RESUMO
Triggering receptors expressed on myeloid cells-1 (TREM-1) are transmembrane molecules expressed in cells of the immune system. Activation of TREM-1 leads to the release of pro-inflammatory mediators, which act as amplifiers of inflammation and thereby contribute to the pathogenesis of various diseases, whether inflammatory or not. This study explored the role of TREM-1 in the etiopathogenic context of fibromyalgia syndrome (FMS) and its association with disease activity. This randomized controlled and observational study included 45 patients diagnosed with FMS according to the 2016 American College of Rheumatology criteria. Serum TREM-1 levels were assessed using ELISA, and disease activity was measured using various scales such as the fibromyalgia impact questionnaire (FIQ). Patients were divided into 2 groups according to disease severity based on the FIQ score. Compared to a control group of 46 healthy individuals, patients with FMS exhibited significantly elevated concentrations of TREM-1 (meanâ ±â SDâ =â 216.97 pg/mLâ ±â 16.04), Pâ <â .05. The FIQ, Pittsburgh sleep quality index, hospital anxiety and depression scale, fatigue severity scale, and visual analog scale, which confirm symptoms such as pain, disease severity, sleep disturbance, depression, anxiety, and fatigue seen in FMS was significantly correlated with TREM-1 level (Pâ <â .001). The optimal threshold value for TREM-1 to disease activity was determined to be 182.250, showing (area under the curve) (CI (95%)): [0.940] (0.887-0.993), a sensitivity of 97% and a specificity of 89% according to the receiver operating characteristic analysis. The positive correlation of TREM-1 with various symptom severity scales and hematological inflammatory indices may be a suitable biomarker for the diagnosis of FMS and a potential therapeutic target.
Assuntos
Biomarcadores , Fibromialgia , Índice de Gravidade de Doença , Receptor Gatilho 1 Expresso em Células Mieloides , Humanos , Fibromialgia/sangue , Fibromialgia/diagnóstico , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Feminino , Biomarcadores/sangue , Estudos Transversais , Pessoa de Meia-Idade , Masculino , Adulto , Curva ROCRESUMO
BACKGROUND AND OBJECTIVES: Neutrophils, underestimated in multiple sclerosis (MS), are gaining increased attention for their significant functions in patients with MS and the experimental autoimmune encephalomyelitis (EAE) animal model. However, the precise role of neutrophils in cervical lymph nodes (CLNs), the primary CNS-draining lymph nodes where the autoimmune response is initiated during the progression of EAE, remains poorly understood. METHODS: Applying single-cell RNA sequencing (scRNA-seq), we constructed a comprehensive immune cell atlas of CLNs during development of EAE. Through this atlas, we concentrated on and uncovered the transcriptional landscape, phenotypic and functional heterogeneity of neutrophils, and their crosstalk with immune cells within CLNs in the neuroinflammatory processes in EAE. RESULTS: Notably, we observed a substantial increase in the neutrophil population in EAE mice, with a particular emphasis on the significant rise within the CLNs. Neutrophils in CLNs were categorized into 3 subtypes, and we explored the specific roles and developmental trajectories of each distinct neutrophil subtype. Neutrophils were found to engage in extensive interactions with other immune cells, playing crucial roles in T-cell activation. Moreover, our findings highlighted the strong migratory ability of neutrophils to CLNs, partly regulated by triggering the receptor expressed on myeloid cells 1 (TREM-1). Inhibiting TREM1 with LR12 prevents neutrophil migration both in vivo and in vitro. In addition, in patients with MS, we confirmed an increase in peripheral neutrophils with an upregulation of TREM-1. DISCUSSION: Our research provides a comprehensive and precise single-cell atlas of CLNs in EAE, highlighting the role of neutrophils in regulating the periphery immune response. In addition, TREM-1 emerged as an essential regulator of neutrophil migration to CLNs, holding promise as a potential therapeutic target in MS.
Assuntos
Encefalomielite Autoimune Experimental , Camundongos Endogâmicos C57BL , Neutrófilos , Análise de Célula Única , Receptor Gatilho 1 Expresso em Células Mieloides , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/genética , Neutrófilos/metabolismo , Neutrófilos/imunologia , Animais , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Camundongos , Feminino , Análise de Sequência de RNA , Linfonodos/metabolismoRESUMO
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.
Assuntos
Biomarcadores , AVC Isquêmico , Glicoproteínas de Membrana , Receptores Imunológicos , Índice de Gravidade de Doença , Receptor Gatilho 1 Expresso em Células Mieloides , Humanos , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Masculino , Feminino , AVC Isquêmico/metabolismo , AVC Isquêmico/sangue , AVC Isquêmico/patologia , Receptores Imunológicos/metabolismo , Receptores Imunológicos/sangue , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/sangue , Idoso , Pessoa de Meia-Idade , Biomarcadores/sangue , Células Mieloides/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/sangue , Idoso de 80 Anos ou maisRESUMO
OBJECTIVES: Identifying host response biomarkers implicated in the emergence of organ failure during infection is key to improving the early detection of this complication. METHODS: Twenty biomarkers of innate immunity, T-cell response, endothelial dysfunction, coagulation, and immunosuppression were profiled in 180 surgical patients with infections of diverse severity (IDS) and 53 with no infection (nIDS). Those better differentiating IDS/nIDS in the area under the curve were combined to test their association with the sequential organ failure assessment score by linear regression analysis in IDS. Results were validated in another IDS cohort of 174 patients. RESULTS: C-reactive protein, procalcitonin, pentraxin-3, lipocalin-2 (LCN2), tumoral necrosis factor-α, angiopoietin-2, triggering receptor expressed on myeloid cells-1 (TREM-1) and interleukin (IL)-15 yielded an area under the curve ≥0.75 to differentiate IDS from nIDS. The combination of LCN2, IL-15, TREM-1, angiopoietin-2 (Dys-4) showed the strongest association with sequential organ failure assessment score in IDS (adjusted regression coefficient; standard error; P): Dys-4 (3.55;0.44; <0.001), LCN2 (2.24; 0.28; <0.001), angiopoietin-2 (1.92; 0.33; <0.001), IL-15 (1.78; 0.40; <0.001), TREM-1(1.74; 0.46; <0.001), tumoral necrosis factor-α (1.60; 0.31; <0.001), pentraxin-3 (1.12; 0.18; <0.001), procalcitonin (0.85; 0.12; <0.001). Dys-4 provided similar results in the validation cohort. CONCLUSIONS: There is a synergistic impact of innate immunity hyper-activation (LCN2, IL-15, TREM-1) and endothelial dysfunction (angiopoietin-2) on the magnitude of organ failure during infection.
Assuntos
Angiopoietina-2 , Biomarcadores , Proteína C-Reativa , Imunidade Inata , Insuficiência de Múltiplos Órgãos , Sepse , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Biomarcadores/sangue , Insuficiência de Múltiplos Órgãos/imunologia , Sepse/imunologia , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Angiopoietina-2/sangue , Idoso , Receptor Gatilho 1 Expresso em Células Mieloides , Componente Amiloide P Sérico/metabolismo , Pró-Calcitonina/sangue , Lipocalina-2/sangue , Interleucina-15/sangue , Fator de Necrose Tumoral alfa/sangue , AdultoRESUMO
AIM: Identifying and intervening with high-risk postoperative pulmonary infections patients pose challenges in clinical practice. This study aims to conduct a comprehensively analysis of the risk factors and predictive factors associated with post-gastrointestinal surgery pulmonary infections and to develop a predictive model that can predict occurrence of pulmonary infection. METHODS: A retrospective analysis was conducted on 96 patients who underwent gastrointestinal surgery at our hospital from May 2021 to October 2023. The occurrence rate of postoperative pulmonary infections was calculated, and patients were categorized into two groups: those with pulmonary infections (the occurrence group) and those without pulmonary infections (the non-occurrence group). Logistic regression analysis was utilized to identify the risk factors for post-gastrointestinal surgery pulmonary infections and to evaluate the predictive value of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and T cell immunoglobulin and mucin domain-4 (TIM-4) using nomograms, calibration curves, and Receiver Operating Characteristic (ROC) curves. RESULTS: Out of 96 patients, 20 (20.83%) developed postoperative pulmonary infections. Significant differences were noted between occurrence and non-occurrence groups in terms of smoking (65.00% vs. 34.21%, p = 0.013), surgical duration (70.00% vs. 31.58%, p = 0.002), Preoperative hemoglobin level (35.00% vs. 65.79%, p = 0.013), sTREM-1 levels (23.57 ± 3.16 pg/mL vs. 15.62 ± 2.48 pg/mL, p < 0.001), and TIM-4 levels (61.48 ± 6.35 pg/mL vs. 44.73 ± 5.22 pg/mL, p < 0.001). Logistic regression analysis leads to the development of a risk prediction model for post-gastrointestinal surgery pulmonary infections. The high predictive values of sTREM-1 (Area Under Curve (AUC) = 0.962, 95% confidence interval (CI) 0.917~0.999) and TIM-4 (AUC = 0.970, 95% CI 0.925~1.000) were highlighted by the AUC values, underscoring their clinical importance. CONCLUSIONS: A predictive model utilizing sTREM-1 and TIM-4 for pulmonary infection following gastrointestinal surgery was developed. Additionally, other risk factors such as smoking, surgical duration, and preoperative hemoglobin level were evaluated. This finding can be applied in clinical practice to identify potentially susceptible patients and facilitate early intervention measures.
Assuntos
Procedimentos Cirúrgicos do Sistema Digestório , Complicações Pós-Operatórias , Receptor Gatilho 1 Expresso em Células Mieloides , Humanos , Estudos Retrospectivos , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Feminino , Masculino , Fatores de Risco , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Idoso , Valor Preditivo dos Testes , Adulto , Curva ROC , NomogramasAssuntos
Envelhecimento , Doença de Alzheimer , Imunidade Inata , Receptor Gatilho 1 Expresso em Células Mieloides , Doença de Alzheimer/imunologia , Humanos , Envelhecimento/imunologia , Animais , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genética , CamundongosRESUMO
Background: The disruption of the circadian clock is associated with inflammatory and immunological disorders. BMAL2, a critical circadian protein, forms a dimer with CLOCK, activating transcription. Extracellular cold-inducible RNA-binding protein (eCIRP), released during sepsis, can induce macrophage endotoxin tolerance. We hypothesized that eCIRP induces BMAL2 expression and promotes macrophage endotoxin tolerance through triggering receptor expressed on myeloid cells-1 (TREM-1). Methods: C57BL/6 wild-type (WT) male mice were subjected to sepsis by cecal ligation and puncture (CLP). Serum levels of eCIRP 20 h post-CLP were assessed by ELISA. Peritoneal macrophages (PerM) were treated with recombinant mouse (rm) CIRP (eCIRP) at various doses for 24 h. The cells were then stimulated with LPS for 5 h. The levels of TNF-α and IL-6 in the culture supernatants were assessed by ELISA. PerM were treated with eCIRP for 24 h, and the expression of PD-L1, IL-10, STAT3, TREM-1 and circadian genes such as BMAL2, CRY1, and PER2 was assessed by qPCR. Effect of TREM-1 on eCIRP-induced PerM endotoxin tolerance and PD-L1, IL-10, and STAT3 expression was determined by qPCR using PerM from TREM-1-/- mice. Circadian gene expression profiles in eCIRP-treated macrophages were determined by PCR array and confirmed by qPCR. Induction of BMAL2 activation in bone marrow-derived macrophages was performed by transfection of BMAL2 CRISPR activation plasmid. The interaction of BMAL2 in the PD-L1 promoter was determined by computational modeling and confirmed by the BIAcore assay. Results: Serum levels of eCIRP were increased in septic mice compared to sham mice. Macrophages pre-treated with eCIRP exhibited reduced TNFα and IL-6 release upon LPS challenge, indicating macrophage endotoxin tolerance. Additionally, eCIRP increased the expression of PD-L1, IL-10, and STAT3, markers of immune tolerance. Interestingly, TREM-1 deficiency reversed eCIRP-induced macrophage endotoxin tolerance and significantly decreased PD-L1, IL-10, and STAT3 expression. PCR array screening of circadian clock genes in peritoneal macrophages treated with eCIRP revealed the elevated expression of BMAL2, CRY1, and PER2. In eCIRP-treated macrophages, TREM-1 deficiency prevented the upregulation of these circadian genes. In macrophages, inducible BMAL2 expression correlated with increased PD-L1 expression. In septic human patients, blood monocytes exhibited increased expression of BMAL2 and PD-L1 in comparison to healthy subjects. Computational modeling and BIAcore assay identified a putative binding region of BMAL2 in the PD-L1 promoter, suggesting BMAL2 positively regulates PD-L1 expression in macrophages. Conclusion: eCIRP upregulates BMAL2 expression via TREM-1, leading to macrophage endotoxin tolerance in sepsis. Targeting eCIRP to maintain circadian rhythm may correct endotoxin tolerance and enhance host resistance to bacterial infection.
Assuntos
Proteínas de Ligação a RNA , Sepse , Animais , Humanos , Masculino , Camundongos , Fatores de Transcrição ARNTL/genética , Modelos Animais de Doenças , Endotoxinas/imunologia , Tolerância Imunológica , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Sepse/imunologia , Sepse/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismoRESUMO
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.
Assuntos
Carcinoma Hepatocelular , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas , Receptor Gatilho 1 Expresso em Células Mieloides , Feminino , Humanos , Masculino , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Metástase Neoplásica , Prognóstico , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/patologiaRESUMO
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.
Assuntos
Neoplasias , Transdução de Sinais , Receptor Gatilho 1 Expresso em Células Mieloides , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Humanos , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/genética , Neoplasias/patologia , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
ABSTRACT: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. As an amplifier of the inflammatory response, TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival. TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders. More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases. There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease. This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury, renal fibrosis, diabetic nephropathy, immune nephropathy, and renal cell carcinoma.
Assuntos
Biomarcadores , Nefropatias , Receptor Gatilho 1 Expresso em Células Mieloides , Humanos , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Nefropatias/metabolismo , Biomarcadores/metabolismo , Receptores Imunológicos/metabolismo , Glicoproteínas de Membrana/metabolismo , Nefropatias Diabéticas/metabolismo , Transdução de Sinais , Injúria Renal Aguda/metabolismo , Animais , Carcinoma de Células Renais/metabolismoRESUMO
The Triggering Receptor Expressed on Myeloid Cells (TREM) family of receptors plays a crucial role in the immune response across various species. Particularly, TREM-1 and TREM-2 have been extensively studied, both in terms of their applications and their expression sites and signaling pathways. However, the same is not observed for the other family members collectively known as TREM-like-transcripts (TREML). The TREML family consists of eight receptors, with TREML1-5 identified in humans and mice, TREML-6 exclusive found in mice, TREML-7 in dogs and horses, and TREML-8 in rabbits and opossums. Despite the limited data available on the TREML members, they have been implicated in different immune and non-immune activities, which have been proposed to display both pro and anti-inflammatory activities, and to influence fundamental biological processes such as coagulation, bone and neurological development. In this review, we have compiled available information regarding the already discovered members of the family and provided foundational framework for understanding the function, localization, and therapeutic potential of all TREML members. Additionally, we hope that this review may shed light on this family of receptors, whose underlying mechanisms are still awaiting elucidation, while emphasizing the need for future studies to explore their functions and potential therapeutic application.
Assuntos
Receptores Imunológicos , Animais , Humanos , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Transdução de Sinais , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genéticaRESUMO
BACKGROUND: Acute decompensation (AD) of cirrhosis is associated with high short-term mortality, mainly due to the development of acute-on-chronic liver failure (ACLF). Thus, there is a need for biomarkers for early and accurate identification of AD patients with high risk of development of ACLF and mortality. Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is released from activated innate immune cells and correlated with various inflammatory processes. AIM: To explore the prognostic value of sTREM-1 in patients with AD of cirrhosis. METHODS: A multicenter prospective cohort of 442 patients with cirrhosis hospitalized for AD was divided into a study cohort (n = 309) and validation cohort (n = 133). Demographic and clinical data were collected, and serum sTREM-1 was measured at admission. All enrolled patients were followed-up for at least 1 year. RESULTS: In patients with AD and cirrhosis, serum sTREM-1 was an independent prognosis predictor for 1-year survival and correlated with liver, coagulation, cerebral and kidney failure. A new prognostic model of AD (P-AD) incorporating sTREM-1, blood urea nitrogen (BUN), total bilirubin (TBil), international normalized ratio (INR) and hepatic encephalopathy grades was established and performed better than the model for end-stage liver disease (MELD), MELD-sodium (MELD-Na), chronic liver failure-consortium (CLIF-C) ACLF and CLIF-C AD scores. Additionally, sTREM-1 was increased in ACLF and predicted the development of ACLF during first 28-d follow-up. The ACLF risk score incorporating serum sTREM-1, BUN, INR, TBil and aspartate aminotransferase levels was established and significantly superior to MELD, MELD-Na, CLIF-C ACLF, CLIF-C AD and P-AD in predicting risk of ACLF development. CONCLUSION: Serum sTREM-1 is a promising prognostic biomarker for ACLF development and mortality in patients with AD of cirrhosis.
Assuntos
Insuficiência Hepática Crônica Agudizada , Doença Hepática Terminal , Humanos , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/complicações , Biomarcadores , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Receptor Gatilho 1 Expresso em Células MieloidesRESUMO
OBJECTIVE: Early diagnosis of Severity Mycoplasma Pneumoniae Pneumonia (SMPP) has been a worldwide concern in clinical practice. Two cytokines, soluble Triggering Receptor Expressed on Myeloid cells (sTREM-1) and Interferon-Inducible Protein-10 (IP-10), were proved to be implicated in bacterial infection diseases. However, the diagnostic value of sTREM-1 and IP-10 in MPP was poorly known. This study aimed to investigate the diagnostic value of sTREM-1 and IP-10 for SMPP. METHODS: In this prospective study, the authors enrolled 44 children with MPP, along with their clinical information. Blood samples were collected, and cytokine levels of sTREM-1 and IP-10 were detected with ELISA assay. RESULTS: Serum levels of sTREM-1 and IP-10 were positively correlated with the severity of MPP. In addition, sTREM-1 and IP-10 have significant potential in the diagnosis of SMPP with an Area Under Curve (AUC) of 0.8564 (p-value = 0.0001, 95% CI 0.7461 to 0.9668) and 0.8086 (p-value = 0.0002, 95% CI 0.6918 to 0.9254) respectively. Notably, the combined diagnostic value of sTREM-1 and IP-10 is up to 0.911 in children with SMPP (p-value < 0.001, 95% CI 0.830 to 0.993). CONCLUSIONS: Serum cytokine levels of sTREM-1 and IP-10 have a great potential diagnostic value in children with SMPP.
Assuntos
Biomarcadores , Quimiocina CXCL10 , Ensaio de Imunoadsorção Enzimática , Pneumonia por Mycoplasma , Receptores Imunológicos , Índice de Gravidade de Doença , Receptor Gatilho 1 Expresso em Células Mieloides , Humanos , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Feminino , Masculino , Pneumonia por Mycoplasma/diagnóstico , Pneumonia por Mycoplasma/sangue , Criança , Estudos Prospectivos , Pré-Escolar , Quimiocina CXCL10/sangue , Receptores Imunológicos/sangue , Biomarcadores/sangue , Glicoproteínas de Membrana/sangue , Mycoplasma pneumoniae , Lactente , Sensibilidade e Especificidade , Curva ROC , AdolescenteRESUMO
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.
Assuntos
Lesões Encefálicas Traumáticas , Microglia , Doenças Neuroinflamatórias , Quinase Syk , Receptor Gatilho 1 Expresso em Células Mieloides , Proteínas Quinases p38 Ativadas por Mitógeno , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/tratamento farmacológico , Animais , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Microglia/metabolismo , Microglia/efeitos dos fármacos , Quinase Syk/metabolismo , Quinase Syk/antagonistas & inibidores , Masculino , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Edema Encefálico/metabolismo , Edema Encefálico/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos Endogâmicos C57BLRESUMO
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.
Assuntos
Eosinófilos , Pneumonia , Receptor Gatilho 1 Expresso em Células Mieloides , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Animais , Eosinófilos/metabolismo , Eosinófilos/imunologia , Eosinófilos/patologia , Camundongos , Pneumonia/metabolismo , Pneumonia/patologia , Camundongos Endogâmicos C57BL , Asma/metabolismo , Asma/patologia , Asma/imunologia , Pulmão/patologia , Pulmão/metabolismo , Pulmão/imunologiaRESUMO
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.
Assuntos
Envelhecimento , Doença de Alzheimer , Modelos Animais de Doenças , Metabolismo Energético , Microglia , Receptor Gatilho 1 Expresso em Células Mieloides , Animais , Camundongos , Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Cognição/fisiologia , Metabolismo Energético/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genéticaRESUMO
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.
Assuntos
Células-Tronco Neoplásicas , Receptor Gatilho 1 Expresso em Células Mieloides , Microambiente Tumoral , Macrófagos Associados a Tumor , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/imunologia , Animais , Linhagem Celular Tumoral , Transdução de Sinais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/imunologia , Glioma/patologia , Glioma/genética , Glioma/metabolismo , Glioma/imunologia , Camundongos , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/imunologia , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Regulação Neoplásica da Expressão Gênica , Proteína Smad2/metabolismo , Proteína Smad2/genéticaRESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Imunoterapia Adotiva , Neoplasias Pulmonares , Proteínas de Membrana , Receptores de Antígenos Quiméricos , Carcinoma de Pequenas Células do Pulmão , Receptor Gatilho 1 Expresso em Células Mieloides , Ensaios Antitumorais Modelo de Xenoenxerto , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapia , Humanos , Animais , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia Adotiva/métodos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Linhagem Celular Tumoral , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Camundongos SCID , FemininoRESUMO
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.
Assuntos
Interleucina-6 , Neoplasias do Colo do Útero , Humanos , Feminino , Receptor Gatilho 1 Expresso em Células Mieloides , Citocinas , Inflamação , BiomarcadoresRESUMO
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.