] per one standard deviation [SD] increase = 1.064, 95% CI 1.012-1.119, P = 0.014, PFDR = 0.056). Moreover, there was significant association between plasma sTrem1 level and the risk of epilepsy (OR per one SD increase = 1.044, 95% CI 1.016-1.072, P = 0.002, PFDR = 0.032), with a modest statistical power of 41%. Null associations were found for plasma sTrem1 with other neurological diseases and their subtypes. CONCLUSIONS: Taken together, this study indicates suggestive association between plasma sTrem1 and AD. Moreover, higher plasma sTrem1 was associated with the increased risk of epilepsy. The findings support the hypothesis that sTrem1 may be a vital element on the causal pathway to AD and epilepsy.

FOXM1 network in association with TREM1 suppression regulates NET formation in diabetic foot ulcers.

Diabetic foot ulcers (DFU) are a serious complication of diabetes mellitus and associated with reduced quality of life and high mortality rate. DFUs are characterized by a deregulated immune response with decreased neutrophils due to loss of the transcription factor, FOXM1. Diabetes primes neutrophils to form neutrophil extracellular traps (NETs), contributing to tissue damage and impaired healing. However, the role of FOXM1 in priming diabetic neutrophils to undergo NET formation remains unknown. Here, we found that FOXM1 regulates reactive oxygen species (ROS) levels in neutrophils and inhibition of FOXM1 results in increased ROS leading to NET formation. Next generation sequencing revealed that TREM1 promoted the recruitment of FOXM1+ neutrophils and reversed effects of diabetes and promoted wound healing in vivo. Moreover, we found that TREM1 expression correlated with clinical healing outcomes of DFUs, indicating TREM1 may serve as a useful biomarker or a potential therapeutic target. Our findings highlight the clinical relevance of TREM1, and indicates FOXM1 pathway as a novel regulator of NET formation during diabetic wound healing, revealing new therapeutic strategies to promote healing in DFUs.

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.