TREM1/DAP12 based novel multiple chain CAR-T cells targeting DLL3 show robust anti-tumour efficacy for small cell lung cancer.

Small cell lung cancer (SCLC), recognized as the most aggressive subtype of lung cancer, presents an extremely poor prognosis. Currently, patients with small cell lung cancer face a significant dearth of effective alternative treatment options once they experience recurrence and progression after first-line therapy. Despite the promising efficacy of immunotherapy, particularly immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) and various other tumours, its impact on significantly enhancing the prognosis of SCLC patients remains elusive. DLL3 has emerged as a compelling target for targeted therapy in SCLC due to its high expression on the membranes of SCLC and other neuroendocrine carcinoma cells, with minimal to no expression in normal cells. Our previous work led to the development of a novel multiple chain chimeric antigen receptor (CAR) leveraging the TREM1 receptor and DAP12, which efficiently activated T cells and conferred potent cell cytotoxicity. In this study, we have developed a DLL3-TREM1/DAP12 CAR-T (DLL3-DT CAR-T) therapy, demonstrating comparable anti-tumour efficacy against SCLC cells in vitro. In murine xenograft and patient-derived xenograft models, DLL3-DT CAR-T cells exhibited a more robust tumour eradication efficiency than second-generation DLL3-BBZ CAR-T cells. Furthermore, we observed elevated memory phenotypes, induced durable responses, and activation under antigen-presenting cells in DLL3-DT CAR-T cells. Collectively, these findings suggest that DLL3-DT CAR-T cells may offer a novel and potentially effective therapeutic strategy for treating DLL3-expressing SCLC and other solid tumours.

Systemic neutrophils are triggered by respiratory Bacillus Calmette- Guérin and mediate pulmonary mycobacterial clearance in synergy with the triggering receptor expressed on myeloid cells 1.

Tuberculosis remains a threat to public health. The only approved vaccine, Bacillus Calmette-Guérin (BCG), is administered intradermally and provides limited protection, and its effect on innate immunity via the respiratory route has not been fully elucidated. A mouse model with genetically depleted TREM1 and seven-color flow cytometry staining were used to characterize the comprehensive immune response induced by respiratory BCG, through evaluating organ bacterial loads, lung histopathology, and lung immunohistochemistry. During respiratory BCG infection, the murine lungs displayed effective bacterial clearance. Notably, marked differences in neutrophils were observed between thymus and bone marrow cells, characterized by a significant increase in the expression of the triggering receptor expressed on myeloid cells 1 (TREM1). Subsequently, upon depletion of TREM1, a reduction in pulmonary neutrophils was observed, which further exacerbated bacterial loads and resulted in worsened pathology following respiratory BCG infection. In summary, up-regulated expression of TREM1 in rapidly increasing circulating neutrophil by pulmonary BCG is required for an efficient host response to BCG infection, and suggests the important role of TREM1 in neutrophil-related pulmonary bacteria clearance and pathology.

TREM1: Activation, signaling, cancer and therapy.

Triggering receptor expressed on myeloid cells 1 (TREM1) is a cell surface receptor expressed on neutrophils, monocytes and some tissue macrophages, where it functions as an immunoregulator that controls myeloid cell responses. The activation of TREM1 is suggested to be an upregulation-based, ligands-induced and structural multimerization-mediated process, in which damage- and pathogen-associated molecular patterns play important roles. Activated TREM1 initiates an array of downstream signaling pathways that ultimately result in the production of pro-inflammatory cytokines and chemokines, whereby it functions as an amplifier of inflammation and is implicated in the pathogenesis of many inflammation-associated diseases. Over the past decade, there has been growing evidence for the involvement of TREM1 overactivation in tumor stroma inflammation and cancer progression. Indeed, it was shown that TREM1 promotes tumor progression, immunosuppression, and resistance to therapy by activating tumor-infiltrating myeloid cells. TREM1-deficiency or blockade provide protection against tumors and reverse the resistance to anti-PD-1/PD-L1 therapy and arginine-deprivation therapy in preclinical models. Here, we first review the structure, activation modes and signaling pathways of TREM1 and emphasize the role of soluble TREM1 as a biomarker of infection and cancer. We then focus on the role of TREM1 in cancer and systematically summarize its expression patterns, upregulation mechanisms and functions in tumor development and progression. Lastly, we discuss the therapeutic prospects of TREM1 inhibition, via effective pharmacological inhibitors, in treating cancer and other diseases.

Triggering receptor expressed on myeloid cells-1 in sepsis, and current insights into clinical studies.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor and plays a critical role in the immune response. TREM-1 activation leads to the production and release of proinflammatory cytokines, chemokines, as well as its own expression and circulating levels of the cleaved soluble extracellular portion of TREM-1 (sTREM-1). Because patients with sepsis and septic shock show elevated sTREM-1 levels, TREM-1 has attracted attention as an important contributor to the inadequate immune response in this often-deadly condition. Since 2001, when the first blockade of TREM-1 in sepsis was performed, many potential TREM-1 inhibitors have been established in animal models. However, only one of them, nangibotide, has entered clinical trials, which have yielded promising data for future treatment of sepsis, septic shock, and other inflammatory disease such as COVID-19. This review discusses the TREM-1 pathway and important ligands, and highlights the development of novel inhibitors as well as their clinical potential for targeted treatment of various inflammatory conditions.

Soluble Triggering Receptors Expressed on Myeloid Cells (sTREM) in Acute Ischemic Stroke: A Potential Pathway of sTREM-1 and sTREM-2 Associated with Disease Severity.

In 2022, stroke emerged as the most significant cerebrovascular disorder globally, causing 6.55 million deaths. Microglia, crucial for CNS preservation, can exacerbate brain damage in ischemic stroke by triggering neuroinflammation. This process is mediated by receptors on microglia, triggering receptors expressed on myeloid cells (TREM-1 and TREM-2), which have contrasting roles in neuroinflammation. In this study, we recruited 38 patients within 4.5 h from the onset of ischemic stroke. The degree of severity was evaluated by means of the National Institutes of Health Stroke Scale (NIHSS) at admission (T0) and after one week of ischemic events (TW) and the Modified Rankin Scale (mRS) at three months. The plasma concentration of TREMs (sTREM) was analyzed by next-generation ELISA at T0 and TW. The sTREM-1 concentrations at T0 were associated with mRS, while the sTREM-2 concentrations at T0 were associated with both the NIHSS at T0 and the mRS. A strong correlation between sTREM-1 and sTREM-2 was observed, suggesting a dependent modulation of the levels. This study provides insights into the potential pathway of TREM-1 and TREM-2 as a future biomarker for stratifying high-risk patients with ischemic stroke.

The Interaction of HMGB1 with the Proinflammatory TREM-1 Receptor Generates Cytotoxic Lymphocytes Active against HLA-Negative Tumor Cells.

High mobility group protein (HMGB1) is secreted by myeloid cells and cells of damaged tissues during inflammation, causing inflammatory reactions through various receptors, including TLRS and RAGE. TREM-1 is considered to be one of the potential HMGB1 receptors. In this work, we have shown that the HMGB1 protein is able to bind to the TREM-1 receptor at high affinity both in solution and on the cell surface. This binding causes lymphocytes to release cytokines IL-2, IL-1b, IL-6, TNF and Ifny into the medium, which leads to the appearance of cytotoxic lymphocytes in PBMC capable of lysing HLA-negative tumor cells. Expanding the spectra of proinflammatory receptor ligands and understanding the mechanisms of their action is essential for the creation of new immunotherapy pathways.

Microglia TREM1-mediated neuroinflammation contributes to central sensitization via the NF-κB pathway in a chronic migraine model.

BACKGROUND: Neuroinflammation, mediated by the activation of microglia, contributes to central sensitization, which is associated with the development of chronic migraine (CM). TREM1 receptors amplify the inflammatory response. However, their relationship to CM is unclear. Thus, this study endeavoured to elucidate the exact role of TREM1 in CM. METHODS: Nitroglycerin (NTG) was repeatedly administered intraperitoneally to establish the CM model. Mechanical and thermal sensitivities were assessed using von Frey filaments and hot plate assays. Using Western blotting, TREM1, NF-κB pathway, NLRP3 inflammasome components, and proinflammatory cytokines were all detected. Immunofluorescence was used to examine the cellular distribution of TREM1 and NLRP3, the number of microglia, immunoreactivity, and morphological changes. We examined the effects of TREM1 antagonists (LR12) and NF-κB inhibitors (PDTC) on pain behaviour, as well as the production of c-fos and CGRP. Additionally, we investigated whether LR12 and PDTC affect the activation of microglia and the NLRP3 inflammasome. We synthesized siRNA and TREM1-overexpressing plasmids to transfect BV2 cells treated with LPS and normal BV2 cells and treated TREM1-overexpressing BV2 cells with PDTC. The NF-κB pathway, NLRP3 inflammasome components, and proinflammatory cytokines were quantified using Western blotting. RESULTS: Following NTG administration, the expression of TREM1 was significantly upregulated and exclusively localized in microglia in the TNC, and was well co-localized with NLRP3. Furthermore, activation of the classical NF-κB pathway was observed. Pre-treatment with LR12 and PDTC effectively attenuated mechanical hypersensitivity, suppressed the expression of c-fos and CGRP, and inhibited NF-κB activity in CM mice. Additionally, inhibition of TREM1 and NF-κB activity mitigated NTG-induced microglia and NLRP3 activation, as well as proinflammatory cytokines production. In vitro, knockdown of TREM1 resulted in attenuated activation of the NF-κB pathway following lipopolysaccharide (LPS) treatment and reduced expression of NLRP3 inflammasome components as well as proinflammatory cytokines. After TREM1 overexpression, the NF-κB pathway was activated, NLRP3 inflammasome components and proinflammatory cytokines were upregulated, and PDTC reversed this phenomenon. CONCLUSIONS: Our findings suggest that TREM1 regulates microglia and NLRP3 activation via the NF-κB pathway, thereby contributing to central sensitization and implicating its involvement in chronic migraine pathogenesis.

Expression of Inflammation Depending on the Stage of Cervical Cancer.

Background and Objectives: Cervical cancer (CC) remains a major public health problem, ranking as the fourth most common cause of cancer incidence and mortality in women globally. The development of CC is believed to be closely related to chronic inflammation. Thus, we aimed to evaluate the expression of systemic inflammation in patients with CC and to determine the threshold prognostic value of the systemic inflammation markers for CC and its advanced stage. Materials and Methods: 182 participants were recruited: 94 histology-proven patient with CC and 88 healthy women with NILM confirmed by liquid-based cytology test. The pre-treatment serum concentrations of cytokines, including IFN-ß, IFN-γ, IL-1ß, IL-2, IL-6, IL-10, IL-12p70, LCN2, TREM-1, and TNF-α, were determined for all study patients. Results: The odds ratio (OR) of having IL-6 concentration >17.4 pg/mL in the CC group compared to control patients was 11.4 (95% CI: 4.897-26.684); that of having TREM-1 concentration >355.6 pg/mL was 5.9 (95% CI: 2.257-15.767); and that of having LCN2 concentration >23,721.5 pg/mL was 3.4 (95% CI: 1.455-8.166). The odds ratio (OR) of having IL-6 concentration >28.7 pg/mL in advanced-stage CC (III-IV stage) compared to early-stage CC (I-II stage) was 2.921 (95% CI: 1.06-8.045), and that of having LCN2 concentration >25,640.0 pg/mL was 4.815 (95% CI: 1.78-13.026). Conclusions: The pre-treatment serum inflammation markers IL-6, TREM-1, and LCN2 at specified levels could be used as predictors of cervical cancer, and IL-6 and LCN2 as predictors of an increased chance of advanced-stage (III-IV stages) cervical cancer. Patients with cervical cancer had expressed systemic inflammation, and expression of inflammation elevated the chance of having CC and advanced-stage disease.

CCR2+TREM-1+ monocytes promote natural killer T cell dysfunction contributing towards HBV disease progression.

Natural killer T (NKT) cells are amongst the most important innate immune cells against hepatitis B virus (HBV) infection. Moreover, previous studies have shown that HBV infection induced TREM-1+ expression in monocyte and secretion of inflammatory cytokines. Thus, this prompted us to elucidate the role of TREM-1+ monocytes in regulating the function of iNKT cells. Ninety patients and 20 healthy participants were enrolled in the study. The percentage and phenotype of iNKT cells and TREM-1+ monocytes were measured in the peripheral blood of healthy controls (HC), patients with chronic HBV infection (CHB), HBV-related liver cirrhosis (LC), and HBV-related acute-on-chronic liver failure (ACLF) via flow cytometry. Moreover, co-culture experiments with iNKT cells and TREM-1 overexpressing THP-1 cells were performed to determine the role of TREM-1 in the regulation of NKT cell function. We observed that the percentage of iNKT cells and CD4-iNKT cells gradually decreased, whereas the percentage of CCR2+TREM-1+ monocytes increased with the progression of the disease. In addition, activation of the TREM-1 signaling pathway induced the secretion of inflammatory cytokines leading to pyroptosis of iNKT cells and secretion of IL-17 contributing towards disease progression. Therefore, this study suggests that blocking the activation of TREM-1 in monocytes could promote the elimination of HBV by inhibiting pyroptosis of iNKT cells and restoring their function. However, further studies are required to validate these results that would help in developing new treatment strategies for patients with HBV infections.

Eosinophil expression of triggering receptor expressed on myeloid cells 1 (TREM-1) restricts type 2 lung inflammation.

Asthma affects 25 million Americans, and recent advances in treatment are effective for only a portion of severe asthma patients. TREM-1, an innate receptor that canonically amplifies inflammatory signaling in neutrophils and monocytes, plays a central role in regulating lung inflammation. It is unknown how TREM-1 contributes to allergic asthma pathology. Utilizing a murine model of asthma, flow cytometry revealed TREM-1+ eosinophils in the lung tissue and airway during allergic airway inflammation. TREM-1 expression was restricted to recruited, inflammatory eosinophils. Expression was induced on bone marrow-derived eosinophils by incubation with interleukin 33, lipopolysaccharide, or granulocyte-macrophage colony-stimulating factor. Compared to TREM-1- airway eosinophils, TREM-1+ eosinophils were enriched for proinflammatory gene sets, including migration, respiratory burst, and cytokine production. Unexpectedly, eosinophil-specific ablation of TREM-1 exacerbated airway interleukin (IL) 5 production, airway MUC5AC production, and lung tissue eosinophil accumulation. Further investigation of transcriptional data revealed apoptosis and superoxide generation-related gene sets were enriched in TREM-1+ eosinophils. Consistent with these findings, annexin V and caspase-3/7 staining demonstrated higher rates of apoptosis among TREM-1+ eosinophils compared to TREM-1- eosinophils in the inflammatory airway. In vitro, Trem1/3-/- bone marrow-derived eosinophils consumed less oxygen than wild-type in response to phorbol myristate acetate, suggesting that TREM-1 promotes superoxide generation in eosinophils. These data reveal protein-level expression of TREM-1 by eosinophils, define a population of TREM-1+ inflammatory eosinophils, and demonstrate that eosinophil TREM-1 restricts key features of type 2 lung inflammation.

Increased serum levels of high-mobility group box 1 protein and the location characteristics in the patients of intracranial aneurysms.

OBJECTIVE: Inflammation-related factors play a crucial role in intracranial aneurysms (IA) initiation, progression, and rupture. High mobility group box 1 (HMGB-1) serves as an alarm to drive the pathogenesis of the inflammatory disease. This study aimed to evaluate the role of HMGB-1 in IA and explore the correlation with other inflammatory-related factors. METHODS: A total of twenty-eight adult male Japanese white rabbits were included in with elastase-induced aneurysms, n = 18) and the control group (normal rabbits, n = 10). To assess the expression of HMGB-1, both reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) was performed on serum samples obtained from human subjects (10 patients with IA and 10 healthy donors) as well as from rabbits (aneurysm group and control group). Immunohistochemistry and immunofluorescence were employed to evaluate the expression levels of elastic fibers, HMGB-1, tumor necrosis factor-alpha (TNF-α), and triggering receptor expressed on myeloid cells-1 (TREM-1). RESULTS: The expression of HMGB-1 was found to be significantly higher in the IA group compared to the control group, both at the mRNA and protein levels (P < 0.0001). Similar findings were observed in the rabbit aneurysm model group compared to the control group (P < 0.0001). HMGB-1 expression was observed to be more abundant in the inner wall of the aneurysm compared to the external wall, whereas in the control group, it was rarely scattered. Additionally, the localization patterns of TNF-α and TREM-1 exhibited similar characteristics to HMGB-1. CONCLUSION: Our findings demonstrate that HMGB-1 is highly expressed in both IA patients and rabbit aneurysm models. Furthermore, the similar localization patterns of HMGB-1, TNF-α, and TREM-1 suggest their potential involvement in the inflammatory processes associated with IA. These results highlight the potential of HMGB-1 as a novel therapeutic target for IA.

Inhibition of TREM-1 alleviates neuroinflammation by modulating microglial polarization via SYK/p38MAPK signaling pathway after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI), as a major public health problem, is characterized by high incidence rate, disability rate, and mortality rate. Neuroinflammation plays a crucial role in the pathogenesis of TBI. Triggering receptor expressed on myeloid cells-1 (TREM-1) is recognized as an amplifier of the inflammation in diseases of the central nervous system (CNS). However, the function of TREM-1 remains unclear post-TBI. This study aimed to investigate the function of TREM-1 in neuroinflammation induced by TBI. METHODS: Brain water content (BWC), modified neurological severity score (mNSS), and Morris Water Maze (MWM) were measured to evaluate the effect of TREM-1 inhibition on nervous system function and outcome after TBI. TREM-1 expression in vivo was evaluated by Western blotting. The cellular localization of TREM-1 in the damaged region was observed via immunofluorescence staining. We also conducted Western blotting to examine expression of SYK, p-SYK and other downstream proteins. RESULTS: We found that inhibition of TREM-1 reduced brain edema, decreased mNSS and improved neurobehavioral outcomes after TBI. It was further determined that TREM-1 was expressed on microglia and modulated subtype transition of microglia. Inhibition of TREM-1 alleviated neuroinflammation, which was associated with SYK/p38MAPK signaling pathway. CONCLUSIONS: These findings suggest that TREM-1 can be a potential clinical therapeutic target for alleviating neuroinflammation after TBI.

Cigarette Smoke Extract-Treated Mouse Airway Epithelial Cells-Derived Exosomal LncRNA MEG3 Promotes M1 Macrophage Polarization and Pyroptosis in Chronic Obstructive Pulmonary Disease by Upregulating TREM-1 via m6A Methylation.

Cigarette smoke extract (CSE)-treated mouse airway epithelial cells (MAECs)-derived exosomes accelerate the progression of chronic obstructive pulmonary disease (COPD) by upregulating triggering receptor expressed on myeloid cells 1 (TREM-1); however, the specific mechanism remains unclear. We aimed to explore the potential mechanisms of CSE-treated MAECs-derived exosomes on M1 macrophage polarization and pyroptosis in COPD. In vitro, exosomes were extracted from CSE-treated MAECs, followed by co-culture with macrophages. In vivo, mice exposed to cigarette smoke (CS) to induce COPD, followed by injection or/and intranasal instillation with oe-TREM-1 lentivirus. Lung function and pathological changes were evaluated. CD68+ cell number and the levels of iNOS, TNF-α, IL-1ß (M1 macrophage marker), and pyroptosis-related proteins (NOD-like receptor family pyrin domain containing 3, apoptosis-associated speck-like protein containing a caspase-1 recruitment domain, caspase-1, cleaved-caspase-1, gasdermin D [GSDMD], and GSDMD-N) were examined. The expression of maternally expressed gene 3 (MEG3), spleen focus forming virus proviral integration oncogene (SPI1), methyltransferase 3 (METTL3), and TREM-1 was detected and the binding relationships among them were verified. MEG3 increased N6-methyladenosine methylation of TREM-1 by recruiting SPI1 to activate METTL3. Overexpression of TREM-1 or METTL3 negated the alleviative effects of MEG3 inhibition on M1 polarization and pyroptosis. In mice exposed to CS, EXO-CSE further aggravated lung injury, M1 polarization, and pyroptosis, which were reversed by MEG3 inhibition. TREM-1 overexpression negated the palliative effects of MEG3 inhibition on COPD mouse lung injury. Collectively, CSE-treated MAECs-derived exosomal long non-coding RNA MEG3 may expedite M1 macrophage polarization and pyroptosis in COPD via the SPI1/METTL3/TREM-1 axis.

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.

TREM1+ tumor-associated macrophages secrete CCL7 to promote hepatocellular carcinoma metastasis.

PURPOSE: Tumor-associated macrophages (TAMs) play a critical role in hepatocellular carcinoma (HCC) progression and metastasis. Systematic investigation of the cross-talk between TAMs and HCC may help in searching for the critical target to guard against HCC metastasis. METHODS AND RESULTS: Herein, we found that TREM1 highly expressed in HCC tissue by analyzing the data obtain from GEO database. Interestingly, the results indicated that TREM1 was primarily expressed by monocytes. Immune infiltration studies further validated that TREM1 expression was positively related with increased infiltration of macrophages in HCC tissues. In vitro, we observed that TREM1 knockdown significantly abrogated the effect of TAMs in promoting the metastasis and epithelial-mesenchymal transition (EMT) of HCC cells. Additionally, cytokine array detection identified CCL7 as the main responsive cytokine following with TREM1 knockdown in TAMs. CONCLUSION: Taken together, our findings strongly suggested that high expression of TREM1 was positively associated with metastasis and poor prognosis of HCC. Furthermore, TAMs expressing TREM1 contribute to EMT-based metastasis through secreting CCL7. These results provide a novel insight into the potential development of targeting the TREM1/CCL7 pathway for preventing metastatic HCC.

Triggering Receptor Expression on Myeloid Cells-1 (TREM1) Promoter Hypomethylation and Its Overexpression Associated With Poor Survival of Cancer Patients: A Pan-Cancer Analysis.

Background Triggering receptor expression on myeloid cells-1 (TREM1) belongs to the immunoglobulin superfamily and is implicated in various conditions, including infectious and non-infectious diseases, autoimmune disorders, and cancer. Notably, TREM1 is significantly dysregulated in numerous cancer types. However, the underlying mechanism driving TREM1 mRNA expression in cancers remains unclear.  Objective This study aims to analyze the promoter methylation level of TREM1 and its overexpression with cancer. Methods  This study utilized The Cancer Genome Atlas (TCGA) cohort to analyze the methylation and expression levels of TREM1 in cancers. The University of ALabama at Birmingham CANcer (UALCAN) database facilitated data analysis from the TCGA dataset. Additionally, survival analysis was conducted using the TCGA dataset via Kaplan-Meier (KM) plots to identify significant associations with prognosis. Results Promoter methylation analysis revealed that TREM1 is hypomethylated in cancers, resulting in significantly overexpressed mRNA across various cancer types. This methylation and expression showed a negative correlation. Furthermore, high TREM1 mRNA expression was linked to poor prognosis in several cancers. Conclusion TREM1 gene expression negatively correlates with promotor DNA methylation and is associated with poor survival. It may serve as a prognostic marker and biomarker for various cancers. Future research should focus on further validation and antitumor immunity to elucidate its oncogenic role in cancers.

Pharmacological Inhibition or Silencing of TREM1 Restrains HCC Cell Metastasis by Inactivating TLR/PI3K/AKT Signaling.

Hepatocellular carcinoma (HCC), a widely prevalent malignancy strongly linked to inflammation, remains a significant public health concern. Triggering receptor expressed on myeloid cells 1 (TREM1), a modulator of inflammatory responses identified in recent years, has emerged as a crucial facilitator in cancer progression. Despite its significance, the precise regulatory mechanism of TREM1 in HCC metastasis remains unanswered. In the present investigation, we observed aberrant upregulation of TREM1 in HCC tissues, which was significantly linked to poorer overall survival. Inhibition of TREM1 expression resulted in a significant reduction in HCC Huh-7 and MHCC-97H cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) process. Furthermore, inhibiting TREM1 decreased protein expressions of toll-like receptor 2/4 (TLR2/4) and major myeloid differentiation response gene 88 (MyD88), leading to the inactivation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in HCC cells. Notably, these effects were reversed by treatment with TLR2-specific agonist (CU-T12-9), indicating a potential crosstalk between TREM1 and TLR2/4. Mechanistic studies revealed a direct interaction between TREM1 and both TLR2 and TLR4. In vivo studies demonstrated that inhibition of TREM1 suppressed the growth of HCC cells in the orthotopic implant model and its metastatic potential in the experimental lung metastasis model. Overall, our findings underscore the role of TREM1 inhibition in regulating EMT and metastasis of HCC cells by inactivating the TLR/PI3K/AKT signaling pathway, thereby providing deeper mechanistic insights into how TREM1 regulates metastasis during HCC progression.

Osteoclast-derived exosomes influence osteoblast differentiation in osteoporosis progression via the lncRNA AW011738/ miR-24-2-5p/ TREM1 axis.

AIMS: To investigate the molecular mechanism of osteoclast-derived exosomes in osteoporosis. MAIN METHODS: RANKL induced osteoclast model was screened for significantly differentially expressed lncRNAs and mRNAs by whole RNA sequencing. Exosomes were characterized using electron microscopy, western blotting and nanosight. Overexpression or knockdown of AW011738 was performed to explore its function. The degree of osteoporosis in an osteoporosis model was assessed by mirco-CT. The osteoclast model, osteoblast differentiation ability and the molecular mechanism of lncRNA AW011738/miR-24-2-5p/TREM1 axis in osteoporosis were assessed by dual luciferase reporter gene assay, Western blotting (WB), immunofluorescence and ALP staining. Bioinformatics was used to predict interactions of key osteoporosis-related genes with miRNAs, transcription factors, and potential drugs after upregulation of AW011738. To predict the protein-protein interaction (PPI) network associated with key genes, GO and KEGG analyses were performed on the key genes. The ssGSVA was used to predict changes in the immune microenvironment. KEY FINDINGS: Osteoclast-derived exosomes containing lncRNA AW011738 decreased the osteogenesis-related markers and accelerated bone loss in OVX mice. Osteoclast (si-AW011738)-derived exosomes showed a significant increase in biomarkers of osteoblast differentiation in vitro compared to the si-NC group. As analyzed by mirco-CT, tail vein injected si-AW011738 OVX mice were less osteoporotic than the control group. AW011738 inhibited osteoblast differentiation by regulating TREM1 expression through microRNA. Meanwhile, overexpression of miR-24-2-5p inhibited TREM1 expression to promote osteoblast differentiation. SIGNIFICANCE: Osteoclast-derived exosomes containing lncRNA AW011738 inhibit osteogenesis in MC3T3-E1 cells through the lncRNA AW011738/miR-24-2-5p/TREM1 axis and exacerbate osteoporosis in OVX mice.

TREM1 promotes cancer associated malignant phenotype through activated MAPK signaling pathway and predicts poor prognosis in gastric cancer.

Background: CD molecules plays a vital role in gastric cancer (GC). We used bioinformatics analysis methods to develop prognosis related CD molecules risk signature; On the other hand, we used the experiments to further explore the function and mechanism of differentially expressed prognostic CD molecules (TREM1) in GC. Methods: Kaplan-Meier survival and univariate Cox regression analysis were used to evaluate the overall survival of CD molecule genes in gastric cancer. ROC curve and Kaplan-Meier curves were used to analyze the predictive value of CD molecule related genes risk signature by "survival and timeROC" R packages. GSEA, and Cibersortx software were used to analyze the functional enrichment. Finally, we verified the function and mechanism of TREM1 in GC by gene silencing and MAPK inhibitor (SB203580) in vitro and vivo. Results: A total of 41 prognosis related risk factors in gastric cancer were identified based on CD molecules, including TREM1 and ect. The high-risk patients had higher risk score and shorter survival time. ROC curves revealed that this risk signature accurately predicted survival times of gastric cancer patients at the 1-, 2-, 3-, 4- and 5-year. The frequency of T cells follicular helper and NK cells activated were added in low-risk group. Next, differentially expressed prognostic CD molecules analysis revealed that TREM1 was identified as key genes in GC progression based on TCGA and GES158662 and GSE15459 datasets of GC. In vitro experiments, TREM1 silencing significantly inhibited GC cell proliferation and migration, induced cell apoptosis. GSEA revealed that TREM1 activated cancer related signaling pathway, including MAPK signaling pathway and ect. High expression of TREM1 was related Macrophages M2 and Mast cells resting in GC tissues. Moreover, knockdown of TREM1 inhibited tumor growth through downregulated MAPK signaling pathway in vivo. Conclusion: These results identified that CD molecule related genes as a novel prognostic and diagnostic biomarker in gastric cancer. TREM1 acts as an oncogene role in GC by activated MAPK signaling pathway.

The microglial innate immune protein PGLYRP1 mediates neuroinflammation and consequent behavioral changes.

Peptidoglycan recognition protein 1 (PGLYRP1) is a pattern-recognition protein that mediates antibacterial actions and innate immune responses. Its expression and role in neuroinflammatory conditions remain unclear. We observed the upregulation of PGLYRP1 in inflamed human and mouse spinal cord and brain, with microglia being the primary cellular source. Experiments using a recombinant PGLYRP1 protein show that PGLYRP1 potentiates reactive gliosis, neuroinflammation, and consequent behavioral changes in multiple animal models of neuroinflammation. Furthermore, shRNA-mediated knockdown of Pglyrp1 gene expression attenuates this inflammatory response. In addition, we identify triggering receptor expressed on myeloid cell-1 (TREM1) as an interaction partner of PGLYRP1 and demonstrate that PGLYRP1 promotes neuroinflammation through the TREM1-Syk-Erk1/2-Stat3 axis in cultured glial cells. Taken together, our results reveal a role for microglial PGLYRP1 as a neuroinflammation mediator. Finally, we propose that PGLYRP1 is a potential biomarker and therapeutic target in various neuroinflammatory diseases.