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Flores E, Estébanez B, Quintana M, Fernández-Puntero B, Nanwani K, Cachafeiro L, Martínez JR, Agrifoglio A, Sánchez-Sánchez M. Usefulness of mid-regional proadrenomedullin levels in the resuscitation phase of severely burned patients and its utility in early sepsis detection. Burns 2024; 50:1519-1527. [PMID: 38570251 DOI: 10.1016/j.burns.2024.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 02/29/2024] [Accepted: 03/05/2024] [Indexed: 04/05/2024]
Abstract
INTRODUCTION Mid-regional proadrenomedullin (MR-proADM) reflects the adrenomedullin level, which has vasodilatory activity, decreases endothelial permeability, and downregulates proinflammatory cytokines. Sepsis diagnosis in these patients is difficult, and MR-proADM is a widely studied sepsis biomarker. This study evaluates MR-proADM levels during the resuscitation phase, considering the potential influence of haemodynamic changes and its usefulness for the early sepsis detection in burn patients. METHODS A prospective observational study performed in the Critical Burn Unit. Demographic data, burn characteristics, comorbidities, prognostic/severity scales, and haemodynamic parameters were collected. The resuscitation protocol guided by diuresis, transpulmonary thermodilution, and lactate levels was followed. Blood samples were collected at various time points for biomarker measurement. Biomarker levels, including MR-proADM, C-reactive protein, and procalcitonin were measured during the resuscitation phase and septic episodes. RESULTS Twenty-seven patients were included, with a mean age of 51 years, a mean total body surface area burn of 41.8%, a mean Abbreviated Burn Severity Index of 9.7, and a mean Baux score of 92. MR-proADM levels were elevated on admission (0.9 ± 0.5 nmol/l) and continued to increase slightly during the resuscitation phase (2.4 ± 2.2 nmol/l). Haemodynamic changes during resuscitation did not significantly affect MR-proADM levels. Twelve of the 27 patients developed sepsis, whose MR-proADM levels were significantly elevated on the day of clinical diagnosis (3.91 ± 2.99 nmol/l) and even the day before (2.57 ± 3.37). Higher MR-proADM levels were associated with greater severity as measured by the Sequential Organ Failure Assessment score. The mean MR-proadrenomedullin values during resuscitation in the patients who died was 3.51 ± 2.30 nmol/l, whereas in the survivors it was 1.28 ± 1.10 nmol/l (p = 0.0001). CONCLUSION MR-proadrenomedullin values are elevated after thermal injury but are not affected by haemodynamic changes. During septic episodes in burn patients, MR-proADM rises early (the day before sepsis diagnosis). Higher levels of MR-proADM are associated with greater organ dysfunction and mortality.
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Affiliation(s)
- Eva Flores
- Intensive Medicine Department, Hospital Universitario La Paz, Madrid, Spain.
| | - Belén Estébanez
- Intensive Medicine Department, Hospital Universitario La Paz, Madrid, Spain
| | - Manuel Quintana
- Intensive Medicine Department, Hospital Universitario La Paz, Madrid, Spain
| | | | - Kapil Nanwani
- Intensive Medicine Department, Hospital Universitario La Paz, Madrid, Spain
| | - Lucia Cachafeiro
- Intensive Medicine Department, Hospital Universitario La Paz, Madrid, Spain
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Wilson EN, Wang C, Swarovski MS, Zera KA, Ennerfelt HE, Wang Q, Chaney A, Gauba E, Ramos Benitez JA, Le Guen Y, Minhas PS, Panchal M, Tan YJ, Blacher E, A Iweka C, Cropper H, Jain P, Liu Q, Mehta SS, Zuckerman AJ, Xin M, Umans J, Huang J, Durairaj AS, Serrano GE, Beach TG, Greicius MD, James ML, Buckwalter MS, McReynolds MR, Rabinowitz JD, Andreasson KI. TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models. Nat Neurosci 2024; 27:873-885. [PMID: 38539014 PMCID: PMC11102654 DOI: 10.1038/s41593-024-01610-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 02/22/2024] [Indexed: 04/21/2024]
Abstract
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-β42 oligomer-induced bioenergetic changes, suggesting that amyloid-β42 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.
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Affiliation(s)
- Edward N Wilson
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
| | - Congcong Wang
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Michelle S Swarovski
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Kristy A Zera
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Hannah E Ennerfelt
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Qian Wang
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Aisling Chaney
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Esha Gauba
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Javier A Ramos Benitez
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Yann Le Guen
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Paras S Minhas
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Maharshi Panchal
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Yuting J Tan
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Eran Blacher
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Chinyere A Iweka
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Haley Cropper
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Poorva Jain
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Qingkun Liu
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Swapnil S Mehta
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Abigail J Zuckerman
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Matthew Xin
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Jacob Umans
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Jolie Huang
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Aarooran S Durairaj
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Geidy E Serrano
- Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA
| | - Thomas G Beach
- Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA
| | - Michael D Greicius
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
| | - Michelle L James
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Marion S Buckwalter
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Melanie R McReynolds
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
- Department of Chemistry, Princeton University, Princeton, NJ, USA
- Department of Biochemistry and Molecular Biology, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA
| | - Joshua D Rabinowitz
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
- Department of Chemistry, Princeton University, Princeton, NJ, USA
| | - Katrin I Andreasson
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
- Chan Zuckerberg Biohub, San Francisco, CA, USA.
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Chaney AM, Cropper HC, Jain P, Wilson E, Simonetta F, Johnson EM, Alam IS, Patterson ITJ, Swarovski M, Stevens MY, Wang Q, Azevedo C, Nagy SC, Ramos Benitez J, Deal EM, Vogel H, Andreasson KI, James ML. PET imaging of TREM1 identifies CNS-infiltrating myeloid cells in a mouse model of multiple sclerosis. Sci Transl Med 2023; 15:eabm6267. [PMID: 37379371 DOI: 10.1126/scitranslmed.abm6267] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 06/02/2023] [Indexed: 06/30/2023]
Abstract
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that causes substantial morbidity and diminished quality of life. Evidence highlights the central role of myeloid lineage cells in the initiation and progression of MS. However, existing imaging strategies for detecting myeloid cells in the CNS cannot distinguish between beneficial and harmful immune responses. Thus, imaging strategies that specifically identify myeloid cells and their activation states are critical for MS disease staging and monitoring of therapeutic responses. We hypothesized that positron emission tomography (PET) imaging of triggering receptor expressed on myeloid cells 1 (TREM1) could be used to monitor deleterious innate immune responses and disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We first validated TREM1 as a specific marker of proinflammatory, CNS-infiltrating, peripheral myeloid cells in mice with EAE. We show that the 64Cu-radiolabeled TREM1 antibody-based PET tracer monitored active disease with 14- to 17-fold higher sensitivity than translocator protein 18 kDa (TSPO)-PET imaging, the established approach for detecting neuroinflammation in vivo. We illustrate the therapeutic potential of attenuating TREM1 signaling both genetically and pharmacologically in the EAE mice and show that TREM1-PET imaging detected responses to an FDA-approved MS therapy with siponimod (BAF312) in these animals. Last, we observed TREM1+ cells in clinical brain biopsy samples from two treatment-naïve patients with MS but not in healthy control brain tissue. Thus, TREM1-PET imaging has potential for aiding in the diagnosis of MS and monitoring of therapeutic responses to drug treatment.
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Affiliation(s)
- Aisling M Chaney
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
- Department of Radiology, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Haley C Cropper
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
| | - Poorva Jain
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
| | - Edward Wilson
- Department of Neurology and Neurological Science, Stanford University, Stanford, CA 94305, USA
| | - Federico Simonetta
- Division of Hematology, Department of Oncology, Geneva University Hospitals, Geneva 1205, Switzerland
- Translational Research Centre in Onco-Haematology, Faculty of Medicine, University of Geneva, Geneva 1205, Switzerland
| | - Emily M Johnson
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
| | - Israt S Alam
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
| | - Ian T J Patterson
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
| | - Michelle Swarovski
- Department of Neurology and Neurological Science, Stanford University, Stanford, CA 94305, USA
| | - Marc Y Stevens
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
| | - Qian Wang
- Department of Neurology and Neurological Science, Stanford University, Stanford, CA 94305, USA
| | - Carmen Azevedo
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
| | - Sydney C Nagy
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
| | - Javier Ramos Benitez
- Department of Neurology and Neurological Science, Stanford University, Stanford, CA 94305, USA
| | - Emily M Deal
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
| | - Hannes Vogel
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Katrin I Andreasson
- Department of Neurology and Neurological Science, Stanford University, Stanford, CA 94305, USA
- Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
| | - Michelle L James
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
- Department of Neurology and Neurological Science, Stanford University, Stanford, CA 94305, USA
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Ruiz-Pacheco JA, Muñoz-Medina EJ, Castillo-Díaz LA, Chacón-Salinas R, Escobar-Gutiérrez A. Dengue Virus Increases the Expression of TREM-1 and CD10 on Human Neutrophils. Viral Immunol 2023; 36:176-185. [PMID: 36811498 DOI: 10.1089/vim.2022.0124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023] Open
Abstract
Every year, dengue is responsible for 400 million infections worldwide. Inflammation is related to the development of severe forms of dengue. Neutrophils are a heterogeneous cell population with a key role in the immune response. During viral infection, neutrophils are mainly recruited to the infection site; however, their excessive activation is linked to deleterious results. During dengue infection, neutrophils are involved in the pathogenesis through neutrophils extracellular traps production, tumor necrosis factor-alpha, and interleukin-8 secretion. However, other molecules regulate the neutrophil role during viral infection. TREM-1 is expressed on neutrophils and its activation is related to increased production of inflammatory mediators. CD10 is expressed on mature neutrophils and has been associated with the regulation of neutrophil migration and immunosuppression. However, the role of both molecules during viral infection is limited, particularly during dengue infection. Here, we report for the first time that DENV-2 can significantly increase TREM-1 and CD10 expression as well as sTREM-1 production in cultured human neutrophils. Furthermore, we observed that treatment with granulocyte-macrophage colony stimulating factor, a molecule mostly produced in severe cases of dengue, is capable of inducing the overexpression of TREM-1 and CD10 on human neutrophils. These results suggest the participation of neutrophil CD10 and TREM-1 in the pathogenesis of dengue infection.
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Affiliation(s)
- Juan A Ruiz-Pacheco
- Investigador por México, División de Investigación Quirúrgica, Centro de Investigaciones Biomédicas de Occidente, IMSS, Guadalajara, México
| | - E José Muñoz-Medina
- División de Laboratorios de Vigilancia e Investigación Epidemiológica, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Luis A Castillo-Díaz
- División de Ciencias Biológicas y de la Salud, Departamento de Medicina y Ciencias de la Salud, Universidad de Sonora, Hermosillo, México
| | - Rommel Chacón-Salinas
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN, Ciudad de México, México
| | - Alejandro Escobar-Gutiérrez
- Coordinación de Investigaciones Inmunológicas, Instituto de Diagnóstico y Referencia Epidemiológicos, "Dr. Manuel Martínez Báez," Secretaría de Salud, Ciudad de México, México
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Changes in Biomarkers and Hemodynamics According to Antibiotic Susceptibility in a Model of Bacteremia. Microbiol Spectr 2022; 10:e0086422. [PMID: 35862959 PMCID: PMC9430499 DOI: 10.1128/spectrum.00864-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Proper selection of susceptible antibiotics in drug-resistant bacteria is critical to treat bloodstream infection. Although biomarkers that guide antibiotic therapy have been extensively evaluated, little is known about host biomarkers targeting in vivo antibiotic susceptibility. Therefore, we aimed to evaluate the trends of hemodynamics and biomarkers in a porcine bacteremia model treated with insusceptible antibiotics compared to those in susceptible models. Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (E. coli, 5.0 * 10^9 CFU) was intravenously administered to 11 male pigs. One hour after bacterial infusion, pigs were assigned to two groups of antibiotics, ceftriaxone (n = 6) or ertapenem (n = 5). Pigs were monitored up to 7 h after bacterial injection with fluid and vasopressor support to maintain the mean arterial blood pressure over 65 mmHg. Blood sampling for blood culture and plasma acquisition was performed before and every predefined hour after E. coli injection. Cytokine (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, IL-8, IL-10, C-reactive protein, procalcitonin, presepsin, heparan sulfate, syndecan, and soluble triggering receptor expressed on myeloid cells-1 [sTREM-1]) levels in plasma were analyzed using enzyme-linked immunosorbent assays. Bacteremia developed after intravenous injection of E. coli, and negative conversion was confirmed only in the ertapenem group. While trends of other biomarkers failed to show differences, the trend of sTREM-1 was significantly different between the two groups (P = 0.0001, two-way repeated measures analysis of variance). Among hemodynamics and biomarkers, the sTREM-1 level at post 2 h after antibiotics administration represented a significant difference depending on susceptibility, which can be suggested as a biomarker candidate of in vivo antibiotics susceptibility. Further clinical studies are warranted for validation. IMPORTANCE Early and appropriate antibiotic treatment is a keystone in treating patients with sepsis. Despite its importance, blood culture which requires a few days remains as a pillar of diagnostic method for microorganisms and their antibiotic susceptibility. Whether changes in biomarkers and hemodynamics indicate treatment response of susceptible antibiotic compared to resistant one is not well understood to date. In this study using extended-spectrum β-lactamase -producing E. coli bacteremia porcine model, we have demonstrated the comprehensive cardiovascular hemodynamics and trends of plasma biomarkers in sepsis and compared them between two groups with susceptible and resistant antibiotics. While other hemodynamics and biomarkers have failed to differ, we have identified that levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) significantly differed between the two groups over time. Based on the data in this study, trends of sTREM-1 obtained before the antibiotics and 2~4 h after the antibiotics could be a novel host biomarker that triggers the step-up choice of antibiotics.
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Sharapova TN, Ivanova OK, Romanova EA, Sashchenko LP, Yashin DV. N-Terminal Peptide of PGLYRP1/Tag7 Is a Novel Ligand for TREM-1 Receptor. Int J Mol Sci 2022; 23:ijms23105752. [PMID: 35628562 PMCID: PMC9144885 DOI: 10.3390/ijms23105752] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/17/2022] [Accepted: 05/19/2022] [Indexed: 11/16/2022] Open
Abstract
An investigation of innate immunity receptors sheds light on the mechanisms of inflammation and associated immune reactions. One of the key immune regulators is the TREM-1 receptor, which is involved in both inflammation and antitumor immune response. In this article, we have obtained a new ligand for the TREM-1 receptor. The peptide, named N3, is a part of the innate immune protein PGLYRP1/Tag7. It is responsible for activating the TREM-1 signaling pathway. Here, we have demonstrated that the N3 peptide acts like other TREM-1 receptor ligands: its binding results in a mild inflammation response and appearance of cytotoxic lymphocytes. We have shown that cytotoxic populations of lymphocytes in N3 peptide-treated PBMCs are similar to those treated with Tag7 or Hsp70. We also determined the part of the N3 peptide responsible for binding to TREM-1. The resulting peptide (N9) consists of nine amino acids and can be considered as a potential peptide that blocks TREM-1 signaling.
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Ford JW, Gonzalez-Cotto M, MacFarlane AW, Peri S, Howard OMZ, Subleski JJ, Ruth KJ, Haseebuddin M, Al-Saleem T, Yang Y, Rayman P, Rini B, Linehan WM, Finke J, Weiss JM, Campbell KS, McVicar DW. Tumor-Infiltrating Myeloid Cells Co-Express TREM1 and TREM2 and Elevated TREM-1 Associates With Disease Progression in Renal Cell Carcinoma. Front Oncol 2022; 11:662723. [PMID: 35223446 PMCID: PMC8867210 DOI: 10.3389/fonc.2021.662723] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 09/27/2021] [Indexed: 12/22/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) contribute to cancer-related inflammation and tumor progression. While several myeloid molecules have been ascribed a regulatory function in these processes, the triggering receptors expressed on myeloid cells (TREMs) have emerged as potent modulators of the innate immune response. While various TREMs amplify inflammation, others dampen it and are emerging as important players in modulating tumor progression-for instance, soluble TREM-1 (sTREM-1), which is detected during inflammation, associates with disease progression, while TREM-2 expression is associated with tumor-promoting macrophages. We hypothesized that TREM-1 and TREM-2 might be co-expressed on tumor-infiltrating myeloid cells and that elevated sTREM-1 associates with disease outcomes, thus representing a possibility for mutual modulation in cancer. Using the 4T1 breast cancer model, we found TREM-1 and TREM-2 expression on MDSC and TAM and that sTREM-1 was elevated in tumor-bearing mice in multiple models and correlated with tumor volume. While TREM-1 engagement enhanced TNF, a TREM-2 ligand was detected on MDSC and TAM, suggesting that both TREM could be functional in the tumor setting. Similarly, we detected TREM-1 and Trem2 expression in myeloid cells in the RENCA model of renal cell carcinoma (RCC). We confirmed these findings in human disease by demonstrating the expression of TREM-1 on tumor-infiltrating myeloid cells from patients with RCC and finding that sTREM-1 was increased in patients with RCC. Finally, The Cancer Genome Atlas analysis shows that TREM1 expression in tumors correlates with poor outcomes in RCC. Taken together, our data suggest that manipulation of the TREM-1/TREM-2 balance in tumors may be a novel means to modulate tumor-infiltrating myeloid cell phenotype and function.
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Affiliation(s)
- Jill W Ford
- Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), Frederick, MD, United States
| | - Marieli Gonzalez-Cotto
- Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), Frederick, MD, United States
| | - Alexander W MacFarlane
- Blood Cell Development and Function Program, Institute for Cancer Research, Philadelphia, PA, United States
| | - Suraj Peri
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - O M Zack Howard
- Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), Frederick, MD, United States
| | - Jeffrey J Subleski
- Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), Frederick, MD, United States
| | - Karen J Ruth
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Mohammed Haseebuddin
- Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Tahseen Al-Saleem
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Youfeng Yang
- Urologic Oncology Branch, National Cancer Institute (NCI), Bethesda, MD, United States
| | - Pat Rayman
- Cleveland Clinic, Department of Immunology, Lerner Research Institute, Cleveland, OH, United States
| | - Brian Rini
- Cleveland Clinic, Department of Solid Tumor Oncology, Cleveland, OH, United States
| | - W Marston Linehan
- Urologic Oncology Branch, National Cancer Institute (NCI), Bethesda, MD, United States
| | - James Finke
- Cleveland Clinic, Department of Immunology, Lerner Research Institute, Cleveland, OH, United States
| | - Jonathan M Weiss
- Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), Frederick, MD, United States
| | - Kerry S Campbell
- Blood Cell Development and Function Program, Institute for Cancer Research, Philadelphia, PA, United States
| | - Daniel W McVicar
- Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), Frederick, MD, United States
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Aulin LB, de Lange DW, Saleh MA, van der Graaf PH, Völler S, van Hasselt JC. Biomarker-Guided Individualization of Antibiotic Therapy. Clin Pharmacol Ther 2021; 110:346-360. [PMID: 33559152 PMCID: PMC8359228 DOI: 10.1002/cpt.2194] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 02/02/2021] [Indexed: 12/11/2022]
Abstract
Treatment failure of antibiotic therapy due to insufficient efficacy or occurrence of toxicity is a major clinical challenge, and is expected to become even more urgent with the global rise of antibiotic resistance. Strategies to optimize treatment in individual patients are therefore of crucial importance. Currently, therapeutic drug monitoring plays an important role in optimizing antibiotic exposure to reduce treatment failure and toxicity. Biomarker-based strategies may be a powerful tool to further quantify and monitor antibiotic treatment response, and reduce variation in treatment response between patients. Host response biomarkers, such as CRP, procalcitonin, IL-6, and presepsin, could potentially carry significant information to be utilized for treatment individualization. To achieve this, the complex interactions among immune system, pathogen, drug, and biomarker need to be better understood and characterized. The purpose of this tutorial is to discuss the use and evidence of currently available biomarker-based approaches to inform antibiotic treatment. To this end, we also included a discussion on how treatment response biomarker data from preclinical, healthy volunteer, and patient-based studies can be further characterized using pharmacometric and system pharmacology based modeling approaches. As an illustrative example of how such modeling strategies can be used, we describe a case study in which we quantitatively characterize procalcitonin dynamics in relation to antibiotic treatments in patients with sepsis.
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Affiliation(s)
- Linda B.S. Aulin
- Division of Systems Biomedicine and PharmacologyLeiden Academic Centre for Drug ResearchLeiden UniversityLeidenThe Netherlands
| | - Dylan W. de Lange
- Department of Intensive Care MedicineUniversity Medical CenterUniversity UtrechtUtrechtThe Netherlands
| | - Mohammed A.A. Saleh
- Division of Systems Biomedicine and PharmacologyLeiden Academic Centre for Drug ResearchLeiden UniversityLeidenThe Netherlands
| | - Piet H. van der Graaf
- Division of Systems Biomedicine and PharmacologyLeiden Academic Centre for Drug ResearchLeiden UniversityLeidenThe Netherlands
- CertaraCanterburyUK
| | - Swantje Völler
- Division of Systems Biomedicine and PharmacologyLeiden Academic Centre for Drug ResearchLeiden UniversityLeidenThe Netherlands
- Pharmacy, Leiden Academic Centre for Drug ResearchLeiden UniversityLeidenThe Netherlands
| | - J.G. Coen van Hasselt
- Division of Systems Biomedicine and PharmacologyLeiden Academic Centre for Drug ResearchLeiden UniversityLeidenThe Netherlands
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9
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Surface TREM-1 as a Prognostic Biomarker in Pediatric Sepsis. Indian J Pediatr 2021; 88:134-140. [PMID: 32572693 DOI: 10.1007/s12098-020-03355-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 05/14/2020] [Indexed: 01/07/2023]
Abstract
OBJECTIVES To investigate the association between the triggering receptor expressed on myeloid cells-1 (TREM-1) levels and prognosis in septic children. METHODS Patients admitted to pediatric intensive care units (PICU) of three tertiary centers were included in this prospective observational study. Serum samples were taken at admission from patients who were hospitalized with sepsis. RESULTS Of the 87 patients included, 34 (39.1%) had severe sepsis and 53 (60.9%) had septic shock. The median age was 2 y (2 mo to 16 y). TREM-1 values were found to be significantly higher in septic shock patients 129 pg/ml (min 9.85- max 494.90) compared to severe sepsis 105 pg/ml (min 8.21- max 289.17) (p = 0.048). Despite higher TREM-1 levels been measured in non-survivors compared to survivors, it was not statistically significant [168.98 pg/ml (min 9.85- max 494.90) vs. 110.79 pg/ml (min 8.21- max 408.90), (p = 0.075)]. CONCLUSIONS Admission TREM-1 levels were higher in septic shock compared to severe sepsis patients. There was no association between mortality and TREM-1 levels in sepsis. TREM-1 measurements should be used carefully in pediatric sepsis prognosis.
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10
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Matos ADO, Dantas PHDS, Silva-Sales M, Sales-Campos H. TREM-1 isoforms in bacterial infections: to immune modulation and beyond. Crit Rev Microbiol 2021; 47:290-306. [PMID: 33522328 DOI: 10.1080/1040841x.2021.1878106] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
The triggering receptor expressed on myeloid cells 1 (TREM-1) is an innate immunity receptor associated with the amplification of inflammation in sterile and non-sterile inflammatory disorders. Since its first description, the two isoforms of the receptor, membrane and soluble (mTREM-1 and sTREM-1, respectively) have been largely explored in the immunopathogenesis of several bacterial diseases and sepsis. The role of the receptor in these scenarios seems to be at least partly dependent on the source/type of bacteria, host and context. As uncontrolled inflammation is a result of several bacterial infections, the inhibition of the receptor has been considered as a promising approach to treat such conditions. Further, sTREM-1 has been explored as a biomarker for diagnosis and/or prognosis of several bacterial diseases. Therefore, this review aims to provide an updated insight into how the receptor influences and is influenced by bacterial infections, highlighting the advances regarding the use/manipulation of TREM-1 isoforms in biomedical research and clinical practice.
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Affiliation(s)
| | | | - Marcelle Silva-Sales
- Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Brazil
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11
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Serum Presepsin, Proadrenomedullin and Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) as Biomarkers for the Diagnosis of Acute Pyelonephritis. Indian Pediatr 2020. [DOI: 10.1007/s13312-020-1914-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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12
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François B, Wittebole X, Ferrer R, Mira JP, Dugernier T, Gibot S, Derive M, Olivier A, Cuvier V, Witte S, Pickkers P, Vandenhende F, Garaud JJ, Sánchez M, Salcedo-Magguilli M, Laterre PF. Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial. Intensive Care Med 2020; 46:1425-1437. [PMID: 32468087 DOI: 10.1007/s00134-020-06109-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 05/11/2020] [Indexed: 01/03/2023]
Abstract
PURPOSE Nangibotide is a specific TREM-1 inhibitor that tempered deleterious host-pathogens interactions, restored vascular function, and improved survival, in animal septic shock models. This study evaluated the safety and pharmacokinetics of nangibotide and its effects on clinical and pharmacodynamic parameters in septic shock patients. METHODS This was a multicenter randomized, double-blind, two-stage study. Patients received either continuous infusion of nangibotide (0.3, 1.0, or 3.0 mg/kg/h) or placebo. Treatment began < 24 h after shock onset and continued for up to 5 days. Safety primary outcomes were adverse events (AEs), whether serious or not, and death. Exploratory endpoints evaluated nangibotide effects on pharmacodynamics, organ function, and mortality, and were analyzed according to baseline sTREM-1 concentrations. RESULTS Forty-nine patients were randomized. All treatment emergent AEs (TEAEs) were collected until Day 28. No significant differences were observed in TEAEs between treatment groups. No drug withdrawal linked to TEAE nor appearance of anti-drug antibodies were reported. Nangibotide pharmacokinetics appeared to be dose-proportional and clearance was dose-independent. Nangibotide did not significantly affect pharmacodynamic markers. Decrease in SOFA score LS mean change (± SE) from baseline to Day 5 in pooled nangibotide groups versus placebo was - 0.7 (± 0.85) in the randomized population and - 1.5 (± 1.12) in patients with high baseline plasma sTREM-1 concentrations (non-significant). This pattern was similar to organ support end points. CONCLUSION No significant increases in TEAEs were detected in nangibotide-treated patients versus placebo. These results encourage further evaluation of nangibotide and further exploration of plasma sTREM-1 concentrations as a predictive efficacy biomarker.
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Affiliation(s)
- Bruno François
- Medical-Surgical ICU Department and Inserm CIC1435 & UMR1092, CRICS-TRIGGERSEP Network, CHU Limoges, Limoges, France.
| | - Xavier Wittebole
- Department of Critical Care Medicine, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
| | - Ricard Ferrer
- ICU Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | | | | | - Sébastien Gibot
- Medical ICU Department, Hospital Central, CHU Nancy, Nancy, France.,Inserm U1116, Nancy Medical Faculty, Lorraine University, Nancy , France
| | | | | | | | | | - Peter Pickkers
- ICU Department, Radboudumc Hospital, Nijmegen, The Netherlands
| | | | | | - Miguel Sánchez
- ICU Department, Hospital Clínico San Carlos, Madrid, Spain
| | | | - Pierre-François Laterre
- Department of Critical Care Medicine, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
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13
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Dantas PHDS, Matos ADO, da Silva Filho E, Silva-Sales M, Sales-Campos H. Triggering receptor expressed on myeloid cells-1 (TREM-1) as a therapeutic target in infectious and noninfectious disease: a critical review. Int Rev Immunol 2020; 39:188-202. [PMID: 32379561 DOI: 10.1080/08830185.2020.1762597] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The triggering receptor expressed on myeloid cells-1 (TREM-1) is an innate immune receptor found in the surface of several immune and non-immune cells. Since its first description in 2000, this molecule and its soluble form (sTREM-1) have been implicated in many diseases with infectious and noninfectious origins. As an amplifier of inflammation, the membrane-associated TREM-1 (mTREM-1) isoform induces the production of pro-inflammatory mediators, thus contributing to the pathogenesis of diseases such as sepsis, arthritis, colitis and infections. In this context, many studies have used molecules capable of inhibiting TREM-1 activity as anti-inflammatory drugs. In this regard, a few peptides have been showing promising results in the amelioration of detrimental immune responses. Some commercially available drugs, including corticosteroids and antibiotics, with known anti-inflammatory effects, have also shown activity in TREM-1 signaling. Therefore, considering the potential of this receptor as a therapeutic target, the present review encompasses the main compounds explored so far in TREM-1 modulation, highlighting and critically discussing its effects and major drawbacks of such approaches.
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Affiliation(s)
| | - Amanda de Oliveira Matos
- Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Goiás, Brazil
| | - Ernandes da Silva Filho
- Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Goiás, Brazil
| | - Marcelle Silva-Sales
- Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Goiás, Brazil
| | - Helioswilton Sales-Campos
- Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Goiás, Brazil
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14
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Inhibition of Triggering Receptor Expressed on Myeloid Cell-1 Alleviates Acute Gouty Inflammation. Mediators Inflamm 2019; 2019:5647074. [PMID: 31885496 PMCID: PMC6925811 DOI: 10.1155/2019/5647074] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 11/23/2019] [Indexed: 12/02/2022] Open
Abstract
Gout is a prevalent form of aseptic inflammation caused by the deposition of monosodium urate (MSU) crystals in joints or tissues. Triggering receptor expressed on myeloid cell-1 (TREM-1) is a superimmunoglobulin receptor expressed on innate immune cells including granulocytes, monocytes, and macrophages. TREM-1 serves as a link between innate immunity and adaptive immunity, playing a crucial role in regulating inflammation and immune response. The purpose of this study was to investigate the potential role of TREM-1 in THP-1 cells and peripheral blood mononuclear cells (PBMCs) from patients with gouty arthritis (GA). In the current study, we found that the mRNA and protein levels of TREM-1 increased in PBMCs from GA patients and soluble TREM-1 in plasma as well. In addition, an increased level of TREM-1 was observed in THP-1 treated with monosodium urate (MSU) in vitro, along with upregulation of proinflammatory cytokines. Moreover, upon specific inhibition of TREM-1, Toll-like receptor 4 (TLR-4), and myeloid differentiation factor 88 (MyD88), the levels of MyD88 and proinflammatory cytokines were decreased after MSU challenge in THP-1 cells. Interestingly, inhibition of TLR-4 could enhance the effect of TREM-1 inhibitor in MSU-induced inflammation. Taken together, our findings suggested that TREM-1 could accelerate MSU-induced acute inflammation. Inhibition of TREM-1 may provide a new strategy for alleviating acute gouty inflammation.
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15
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Liu Q, Johnson EM, Lam RK, Wang Q, Bo Ye H, Wilson EN, Minhas PS, Liu L, Swarovski MS, Tran S, Wang J, Mehta SS, Yang X, Rabinowitz JD, Yang SS, Shamloo M, Mueller C, James ML, Andreasson KI. Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity. Nat Immunol 2019; 20:1023-1034. [PMID: 31263278 PMCID: PMC6778967 DOI: 10.1038/s41590-019-0421-2] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 05/10/2019] [Indexed: 12/14/2022]
Abstract
Stroke is a multiphasic process in which initial cerebral ischemia is followed by secondary injury from immune responses to ischemic brain components. Here we demonstrate that peripheral CD11b+CD45+ myeloid cells magnify stroke injury via activation of triggering receptor expressed on myeloid cells 1 (TREM1), an amplifier of proinflammatory innate immune responses. TREM1 was induced within hours after stroke peripherally in CD11b+CD45+ cells trafficking to ischemic brain. TREM1 inhibition genetically or pharmacologically improved outcome via protective antioxidant and anti-inflammatory mechanisms. Positron electron tomography imaging using radiolabeled antibody recognizing TREM1 revealed elevated TREM1 expression in spleen and, unexpectedly, in intestine. In the lamina propria, noradrenergic-dependent increases in gut permeability induced TREM1 on inflammatory Ly6C+MHCII+ macrophages, further increasing epithelial permeability and facilitating bacterial translocation across the gut barrier. Thus, following stroke, peripheral TREM1 induction amplifies proinflammatory responses to both brain-derived and intestinal-derived immunogenic components. Critically, targeting this specific innate immune pathway reduces cerebral injury.
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Affiliation(s)
- Qingkun Liu
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Emily M Johnson
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Rachel K Lam
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Qian Wang
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Hong Bo Ye
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Edward N Wilson
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Paras S Minhas
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Ling Liu
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
- Department of Chemistry, Princeton University, Princeton, NJ, USA
| | - Michelle S Swarovski
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Stephanie Tran
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Jing Wang
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Swapnil S Mehta
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Xi Yang
- Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Joshua D Rabinowitz
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
- Department of Chemistry, Princeton University, Princeton, NJ, USA
| | - Samuel S Yang
- Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Mehrdad Shamloo
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Michelle L James
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Neuroscience Institute, Stanford University, Stanford, CA, USA
| | - Katrin I Andreasson
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Stanford Neuroscience Institute, Stanford University, Stanford, CA, USA.
- Stanford Immunology Program, Stanford University, Stanford, CA, USA.
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16
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Edel Y, Kliminski V, Pokroy-Shapira E, Oren S, Dortort Lazar A, Pri-Paz Basson Y, Egbaria M, Molad Y. Elevated plasma level of soluble triggering receptor expressed on myeloid cells-1 is associated with inflammation activity and is a potential biomarker of thrombosis in primary antiphospholipid syndrome. Arthritis Res Ther 2019; 21:10. [PMID: 30616644 PMCID: PMC6323669 DOI: 10.1186/s13075-018-1779-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 11/27/2018] [Indexed: 01/28/2023] Open
Abstract
Background Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is an innate-immune receptor found in blood. Its presence reflects innate immune cell activation. We sought to investigate plasma sTREM-1 levels in patients with primary antiphospholipid syndrome (PAPS). Methods A cross-sectional, case-control design was used. Plasma sTREM-1 levels were analyzed by enzyme-linked immunosorbent assay (ELISA) in consecutive patients diagnosed with PAPS or asymptomatic antiphospholipid antibody (APLA) carriers and controls. Results The study cohort included 33 patients with PAPS, 10 asymptomatic APLA carriers, and 73 controls. Mean plasma sTREM-1 levels were significantly higher in patients with PAPS (299.2 ± 146.7 pg/ml) and thrombotic PAPS-ever (current and past thrombotic event) (327.2 ± 151.3 pg/ml) compared with controls (230.2 ± 85.5 pg/ml; p = 0.006 and p = 0.003, respectively), patients with thrombotic PAPS compared with patients with past obstetric APS (195.12 ± 58.52 pg/ml, p = 0.01) and APLA carriers (215.8 ± 51.6 pg/ml, p = 0.02), patients with current thrombotic PAPS (429.5 ± 227.5 pg/ml) compared with patients with past thrombotic PAPS (289.5 ± 94.65 pg/ml, p = 0.01), and patients with PAPS who had ever had a stroke or venous thromboembolic event compared with patients who had not (p = 0.007 and p = 0.02, respectively). On receiver operator characteristic curve analysis, plasma sTREM-1 levels differentiated patients with current thrombotic PAPS from asymptomatic APLA carriers and controls, with an area under the curve of 0.7292 (p = 0.0014) and 0.88 (p < 0.0001), respectively. Multivariate regression analysis to identify sTREM-1 predictors (thrombotic PAPS-ever, age, and sex) yielded an independent association of sTREM-1 levels with thrombotic PAPS (p < 0.0001). Conclusions Plasma sTREM-1 levels are significantly elevated in patients with thrombotic PAPS. Levels of sTREM-1 might serve as a biomarker for thrombosis in patients with PAPS.
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Affiliation(s)
- Yonatan Edel
- Rheumatology Unit, Rabin Medical Center - Beilinson Hospital, 4941492, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Vitaly Kliminski
- Laboratory of Inflammation Research, Felsenstein Medical Research Center, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Elisheva Pokroy-Shapira
- Rheumatology Unit, Rabin Medical Center - Beilinson Hospital, 4941492, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shirly Oren
- Rheumatology Unit, Rabin Medical Center - Beilinson Hospital, 4941492, Petach Tikva, Israel
| | - Ariela Dortort Lazar
- Rheumatology Unit, Rabin Medical Center - Beilinson Hospital, 4941492, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Pri-Paz Basson
- Rheumatology Unit, Rabin Medical Center - Beilinson Hospital, 4941492, Petach Tikva, Israel
| | - Mohammad Egbaria
- Rheumatology Unit, Rabin Medical Center - Beilinson Hospital, 4941492, Petach Tikva, Israel
| | - Yair Molad
- Rheumatology Unit, Rabin Medical Center - Beilinson Hospital, 4941492, Petach Tikva, Israel. .,Laboratory of Inflammation Research, Felsenstein Medical Research Center, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel. .,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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17
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Gao S, Yi Y, Xia G, Yu C, Ye C, Tu F, Shen L, Wang W, Hua C. The characteristics and pivotal roles of triggering receptor expressed on myeloid cells-1 in autoimmune diseases. Autoimmun Rev 2018; 18:25-35. [PMID: 30408584 DOI: 10.1016/j.autrev.2018.07.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 07/09/2018] [Indexed: 01/13/2023]
Abstract
Triggering receptor expressed on myeloid cells-1 (TREM-1) engagement can directly trigger inflammation or amplify an inflammatory response by synergizing with TLRs or NLRs. Autoimmune diseases are a family of chronic systemic inflammatory disorders. The pivotal role of TREM-1 in inflammation makes it important to explore its immunological effects in autoimmune diseases. In this review, we summarize the structural and functional characteristics of TREM-1. Particularly, we discuss recent findings on TREM-1 pathway regulation in various autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type 1 diabetes (T1D), and psoriasis. This receptor may potentially be manipulated to alter the inflammatory response to chronic inflammation and possible therapies are explored in this review.
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Affiliation(s)
- Sheng Gao
- Laboratory Animal Center, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
| | - Yongdong Yi
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Guojun Xia
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Chengyang Yu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Chenmin Ye
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Fuyang Tu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Leibin Shen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Wenqian Wang
- Department of Breast Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China.
| | - Chunyan Hua
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
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18
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Idelalisib impairs TREM-1 mediated neutrophil inflammatory responses. Sci Rep 2018; 8:5558. [PMID: 29615799 PMCID: PMC5882939 DOI: 10.1038/s41598-018-23808-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 02/12/2018] [Indexed: 12/16/2022] Open
Abstract
Triggering receptor expressed on myeloid cells (TREM)-1 on polymorphonuclear neutrophils (PMN) regulates innate immune activation in infectious and non-infectious conditions. TREM-1 ligation activates phosphatidyl-inositol 3 kinase (PI3K) triggering all neutrophil effector functions. As idelalisib is a PI3K inhibitor in clinical use for the treatment of non-Hodgkin lymphomas, we asked whether this inhibitor affects PMN functionalities. We analyzed PMNs from healthy donors or lymphoma patients for oxidative burst, phagocytosis, activation markers and IL-8 release upon TREM-1 or TLR ligation ex vivo. In addition, we performed western blot analyses to characterize the signaling events inhibited by idelalisib and other PI3K inhibitors. Upon TREM-1 ligation, the oxidative burst, degranulation, L-selectin shedding and cytokine release were all strongly reduced in the presence of idelalisib along impaired phosphorylation of P38, AKT and ERK by western blot analyses. In line with this, PMNs from patients receiving idelalisib also displayed an impaired TREM-1 mediated PMN activation ex vivo. In conclusion, PI3K inhibitors might cause a neutropenia-like susceptibility to infections in patients by leading to impaired PMN functionality. This should be considered when evaluating patients for infections treated with such inhibitors in daily clinical routine.
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19
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Carrasco K, Boufenzer A, Jolly L, Le Cordier H, Wang G, Heck AJ, Cerwenka A, Vinolo E, Nazabal A, Kriznik A, Launay P, Gibot S, Derive M. TREM-1 multimerization is essential for its activation on monocytes and neutrophils. Cell Mol Immunol 2018; 16:460-472. [PMID: 29568119 DOI: 10.1038/s41423-018-0003-5] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 01/01/2018] [Accepted: 01/09/2018] [Indexed: 12/18/2022] Open
Abstract
The triggering receptor expressed on myeloid cells-1 (TREM-1) is a receptor expressed on innate immune cells. By promoting the amplification of inflammatory signals that are initially triggered by Toll-like receptors (TLRs), TREM-1 has been characterized as a major player in the pathophysiology of acute and chronic inflammatory diseases, such as septic shock, myocardial infarction, atherosclerosis, and inflammatory bowel diseases. However, the molecular events leading to the activation of TREM-1 in innate immune cells remain unknown. Here, we show that TREM-1 is activated by multimerization and that the levels of intracellular Ca2+ release, reactive oxygen species, and cytokine production correlate with the degree of TREM-1 aggregation. TREM-1 activation on primary human monocytes by LPS required a two-step process consisting of upregulation followed by clustering of TREM-1 at the cell surface, in contrast to primary human neutrophils, where LPS induced a rapid cell membrane reorganization of TREM-1, which confirmed that TREM-1 is regulated differently in primary human neutrophils and monocytes. In addition, we show that the ectodomain of TREM-1 is able to homooligomerize in a concentration-dependent manner, which suggests that the clustering of TREM-1 on the membrane promotes its oligomerization. We further show that the adapter protein DAP12 stabilizes TREM-1 surface expression and multimerization. TREM-1 multimerization at the cell surface is also mediated by its endogenous ligand, a conclusion supported by the ability of the TREM-1 inhibitor LR12 to limit TREM-1 multimerization. These results provide evidence for ligand-induced, receptor-mediated dimerization of TREM-1. Collectively, our findings uncover the mechanisms necessary for TREM-1 activation in monocytes and neutrophils.
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Affiliation(s)
- Kevin Carrasco
- INOTREM, Vandœuvre-les-Nancy, France.,UMR-S 1116, Defaillance cardiovasculaire aigue et chronique, Vandœuvre-les-Nancy, France
| | | | - Lucie Jolly
- INOTREM, Vandœuvre-les-Nancy, France.,UMR-S 1116, Defaillance cardiovasculaire aigue et chronique, Vandœuvre-les-Nancy, France
| | - Helene Le Cordier
- UMR7365, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), CNRS-Université de Lorraine, Vandœuvre-les-Nancy, France
| | - Guanbo Wang
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences and Netherlands Proteomics Center, Utrecht University, Utrecht, The Netherlands
| | - Albert Jr Heck
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences and Netherlands Proteomics Center, Utrecht University, Utrecht, The Netherlands
| | - Adelheid Cerwenka
- Innate Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | | | - Alexandre Kriznik
- Service Commun de Biophysique Interactions Moléculaires (SCBIM), FR3209, Biopôle de l'Université de Lorraine, Vandœuvre-les-Nancy, France
| | | | - Sebastien Gibot
- UMR-S 1116, Defaillance cardiovasculaire aigue et chronique, Vandœuvre-les-Nancy, France
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20
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Shi R, Zhang J, Peng Z, Yuan S, Gao S, Chen L, Yuan Y. Expression level of 12-amino acid triggering receptor on myeloid cells-like transcript 1 derived peptide alleviates lipopolysaccharide-induced acute lung injury in mice. Int J Mol Med 2018; 41:2159-2168. [PMID: 29393375 DOI: 10.3892/ijmm.2018.3443] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 11/23/2017] [Indexed: 11/06/2022] Open
Abstract
Acute lung injury (ALI) is a critical illness with a high morbidity and mortality rate due to severe inflammation in the lungs. The effects and underlying mechanism of the triggering receptor expressed on myeloid cells‑1 (TREM‑1)‑like transcript‑1‑derived peptide (LR12) on ALI remain unclear. The aim of the present study was to determine whether LR12 attenuates lipopolysaccharide (LPS)‑induced ALI and elucidate the mechanism underlying it. Male C57BL/6 mice were randomly assigned to three groups as follows: Sham group, LPS + scramble group and LPS + LR12 group. Normal saline (NS) or LPS was administrated by intratracheal instillation, and NS, LR12 or LR12 scramble was administered intraperitoneally 30 min later. The treatment was repeated every 3 h three times. Mice were sacrificed 24 h later. Pulmonary pathological changes, the lung wet/dry weight ratio, the macrophage and neutrophil counts in bronchoalveolar lavage fluid and myeloperoxidase (MPO) activity in the lung tissues were observed. The inflammatory cytokines were evaluated by enzyme‑linked immunosorbent assay and lung neutrophil infiltration was detected by immunohistochemistry. Nuclear factor (NF)‑κB p65 and TREM‑1 were analyzed by western blotting, and the activation of NF‑κB was detected by electrophoretic mobility shift assay. LPS‑induced pathohistological injury, edema and neutrophil infiltration were significantly alleviated by TREM‑1 inhibitor, LR12. The proinflammatory cytokines [interleukin (IL)‑6, IL‑1β, tumor necrosis factor‑α] and chemokines (keratinocyte chemokine and monocyte chemoattractant protein‑1) were significantly reduced, whereas the anti‑inflammatory cytokines, IL‑10 were significantly increased by LR12. LR12 was identified to significantly decrease p65 expression levels in the nucleus and inhibit the activity of NF‑κB. Furthermore, LR12 alleviated LPS‑induced ALI by reducing the expression of TREM‑1, increasing the release of soluble TREM‑1 and inhibiting activation of the NF-κB signaling pathway.
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Affiliation(s)
- Ruili Shi
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jiancheng Zhang
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Zhang Peng
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Shiying Yuan
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Sumin Gao
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Lin Chen
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yin Yuan
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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21
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Zhao YF, Zhu L, Liu LJ, Shi SF, Lv JC, Zhang H. TREM-1 Contributes to Inflammation in IgA Nephropathy. KIDNEY DISEASES 2018; 4:29-36. [PMID: 29594140 DOI: 10.1159/000485622] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 11/23/2017] [Indexed: 01/15/2023]
Abstract
Background Circulating IgA1-containing immune complexes (cIgA1) were shown to play important roles in IgA nephropathy (IgAN). They could induce the release of multiple inflammatory factors, including MCP-1 and IL-6, and elevated urinary inflammatory factors were also reported in patients with IgAN, which suggested that inflammation is a major contributor to kidney injury in IgAN. After the previous identification of the upregulated release of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) by mesangial cells under cIgA1 challenge using cytokine array, in the present study, we further explored the role of TREM-1, an amplifier of inflammation, in cIgA1-induced kidney injury. Methods In total, 35 patients with IgAN and 17 healthy controls were enrolled. The cIgA1 was isolated from plasma and used to treat cultured mesangial cells. The mRNA expression of TREM-1 as well as levels of sTREM-1, MCP-1, and IL-6 in the mesangial cell supernatant and urine samples were detected. Results We found that cIgA1 from patients with IgAN could significantly upregulate the expression of TREM-1 in mesangial cells compared to healthy controls. The levels of ΔsTREM-1 were positively correlated with MCP-1 levels in the mesangial supernatant. Similarly, higher urinary levels of sTREM-1 were also observed in patients with IgAN compared to healthy controls. Moreover, IgAN patients with detectable urinary sTREM-1 presented with severe clinical and pathological manifestations, including higher IgA and lower eGFR levels, compared to patients whose urinary sTREM-1 levels were below the limit of quantification. Conclusion Our present study suggested that TREM-1 in cIgA1 induced inflammatory kidney injury in IgAN.
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Affiliation(s)
- Yan-Feng Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Li Zhu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Li-Jun Liu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Su-Fang Shi
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Ji-Cheng Lv
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Hong Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
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22
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Tammaro A, Derive M, Gibot S, Leemans JC, Florquin S, Dessing MC. TREM-1 and its potential ligands in non-infectious diseases: from biology to clinical perspectives. Pharmacol Ther 2017; 177:81-95. [PMID: 28245991 DOI: 10.1016/j.pharmthera.2017.02.043] [Citation(s) in RCA: 176] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Triggering receptor expressed on myeloid cells-1 (TREM-1) is expressed on the majority of innate immune cells and to a lesser extent on parenchymal cells. Upon activation, TREM-1 can directly amplify an inflammatory response. Although it was initially demonstrated that TREM-1 was predominantly associated with infectious diseases, recent evidences shed new light into its role in sterile inflammatory diseases. Indeed, TREM-1 receptor and its signaling pathways contribute to the pathology of several non-infectious acute and chronic inflammatory diseases, including atherosclerosis, ischemia reperfusion-induced tissue injury, colitis, fibrosis and cancer. This review, aims to give an extensive overview of TREM-1 in non-infectious diseases, with the focus on the therapeutic potential of TREM-1 intervention strategies herein. In addition, we provide the reader with a functional enrichment analysis of TREM-1 signaling pathway and potential TREM-1 ligands in these diseases, obtained via in silico approach. We discuss pre-clinical studies which show that TREM-1 inhibition, via synthetic soluble TREM-1 protein mimickers, is effective in treating (preventing) specific inflammatory disorders, without significant effects on antibacterial response. Further research aimed at identifying specific TREM-1 ligands, in different inflammatory disorders, is required to further unravel the role of this receptor, and explore new avenues to modulate its function.
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Affiliation(s)
- Alessandra Tammaro
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
| | | | - Sebastien Gibot
- Medical Intensive Care Unit, Hôpital Central, CHU Nancy, Nancy, France; Inserm UMR_S1116, Faculté de Médecine, Université de Lorraine, Nancy, France
| | - Jaklien C Leemans
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Sandrine Florquin
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Mark C Dessing
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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23
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Zhu H, Liu X, Du J, Lei M, Ying S, Yan J, Yu J, Shi Z, Li H. The identification, characterization, and function of two TREMs genes in Chinese Yangzhou goose (Anas cygnoides). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2017; 73:131-138. [PMID: 28344169 DOI: 10.1016/j.dci.2017.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 03/22/2017] [Accepted: 03/22/2017] [Indexed: 06/06/2023]
Abstract
Triggering receptor expressed on myeloid cells (TREM) is a cell-surface receptor primarily expressed on macrophages. Here, two novel TREM genes, AcTREM1 and AcTREM2, were identified from Anas cygnoides. AcTREM1 cDNA contained a putative signal peptide, two IG domains, and a transmembrane domain. The deduced AcTREM2 sequence also contained a signal peptide, an IG domain, and a transmembrane domain. qRT-PCR, fluorescence in situ hybridization, and immunofluorescence experiments showed that AcTREM1 and AcTREM2 were mainly expressed in the liver and spleen, and both genes and proteins were mainly distributed in cytoplasm. AcTREM1 expression in the liver and spleen was significantly upregulated following lipopolysaccharide (LPS) challenge at an early stage of infection and then decreased at a later stage. Changes in AcTREM2 expression were reciprocal to those of AcTREM1 in the liver and spleen after LPS challenge. Our results indicate that AcTREM1 and AcTREM2 participate in the antibacterial immunity of A. cygnoides.
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Affiliation(s)
- Huanxi Zhu
- Laboratory of Animal Improvement and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Xiaoqian Liu
- Laboratory of Animal Improvement and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Jie Du
- National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China
| | - Mingming Lei
- Laboratory of Animal Improvement and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Shijia Ying
- Laboratory of Animal Improvement and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Junshu Yan
- Laboratory of Animal Improvement and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Jianning Yu
- Laboratory of Animal Improvement and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Zhendan Shi
- Laboratory of Animal Improvement and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China.
| | - Hui Li
- Laboratory of Animal Improvement and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China.
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24
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Liu XR, Xu J, Wang YM, Ji MS, Liu FS. The effects of paeoniflorin injection on soluble triggering receptor expressed on myeloid-1 (sTREM-1) levels in severe septic rats. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2016; 20:565-571. [PMID: 27847433 PMCID: PMC5106390 DOI: 10.4196/kjpp.2016.20.6.565] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Revised: 12/03/2015] [Accepted: 12/07/2015] [Indexed: 11/15/2022]
Abstract
Paeoniflorin (PAE) is the most abundant compound in Xuebijing injection widely used to treat sepsis. We aimed to investigate effect of PAE on expression of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in a rat model of sepsis. Wistar rats were divided into Normal, Model, and PAE groups (n=20 each). Endotoxin was administrated at 5 mg/ml/kg in Model and PAE rats to establish rat sepsis model. 1 h after endotoxin administration, PAE was administrated at 4 ml/kg in PAE group once per day for 3 days. Routine blood tests and biochemical indexes were assessed, including aspartate aminotransferase (AST) and creatine kinase-MB (CK-MB). The plasma sTREM-1 level was measured using quantitative ELISA. At the end of experiment, the small intestine, liver, kidney and lung were subjected to pathological examinations. A rat model of sepsis-induced multiple organ dysfunction syndrome (MODS) was established successfully with endotoxin administration (5 mg/ml/kg), evidenced by histo-pathological examinations, routine blood tests and biochemical indexes: platelet count decreased and white blood cell count increased (p<0.05), CK-MB and AST increased (p<0.05). PAE treatment significantly reduced the plasma levels of AST, CK-MB, and sTREM-1, compared to Model group (p<0.05). Meanwhile, sepsis-induced damages in the liver, lung, stomach and intestinal mucosa were also markedly ameliorated by PAE treatment. PAE demonstrated a significantly protective effect in a rat model of sepsis by decreasing plasma sTREM-1 level, reducing inflammation, preventing MODS and protecting organ functions.
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Affiliation(s)
| | - Jie Xu
- ICU, Tianjin TEDA Hospital, Tianjin 300457, China
| | - Yi-Min Wang
- ICU, Tianjin TEDA Hospital, Tianjin 300457, China
| | - Ming-Suo Ji
- ICU, Tianjin TEDA Hospital, Tianjin 300457, China
| | - Fu-Shan Liu
- ICU, Tianjin TEDA Hospital, Tianjin 300457, China
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25
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Bahador M, Cross AS. Review: From therapy to experimental model: a hundred years of endotoxin administration to human subjects. ACTA ACUST UNITED AC 2016; 13:251-79. [DOI: 10.1177/0968051907085986] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
This article is a review of studies in which endotoxin has been administered to human subjects for experimental purposes. Data are presented in tabular form so the reader can better appreciate the objectives of individual studies. Although the original intention was to focus on the adverse events associated with these studies, unexpected serious adverse events rarely have been reported.
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Affiliation(s)
- Marjan Bahador
- Center for Vaccine Development and Division of Infectious Diseases, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA,
| | - Alan S. Cross
- Center for Vaccine Development and Division of Infectious Diseases, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
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26
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Brenner T, Uhle F, Fleming T, Wieland M, Schmoch T, Schmitt F, Schmidt K, Zivkovic AR, Bruckner T, Weigand MA, Hofer S. Soluble TREM-1 as a diagnostic and prognostic biomarker in patients with septic shock: an observational clinical study. Biomarkers 2016; 22:63-69. [PMID: 27319606 DOI: 10.1080/1354750x.2016.1204005] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVES The impact of TREM-1-mediated inflammation was investigated in different inflammatory settings. METHODS Secondary analyses of an observational clinical pilot study, including 60 patients with septic shock, 30 postoperative controls and 30 healthy volunteers. RESULTS Plasma levels of sTREM-1 were found to identify patients with septic shock more effectively than procalcitonin and C-reactive protein. Moreover, sTREM-1 was identified to be an early predictor for survival in patients with septic shock. CONCLUSION Due to its diagnostic as well as prognostic value in sepsis syndrome, implementation of sTREM-1 measurements in routine diagnostics should be taken into account.
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Affiliation(s)
- Thorsten Brenner
- a Department of Anesthesiology , Heidelberg University Hospital , Heidelberg , Germany
| | - Florian Uhle
- a Department of Anesthesiology , Heidelberg University Hospital , Heidelberg , Germany
| | - Thomas Fleming
- b Department of Medicine I and Clinical Chemistry , Heidelberg University Hospital , Heidelberg , Germany
| | - Matthias Wieland
- a Department of Anesthesiology , Heidelberg University Hospital , Heidelberg , Germany
| | - Thomas Schmoch
- a Department of Anesthesiology , Heidelberg University Hospital , Heidelberg , Germany
| | - Felix Schmitt
- a Department of Anesthesiology , Heidelberg University Hospital , Heidelberg , Germany
| | - Karsten Schmidt
- a Department of Anesthesiology , Heidelberg University Hospital , Heidelberg , Germany
| | - Aleksandar R Zivkovic
- a Department of Anesthesiology , Heidelberg University Hospital , Heidelberg , Germany
| | - Thomas Bruckner
- c Institute of Medical Biometry and Informatics , University of Heidelberg , Heidelberg , Germany
| | - Markus A Weigand
- a Department of Anesthesiology , Heidelberg University Hospital , Heidelberg , Germany
| | - Stefan Hofer
- a Department of Anesthesiology , Heidelberg University Hospital , Heidelberg , Germany
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27
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Zhu J, Duan G, Wang H, Cao M, Liu Y. TREM-1 activation modulates dsRNA induced antiviral immunity with specific enhancement of MAPK signaling and the RLRs and TLRs on macrophages. Exp Cell Res 2016; 345:70-81. [PMID: 27237091 DOI: 10.1016/j.yexcr.2016.05.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 04/17/2016] [Accepted: 05/23/2016] [Indexed: 12/24/2022]
Abstract
Triggering receptor expressed on myeloid cells 1(TREM-1) is a newly identified member of the immunoglobulin superfamily and is extensively involved in the regulation of innate immunity. To determine the role of TREM-1 in innate antiviral immunity, we investigated TREM-1 expression and its downstream signaling effect in the murine bone marrow-derived macrophages or RAW264.7 macrophage-like mouse cell line by double-stranded RNA (dsRNA) stimulation. The level of TREM-1 expression was low at the baseline and could up-regulate markedly in dose- and time-dependent manners upon stimulation by dsRNA/poly IC. Inhibitor studies disclosed mitogen-activated protein kinase (MAPK) p38 and PI3K pathways were involved in dsRNA-induced up-regulation of TREM-1. Compared with lipopolysaccharide (LPS), the peak response of poly IC-induced TREM-1 expression is delayed, and cells pretreated with scrambled RNA presented higher expression of TREM-1 upon LPS challenge. After ligation with the agonist antibody, TREM-1 can potentiate type I interferon (IFN) production and antiviral inflammation induced by dsRNA, which is ralated to the enhanced phosphorylation of MAPKs and expression of RLRs and TLRs by TREM-1 ligation. This study is the first to show the regulatory role of TREM-1 in RLRs and TLRs expression, and these findings might enrich the understanding of the up-regulation mechanism and the function of TREM-1.
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Affiliation(s)
- Jiang Zhu
- Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
| | - Guangjie Duan
- Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
| | - Hu Wang
- Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China.
| | - Mianfu Cao
- Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
| | - Yousheng Liu
- Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
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28
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Essa ES, Elzorkany KMA. sTREM-1 in patients with chronic kidney disease on hemodialysis. APMIS 2016; 123:969-74. [PMID: 26495896 DOI: 10.1111/apm.12459] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 09/04/2015] [Indexed: 01/22/2023]
Abstract
The triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. TREM-1 has been implicated as an amplifier of inflammation. Soluble TREM-1 (sTREM-1) was investigated in different clinical conditions, but not in hemodialysis (HD) patients. We aimed to investigate sTREM-1 as a marker of inflammation in HD patients. We investigated 40 CKD patients undergoing chronic HD treatment and 15 controls. Routine laboratory investigations in addition to CRP measured by immunoturbidimetry, TNF- α, and sTREM-1 measured by ELISA were assayed in post-hemodialysis patients' blood samples and in controls' blood samples. CRP, TNF-α, and sTREM-1 levels were significantly higher in HD patients than in controls (p < 0.001 for all). sTREM-1 was positively correlated with CRP and TNF-α (r = +0.50, p < 0.001 and r = +0.53, p < 0.001 respectively). It was negatively correlated with hemoglobin concentration (r = -0.69, p < 0.001). Hemoglobin concentration was the significant predictor of sTREM-1 level (p < 0.001). In conclusion, sTREM-1 level is significantly increased in HD patients as are other pro-inflammatory markers.
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Affiliation(s)
- Enas S Essa
- Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebein ElKom, Egypt
| | - Khaled M A Elzorkany
- Department of General Medicine, Faculty of Medicine, Menoufia University, Shebein ElKom, Egypt
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Schultz HS, Guo L, Keller P, Fleetwood AJ, Sun M, Guo W, Ma C, Hamilton JA, Bjørkdahl O, Berchtold MW, Panina S. OSCAR-collagen signaling in monocytes plays a proinflammatory role and may contribute to the pathogenesis of rheumatoid arthritis. Eur J Immunol 2016; 46:952-63. [PMID: 26786702 DOI: 10.1002/eji.201545986] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 12/15/2015] [Accepted: 01/12/2016] [Indexed: 01/26/2023]
Abstract
Osteoclast-associated receptor (OSCAR) is an activating receptor expressed by human myeloid cells. Collagen type I (ColI) and collagen type II (ColII) serve as ligands for OSCAR. OSCAR-collagen interaction stimulates RANK-dependent osteoclastogenesis. We have recently reported that OSCAR promotes functional maturation of monocyte-derived dendritic cells. OSCAR is upregulated on monocytes from rheumatoid arthritis (RA) patients with active disease, and these monocytes show an increased proosteoclastogenic potential. In the current study, we have addressed a functional role for an OSCAR-collagen interaction on monocytes. We show that OSCAR-ColII signaling promoted the survival of monocytes. Moreover, ColII stimulated the release of proinflammatory cytokines by monocytes from healthy donors, which could be completely blocked by an anti-OSCAR monoclonal antibody. Mononuclear cells from the synovial fluid of RA patients plated on ColII secreted TNF-α and IL-8 in an OSCAR-dependent manner. Global RNA profiling showed that components of multiple signaling pathways relevant to RA pathogenesis are regulated at the transcriptional level by OSCAR in monocytes. Thus, OSCAR can play a proinflammatory role in monocyte-derived cells and may contribute crucially on multiple levels to RA pathogenesis.
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Affiliation(s)
- Heidi S Schultz
- Biopharmaceutical Research Unit, Novo Nordisk A/S, Måløv, Denmark.,Department of Biology, Copenhagen University, Copenhagen, Denmark
| | - Li Guo
- Novo Nordisk Research Centre China CA, Beijing, China
| | - Pernille Keller
- Biopharmaceutical Research Unit, Novo Nordisk A/S, Måløv, Denmark
| | - Andrew J Fleetwood
- Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
| | - Mingyi Sun
- Novo Nordisk Research Centre China CA, Beijing, China
| | - Wei Guo
- Novo Nordisk Research Centre China CA, Beijing, China
| | - Chunyan Ma
- Novo Nordisk Research Centre China CA, Beijing, China
| | - John A Hamilton
- Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
| | - Olle Bjørkdahl
- Biopharmaceutical Research Unit, Novo Nordisk A/S, Måløv, Denmark
| | | | - Svetlana Panina
- Biopharmaceutical Research Unit, Novo Nordisk A/S, Måløv, Denmark
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30
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Baruah S, Keck K, Vrenios M, Pope MR, Pearl M, Doerschug K, Klesney-Tait J. Identification of a Novel Splice Variant Isoform of TREM-1 in Human Neutrophil Granules. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2015; 195:5725-31. [PMID: 26561551 PMCID: PMC4670805 DOI: 10.4049/jimmunol.1402713] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 10/09/2015] [Indexed: 01/28/2023]
Abstract
Triggering receptor expressed on myeloid cells-1 (TREM-1) is critical for inflammatory signal amplification. Humans have two forms of TREM-1: a membrane receptor, associated with the adaptor DAP12, and a soluble receptor detected at times of infection. The membrane receptor isoform acts synergistically with the TLR pathway to promote cytokine secretion and neutrophil migration, whereas the soluble receptor functions as a counterregulatory molecule. In multiple models of sepsis, exogenous administration of soluble forms of TREM-1 attenuates inflammation and markedly improves survival. Despite intense interest in soluble TREM-1, both as a clinical predictor of survival and as a therapeutic tool, the origin of native soluble TREM-1 remains controversial. Using human neutrophils, we identified a 15-kDa TREM-1 isoform in primary (azurophilic) and secondary (specific) granules. Mass spectrometric analysis, ELISA, and immunoblot confirm that the 15-kDa protein is a novel splice variant form of TREM-1 (TREM-1sv). Neutrophil stimulation with Pseudomonas aeruginosa, LPS, or PAM(3)Cys4 resulted in degranulation and release of TREM-1sv. The addition of exogenous TREM-1sv inhibited TREM-1 receptor-mediated proinflammatory cytokine production. Thus, these data reveal that TREM-1 isoforms simultaneously activate and inhibit inflammation via the canonical membrane TREM-1 molecule and this newly discovered granular isoform, TREM-1sv.
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Affiliation(s)
- Sankar Baruah
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Kathy Keck
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Michelle Vrenios
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Marshall R Pope
- Carver College of Medicine Proteomics Facility, University of Iowa, Iowa City, IA 52242; and
| | | | - Kevin Doerschug
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Julia Klesney-Tait
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
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Delanghe JR, Speeckaert MM. Translational research and biomarkers in neonatal sepsis. Clin Chim Acta 2015; 451:46-64. [DOI: 10.1016/j.cca.2015.01.031] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 01/24/2015] [Accepted: 01/24/2015] [Indexed: 01/22/2023]
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Saldir M, Tunc T, Cekmez F, Cetinkaya M, Kalayci T, Fidanci K, Babacan O, Erdem G, Kocak N, Sari E, Akgul EO, Kul M. Endocan and Soluble Triggering Receptor Expressed on Myeloid Cells-1 as Novel Markers for Neonatal Sepsis. Pediatr Neonatol 2015; 56:415-21. [PMID: 26341458 DOI: 10.1016/j.pedneo.2015.03.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Revised: 02/12/2015] [Accepted: 03/17/2015] [Indexed: 10/23/2022] Open
Abstract
BACKGROUND Neonatal sepsis is an important cause of neonatal morbidity and mortality in the neonatal intensive care unit. Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) has been evaluated in sepsis and septic shock, and it was found to be valuable in distinguishing septic cases from nonseptic cases. Endocan is constitutively expressed by endothelial cells, and high levels of endocan may be of relevance for the promotion of systemic inflammation. The aim of this study was to investigate whether the levels of sTREM-1 and endocan were increased in late-onset neonatal sepsis. METHODS Patients were classified into septic and nonseptic groups. Blood was collected from a peripheral vein of all septic newborns and healthy newborns at the time of initial laboratory evaluation before any treatment, and within 48-72 hours after initiation of treatment. Serum sTREM-1 and endocan measurements were performed when the study was finished. RESULTS The study population comprised of 50 neonates: 20 nonseptic neonates and 30 septic neonates. The groups were similar with regards to baseline characteristics. The initial measurements of interleukin-6 (IL-6), sTREM-1, endocan, and immature/total neutrophil ratio (I/T ratio) were significantly higher in septic neonates in comparison with nonseptic neonates. Receiver operating characteristic (ROC) curve analyses revealed that IL-6, sTREM-1, endocan, and I/T ratio resulted in significant areas under the curve (AUC) with respect to early identification of septic neonates. Soluble TREM-1 and IL-6 performed best to distinguish septic neonates from nonseptic neonates. Univariate logistic regression analysis showed that increased IL-6 and sTREM-1 were strong predictors of neonatal late-onset sepsis. CONCLUSION Serum sTREM-1, IL-6, endocan levels, and I/T ratio increased in septic neonates. However, the diagnostic accuracy of circulating sTREM-1 seemed to be better than endocan and I/T ratio, but lower than IL-6.
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Affiliation(s)
- Mehmet Saldir
- Department of Pediatrics, Gulhane Military School of Medicine, Ankara, Turkey
| | - Turan Tunc
- Department of Pediatrics, Division of Neonatology, Gulhane Military School of Medicine, Ankara, Turkey.
| | - Ferhat Cekmez
- Department of Pediatrics, Division of Neonatology, Gulhane Military School of Medicine, Ankara, Turkey
| | - Merih Cetinkaya
- Department of Pediatrics, Division of Neonatology, Istanbul Kanuni Sultan Suleyman Teaching Hospital, Istanbul, Turkey
| | - Tugce Kalayci
- Department of Pediatrics, Division of Neonatology, Istanbul Kanuni Sultan Suleyman Teaching Hospital, Istanbul, Turkey
| | - Kursat Fidanci
- Department of Pediatrics, Gulhane Military School of Medicine, Ankara, Turkey
| | - Oguzhan Babacan
- Department of Pediatrics, Gulhane Military School of Medicine, Ankara, Turkey
| | - Galip Erdem
- Department of Pediatrics, Gulhane Military School of Medicine, Ankara, Turkey
| | - Necmettin Kocak
- Department of Public Health, Gulhane Military School of Medicine, Ankara, Turkey
| | - Erkan Sari
- Department of Pediatrics, Gulhane Military School of Medicine, Ankara, Turkey
| | - Emin Ozgur Akgul
- Department of Clinical Biochemistry, Gulhane Military School of Medicine, Ankara, Turkey
| | - Mustafa Kul
- Department of Pediatrics, Gulhane Haydarpasa Military Hospital, Istanbul, Turkey
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Soluble and cell-associated triggering receptor expressed on myeloid cells-1 and -2 in patients with pulmonary tuberculosis. J Infect 2015; 71:706-9. [PMID: 26384438 DOI: 10.1016/j.jinf.2015.09.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 09/06/2015] [Indexed: 11/18/2022]
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Siegler BH, Weiterer S, Lichtenstern C, Stumpp D, Brenner T, Hofer S, Weigand MA, Uhle F. [Use of biomarkers in sepsis. Update and perspectives]. Anaesthesist 2015; 63:678-90. [PMID: 25002138 DOI: 10.1007/s00101-014-2347-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Sepsis and related complications are a challenge for intensive care medicine. Despite many advances in antibiotic therapy sepsis remains one of the most common diseases of patients in intensive care units and is designated as the main cause of death in critically ill patients. Persisting sepsis leads to impaired immunity, resulting in immunosuppression. Unspecific predictive signs complicate an early diagnosis; however, an early initiation of adequate therapy is of crucial importance for the prognosis. Scoring systems can be applied for the initial evaluation but are controversially discussed concerning the monitoring of disease progression and therapy as well as outcome prediction. Biomarkers are considered as a complementary approach.
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Affiliation(s)
- B H Siegler
- Klinik für Anaesthesiologie und Operative Intensivmedizin, Universitätsklinikum Gießen und Marburg, Standort Gießen, Rudolf-Buchheim Str. 7, 35392, Gießen, Deutschland
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Kojic D, Siegler BH, Uhle F, Lichtenstern C, Nawroth PP, Weigand MA, Hofer S, Brenner T. Are there new approaches for diagnosis, therapy guidance and outcome prediction of sepsis? World J Exp Med 2015; 5:50-63. [PMID: 25992320 PMCID: PMC4436940 DOI: 10.5493/wjem.v5.i2.50] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 01/09/2015] [Accepted: 04/02/2015] [Indexed: 02/06/2023] Open
Abstract
Beside many efforts to improve outcome, sepsis is still one of the most frequent causes of death in critically ill patients. It is the most common condition with high mortality in intensive care units. The complexity of the septic syndrome comprises immunological aspects - i.e., sepsis induced immunosuppression - but is not restricted to this fact in modern concepts. So far, exact mechanisms and variables determining outcome and mortality stay unclear. Since there is no typical risk profile, early diagnosis and risk stratification remain difficult, which hinders rapid and effective treatment initiation. Due to the heterogeneous nature of sepsis, potential therapy options should be adapted to the individual. Biomarkers like C-reactive protein and procalcitonin are routinely used as complementary tools in clinical decision-making. Beyond the acute phase proteins, a wide bunch of promising substances and non-laboratory tools with potential diagnostic and prognostic value is under intensive investigation. So far, clinical decision just based on biomarker assessment is not yet feasible. However, biomarkers should be considered as a complementary approach.
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Schey R, Danzer C, Mattner J. Perturbations of mucosal homeostasis through interactions of intestinal microbes with myeloid cells. Immunobiology 2015; 220:227-235. [PMID: 25466587 PMCID: PMC4273735 DOI: 10.1016/j.imbio.2014.11.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 11/20/2014] [Accepted: 11/21/2014] [Indexed: 12/28/2022]
Abstract
Mucosal surfaces represent the largest areas of interactions of the host with its environment. Subsequently, the mucosal immune system has evolved complex strategies to maintain the integrity of the host by inducing protective immune responses against pathogenic and tolerance against dietary and commensal microbial antigens within the broad range of molecules the intestinal epithelium is exposed to. Among many other specialized cell subsets, myeloid cell populations - due to their strategic location in the subepithelial lamina propria - are the first ones to scavenge and process these intestinal antigens and to send consecutive signals to other immune and non-immune cell subsets. Thus, myeloid cell populations represent attractive targets for clinical intervention in chronic inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD) as they initiate and modulate inflammatory or regulatory immune response and shape the intestinal T cell pool. Here, we discuss the interactions of the intestinal microbiota with dendritic cell and macrophage populations and review in this context the literature on four promising candidate molecules that are critical for the induction and maintenance of intestinal homeostasis on the one hand, but also for the initiation and propagation of chronic intestinal inflammation on the other.
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Affiliation(s)
- Regina Schey
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.
| | - Claudia Danzer
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany; Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.
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Gawish R, Martins R, Böhm B, Wimberger T, Sharif O, Lakovits K, Schmidt M, Knapp S. Triggering receptor expressed on myeloid cells-2 fine-tunes inflammatory responses in murine Gram-negative sepsis. FASEB J 2014; 29:1247-57. [PMID: 25477281 DOI: 10.1096/fj.14-260067] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 11/13/2014] [Indexed: 12/18/2022]
Abstract
During infections, TLR-mediated responses require tight regulation to allow for pathogen removal, while preventing overwhelming inflammation and immunopathology. The triggering receptor expressed on myeloid cells (TREM)-2 negatively regulates inflammation by macrophages and impacts on phagocytosis, but the function of endogenous TREM-2 during infections is poorly understood. We investigated TREM-2's role in regulating TLR4-mediated inflammation by studying wild-type and TREM-2(-/-) mice challenged with LPS and found TREM-2 to dampen early inflammation. Augmented early inflammation in TREM-2(-/-) animals was followed by an accelerated resolution and ultimately improved survival, associated with the induction of the negative regulator A20. Upon infection with Escherichia coli, the otherwise beneficial effect of an exaggerated early immune response in TREM-2(-/-) animals was counteracted by a 50% reduction in bacterial phagocytosis. In line with this, TREM-2(-/-) peritoneal macrophages (PMs) exhibited augmented inflammation following TLR4 stimulation, demonstrating the presence and negative regulatory functionality of TREM-2 on primary PMs. Significantly, we identified a high turnover rate because TREM-2 RNA is 25-fold down-regulated and the protein proteasomally degraded upon LPS encounter, thus ensuring a tightly regulated and versatile system that modulates inflammation. Our results illustrate TREM-2's effects on infection-triggered inflammation and identify TREM-2 as a potential target to prevent overwhelming inflammation while preserving antibacterial-effector functions.
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Affiliation(s)
- Riem Gawish
- *Ce-M-M-, Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria; and National Food Institute, Division for Epidemiology and Microbial Genomics, Technical University of Denmark, Lyngby, Denmark
| | - Rui Martins
- *Ce-M-M-, Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria; and National Food Institute, Division for Epidemiology and Microbial Genomics, Technical University of Denmark, Lyngby, Denmark
| | - Benedikta Böhm
- *Ce-M-M-, Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria; and National Food Institute, Division for Epidemiology and Microbial Genomics, Technical University of Denmark, Lyngby, Denmark
| | - Terje Wimberger
- *Ce-M-M-, Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria; and National Food Institute, Division for Epidemiology and Microbial Genomics, Technical University of Denmark, Lyngby, Denmark
| | - Omar Sharif
- *Ce-M-M-, Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria; and National Food Institute, Division for Epidemiology and Microbial Genomics, Technical University of Denmark, Lyngby, Denmark
| | - Karin Lakovits
- *Ce-M-M-, Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria; and National Food Institute, Division for Epidemiology and Microbial Genomics, Technical University of Denmark, Lyngby, Denmark
| | - Mariane Schmidt
- *Ce-M-M-, Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria; and National Food Institute, Division for Epidemiology and Microbial Genomics, Technical University of Denmark, Lyngby, Denmark
| | - Sylvia Knapp
- *Ce-M-M-, Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria; and National Food Institute, Division for Epidemiology and Microbial Genomics, Technical University of Denmark, Lyngby, Denmark
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Grover V, Pantelidis P, Soni N, Takata M, Shah PL, Wells AU, Henderson DC, Kelleher P, Singh S. A biomarker panel (Bioscore) incorporating monocytic surface and soluble TREM-1 has high discriminative value for ventilator-associated pneumonia: a prospective observational study. PLoS One 2014; 9:e109686. [PMID: 25289689 PMCID: PMC4188746 DOI: 10.1371/journal.pone.0109686] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2014] [Accepted: 09/08/2014] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Ventilator-associated pneumonia (VAP) increases mortality in critical illness. However, clinical diagnostic uncertainty persists. We hypothesised that measuring cell-surface and soluble inflammatory markers, incorporating Triggering Receptor Expressed by Myeloid cells (TREM)-1, would improve diagnostic accuracy. METHODS A single centre prospective observational study, set in a University Hospital medical-surgical intensive Care unit, recruited 91 patients into 3 groups: 27 patients with VAP, 33 ventilated controls without evidence of pulmonary sepsis (non-VAP), and 31 non-ventilated controls (NVC), without clinical infection, attending for bronchoscopy. Paired samples of Bronchiolo-alveolar lavage fluid (BALF) and blood from each subject were analysed for putative biomarkers of infection: Cellular (TREM-1, CD11b and CD62L) and soluble (IL-1β, IL-6, IL-8, sTREM-1, Procalcitonin). Expression of cellular markers on monocytes and neutrophils were measured by flow cytometry. Soluble inflammatory markers were determined by ELISA. A biomarker panel ('Bioscore'), was constructed, tested and validated, using Fisher's discriminant function analysis, to assess its value in distinguishing VAP from non VAP. RESULTS The expression of TREM-1 on monocytes (mTREM-1) and neutrophils (nTREM-1) and concentrations of IL-1β, IL-8, and sTREM-1 in BALF were significantly higher in VAP compared with non-VAP and NVC (p<0.001). The BALF/blood mTREM-1 was significantly higher in VAP patients compared to non-VAP and NVC (0.8 v 0.4 v 0.3 p<0.001). A seven marker Bioscore (BALF/blood ratio mTREM-1 and mCD11b, BALF sTREM-1, IL-8 and IL-1β, and serum CRP and IL-6) correctly identified 88.9% of VAP cases and 100% of non-VAP cases. CONCLUSION A 7-marker bioscore, incorporating cellular and soluble TREM-1, accurately discriminates VAP from non-pulmonary infection.
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Affiliation(s)
- Vimal Grover
- Magill Department of Anaesthesia, Critical Care and Pain, Chelsea and Westminster Hospital National Health Service Foundation Trust, London, United Kingdom
- Immunology Section, Department of Medicine, Imperial College, London, United Kingdom
- Department of Surgery and Cancer, Imperial College, London, United Kingdom
| | - Panagiotis Pantelidis
- Immunology Section, Department of Medicine, Imperial College, London, United Kingdom
- Department of Immunology, Imperial College Healthcare National Health Service Trust, London, United Kingdom
| | - Neil Soni
- Magill Department of Anaesthesia, Critical Care and Pain, Chelsea and Westminster Hospital National Health Service Foundation Trust, London, United Kingdom
- Department of Surgery and Cancer, Imperial College, London, United Kingdom
| | - Masao Takata
- Department of Surgery and Cancer, Imperial College, London, United Kingdom
| | - Pallav L. Shah
- Department of Respiratory Medicine, Chelsea and Westminster Hospital National Health Service Foundation Trust, London, United Kingdom
- Department of Respiratory Medicine, Royal Brompton & Harefield Hospitals National Health Service Foundation Trust, London, United Kingdom
| | - Athol U. Wells
- Department of Respiratory Medicine, Royal Brompton & Harefield Hospitals National Health Service Foundation Trust, London, United Kingdom
| | - Don C. Henderson
- Immunology Section, Department of Medicine, Imperial College, London, United Kingdom
- Department of Immunology, Imperial College Healthcare National Health Service Trust, London, United Kingdom
| | - Peter Kelleher
- Immunology Section, Department of Medicine, Imperial College, London, United Kingdom
- Department of Immunology, Imperial College Healthcare National Health Service Trust, London, United Kingdom
| | - Suveer Singh
- Magill Department of Anaesthesia, Critical Care and Pain, Chelsea and Westminster Hospital National Health Service Foundation Trust, London, United Kingdom
- Department of Surgery and Cancer, Imperial College, London, United Kingdom
- Department of Respiratory Medicine, Chelsea and Westminster Hospital National Health Service Foundation Trust, London, United Kingdom
- * E-mail:
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Palmiere C, Augsburger M. Markers for sepsis diagnosis in the forensic setting: state of the art. Croat Med J 2014; 55:103-14. [PMID: 24778096 PMCID: PMC4009711 DOI: 10.3325/cmj.2014.55.103] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Reliable diagnoses of sepsis remain challenging in forensic pathology routine despite improved methods of sample collection and extensive biochemical and immunohistochemical investigations. Macroscopic findings may be elusive and have an infectious or non-infectious origin. Blood culture results can be difficult to interpret due to postmortem contamination or bacterial translocation. Lastly, peripheral and cardiac blood may be unavailable during autopsy. Procalcitonin, C-reactive protein, and interleukin-6 can be measured in biological fluids collected during autopsy and may be used as in clinical practice for diagnostic purposes. However, concentrations of these parameters may be increased due to etiologies other than bacterial infections, indicating that a combination of biomarkers could more effectively discriminate non-infectious from infectious inflammations. In this article, we propose a review of the literature pertaining to the diagnostic performance of classical and novel biomarkers of inflammation and bacterial infection in the forensic setting.
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Affiliation(s)
- Cristian Palmiere
- Cristian Palmiere, , University Center of Legal Medicine, Lausanne, Switzerland
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40
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Ruiz-Pacheco JA, Vivanco-Cid H, Izaguirre-Hernández IY, Estrada-García I, Arriaga-Pizano L, Chacón-Salinas R, Fonseca-Coronado S, Vaughan G, Tovar KR, Rivera-Osorio MP, Escobar-Gutiérrez A. TREM-1 modulation during early stages of dengue virus infection. Immunol Lett 2014; 158:183-188. [PMID: 24447863 DOI: 10.1016/j.imlet.2014.01.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 01/04/2014] [Accepted: 01/08/2014] [Indexed: 11/17/2022]
Abstract
Uncontrolled and intricate production of inflammatory factors is the characteristic feature of dengue infection. The triggering receptor expressed in myeloid cells-1 (TREM-1), expressed on the surface of monocytes and neutrophils, is capable of enhancing and regulating the inflammatory response via the production of different mediators in bacterial and viral infections. Here, both the expression of TREM-1 on human monocytes and neutrophils from peripheral blood of dengue infected individuals, as well as the levels of the soluble form of TREM-1 (sTREM-1) in the sera of these patients were compared against healthy controls. A significant reduction of TREM-1 expression was observed in neutrophils during the first days of infection, followed by a gradual recovery throughout the course of infection. Also, sera from DENV-infected patients exhibited significantly higher sTREM-1 levels than healthy individuals. The difference was more pronounced during the first 5 days after the onset of symptoms. These findings highlight the dynamic process of TREM-1 expression during DENV infection. We hypothesized that increment of free sTREM-1 could be a compensatory mechanism aiming to counteract the inflammatory process elicited during DENV infection.
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Affiliation(s)
- J A Ruiz-Pacheco
- Departamento de Investigaciones Inmunológicas, Instituto de Diagnóstico y Referencia Epidemiológicos, Secretaría de Salud, México, DF, México; Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN, México, DF, México
| | - H Vivanco-Cid
- Instituto de Investigaciones Médico Biológicas, Universidad Veracruzana, Veracruz, México
| | | | - I Estrada-García
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN, México, DF, México
| | - L Arriaga-Pizano
- Unidad de Investigación Médica en Inmunoquímica, Hospital de Especialidades, Centro Médico Nacional "Siglo XXI", IMSS, México, DF, México
| | - R Chacón-Salinas
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN, México, DF, México
| | - S Fonseca-Coronado
- Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuatitlán-Izcalli, Estado de México, México
| | - G Vaughan
- Departamento de Investigaciones Inmunológicas, Instituto de Diagnóstico y Referencia Epidemiológicos, Secretaría de Salud, México, DF, México
| | - K Ruiz Tovar
- Departamento de Investigaciones Inmunológicas, Instituto de Diagnóstico y Referencia Epidemiológicos, Secretaría de Salud, México, DF, México
| | - M P Rivera-Osorio
- Departamento de Investigaciones Inmunológicas, Instituto de Diagnóstico y Referencia Epidemiológicos, Secretaría de Salud, México, DF, México
| | - A Escobar-Gutiérrez
- Departamento de Investigaciones Inmunológicas, Instituto de Diagnóstico y Referencia Epidemiológicos, Secretaría de Salud, México, DF, México.
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Julián-Jiménez A, Candel-González FJ, González del Castillo J. Utilidad de los biomarcadores de inflamación e infección en los servicios de urgencias. Enferm Infecc Microbiol Clin 2014; 32:177-90. [DOI: 10.1016/j.eimc.2013.01.005] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 12/17/2012] [Accepted: 01/08/2013] [Indexed: 11/15/2022]
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Shin SG, Koh SH, Lim JH. Thein vivoandin vitroRoles of Epithelial Pattern Recognition Receptors in Pneumococcal Infections. ACTA ACUST UNITED AC 2014. [DOI: 10.4167/jbv.2014.44.2.121] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Seul Gi Shin
- Department of Microbiology, Ewha Womans University School of Medicine, Seoul, Korea
| | - Seo Hyun Koh
- Department of Microbiology, Ewha Womans University School of Medicine, Seoul, Korea
| | - Jae Hyang Lim
- Department of Microbiology, Ewha Womans University School of Medicine, Seoul, Korea
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43
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Value of sTREM-1, procalcitonin and CRP as laboratory parameters for postmortem diagnosis of sepsis. J Infect 2013; 67:545-55. [DOI: 10.1016/j.jinf.2013.08.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 07/15/2013] [Accepted: 08/29/2013] [Indexed: 12/12/2022]
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Prüfer S, Weber M, Sasca D, Teschner D, Wölfel C, Stein P, Stassen M, Schild H, Radsak MP. Distinct signaling cascades of TREM-1, TLR and NLR in neutrophils and monocytic cells. J Innate Immun 2013; 6:339-52. [PMID: 24281714 DOI: 10.1159/000355892] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 09/14/2013] [Indexed: 12/15/2022] Open
Abstract
Triggering receptor expressed on myeloid cells 1 (TREM-1) is an important mediator of innate inflammatory responses in microbial infections and sepsis. TREM-1 ligation on neutrophils (PMN) or monocytes results in the production of proinflammatory cytokines. Engagement of TREM-1 induces the activation of MAP kinases as well as rapid Ca(2+) mobilization. However, a detailed understanding of TREM-1 signaling pathways is currently lacking. We evaluated the TREM-1 signaling hierarchy in monocytic cells and found that the acute myeloid leukemia cell line MUTZ-3 expresses TREM-1 in a natural and functional manner. We compared essential signaling molecules of the TREM-1, TLR and NLR cascade in MUTZ-3 cells as well as primary monocytes or PMN by Western blot analysis. These studies confirmed the essential role of phosphatidyl inositide 3-kinase (PI3K) and p38MAPK in the TREM-1 as well as the TLR or NLR cascade of monocytic cells. Importantly, PI3K and p38MAPK signals in monocytic cells both control Ca(2+) mobilization and are directly connected in the TREM-1 signaling hierarchy, which contrasts previous results obtained in PMN. Taken together, our results indicate cell type-specific differences in the TREM-1 signaling cascade and contribute to an enhanced understanding of the regulation of innate inflammatory responses.
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Affiliation(s)
- Steve Prüfer
- Institute for Immunology, Johannes Gutenberg University Medical Center, Mainz, Germany
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45
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Viertlboeck BC, Hanczaruk MA, Amann B, Bader SR, Schmitt R, Sperling B, Schwarz SCN, Schmahl W, Deeg CA, Göbel TW. Chicken immunoregulatory Ig-like receptor families: an overview and expression details on ggTREM-A1. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2013; 41:403-412. [PMID: 23648646 DOI: 10.1016/j.dci.2013.04.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Revised: 04/19/2013] [Accepted: 04/23/2013] [Indexed: 06/02/2023]
Abstract
Paired immunoregulatory receptors facilitate the coordination of the immune response at the cellular level. In recent years, our group characterized chicken homologues to mammalian immunoregulatory Ig-like receptor families. The first part of this review focuses on the current progress on chicken immunoregulatory Ig-like receptor families. One of these receptors is gallus gallus TREM-A1, which was described as the only member of the chicken TREM family with activating potential. The second part of this review presents a study initiated to further characterize ggTREM-A1 expression. For this purpose we established real-time RT-PCR and generated a specific mab to analyze the expression profile of ggTREM-A1 on mRNA and protein level, respectively. GgTREM-A1 mRNA was predominantly expressed in macrophages, but was also detected in brain, bone marrow, bursa, thymus, spleen and PBMC. Analyzing ggTREM-A1 surface expression by mab staining validated the expression on macrophages. Additionally, we showed high expression on blood monocytes, heterophils and NK cells and on monocytes isolated from bone marrow. Moreover, we detected ggTREM-A1 protein also on thrombocytes, B and T cell subsets, but antigen expression seemed to be lower and more variable in these cells. Immunohistochemistry of chicken brain tissue, combining ggTREM-A1 mab and various markers specific for various brain cell subsets showed expression of ggTREM-A1 on microglial cells, but also on neurons, astrocytes and oligodendrocytes. In conclusion, ggTREM-A1 is expressed on a variety of cells, relevant for the immune system, possibly combining physiological function of different mammalian TREM.
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Affiliation(s)
- Birgit C Viertlboeck
- Institute for Animal Physiology, Department of Veterinary Sciences, Ludwig-Maximilians-University, Munich, Germany.
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Kim TH, Lee B, Kwon E, Choi SJ, Lee YH, Song GG, Sohn J, Ji JD. Regulation of TREM-1 expression by 1,25-dihydroxyvitamin D3 in human monocytes/macrophages. Immunol Lett 2013; 154:80-5. [PMID: 24012964 DOI: 10.1016/j.imlet.2013.08.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 08/27/2013] [Accepted: 08/27/2013] [Indexed: 12/22/2022]
Abstract
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified cell surface receptor that is expressed mainly on monocytes and neutrophils, and acts as an amplifier of immune responses. In this study, 1,25(OH)2D3 strongly upregulated the expression of TREM-1 in human monocytes and macrophages. 1,25(OH)2D3 stimulated TREM-1 mRNA expression by augmenting transcription, and not by inhibiting mRNA degradation. The upregulated expression of TREM-1 by 1,25(OH)2D3 was dependent on the NF-κB signaling pathway and required new protein synthesis in differentiated U937 macrophages. Our results show that 1,25(OH)2D3 can affect the innate and inflammatory responses by upregulating TREM-1 expression, and suggest that 1,25(OH)2D3 may function as an enhancer of the innate immune response by upregulating TREM-1 expression, in addition to inducing the antimicrobial peptide cathelicidin.
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Affiliation(s)
- Tae-Hwan Kim
- Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea
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Mishra KP, Jain S, Ganju L, Singh SB. Hypoxic Stress Induced TREM-1 and Inflammatory Chemokines in Human Peripheral Blood Mononuclear Cells. Indian J Clin Biochem 2013; 29:133-8. [PMID: 24757292 DOI: 10.1007/s12291-013-0345-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 05/15/2013] [Indexed: 11/24/2022]
Abstract
Hypoxia is a condition of low pO2, which creates a unique microenvironment affecting cell phenotype and subsequent immune response generation. Little is known about the impact of hypoxia on the phenotypic expression of NK cell, TREM-1, TLR-4 and inflammatory chemokines. In the present study we have determined the frequency of peripheral blood populations of CD16/CD56 (NK Cells) expressing cells, presence of activation marker CD354 (TREM-1), Toll like receptor (CD 284) on the cell surface and chemokines IL-8 and RANTES in the cellular supernatant of normoxia and hypoxia exposed cells by flow cytometry. GRP-78 expression was determined by reverse transcriptase polymerase chain reaction. The blood was collected from healthy individuals and exposed to normoxic and hypoxic (0.5 %) environment for 24 h. The percentage of NK cells (CD 16/56) was marginally up regulated while TLR-4 expression was diminished in hypoxia exposed cells as compare to the normoxic cells. TREM-1 expression was significantly up-regulated (p < 0.05) in hypoxia as compared to the normoxic control. In addition when monocytic cell line THP-1 was exposed to 0.5 % hypoxia for 24 h, TLR4 expression was significantly decreased in hypoxic cells as compared to normoxic cells. Furthermore, GRP-78 mRNA expression was also upregulated by hypoxia or LPS exposure. These events are paralleled by strengthening up-regulation of the chemokines IL-8 and RANTES an otherwise necessary event for the chemotaxis of the neutrophils and macrophages to the inflammatory site. In conclusion, this study provides a novel insight into the mechanism linking low oxygen tension to the regulation of immune and inflammatory responses, leading to new perspectives of the role of hypoxia in programming immune cell functions.
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Affiliation(s)
- K P Mishra
- Immunomodulation Laboratory, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054 India
| | - Sonal Jain
- Immunomodulation Laboratory, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054 India
| | - Lilly Ganju
- Immunomodulation Laboratory, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054 India
| | - S B Singh
- Immunomodulation Laboratory, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054 India
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Activation of Triggering Receptor Expressed on Myeloid Cells-1 Protects Monocyte from Apoptosis through Regulation of Myeloid Cell Leukemia-1. Anesthesiology 2013; 118:1140-9. [DOI: 10.1097/aln.0b013e31828744a5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Abstract
Background:
Triggering receptor expressed on myeloid cells-1 (TREM-1) can amplify the proinflammatory response and may contribute to the pathogenesis of inflammatory disease such as sepsis. However, the role of TREM-1 in monocyte fate and the detailed molecular mechanisms evoked by TREM-1 are unknown.
Methods:
Adenoviruses overexpressing TREM-1 were constructed and transfected into a monocytic cell line. After activation of TREM-1 by agonist antibody with or without lipopolysaccharide, apoptosis was induced and assayed using flow cytometry. The signaling pathways downstream of TREM-1 were illustrated by inhibitory experiments. Proapoptotic/antiapoptotic protein levels were measured using immunoblot. In addition, the relationship between the expression levels of TREM-1 in monocytes and the magnitude of monocyte apoptosis were analyzed in septic patients.
Results:
Activation of TREM-1 protected monocytes from staurosporine-induced apoptosis. This characteristic was also obtained under lipopolysaccharide stimulation. The protection of TREM-1 against monocyte apoptosis was abrogated after inhibition of extracellular signal–regulated kinase or v-akt murine thymoma viral oncogene homologue signaling. Cross-linking of TREM-1 remarkably up-regulated myeloid cell leukemia-1 protein level, and inhibition of extracellular signal–regulated kinase or v-akt murine thymoma viral oncogene homologue resulted in the reduction of myeloid cell leukemia-1 expression. Inhibition of myeloid cell leukemia-1 abolished the antiapoptotic effect of TREM-1. Furthermore, in septic patients, TREM-1 levels were inversely correlated to the magnitude of apoptosis in monocyte.
Conclusions:
TREM-1 played an important role in apoptosis in monocytes. Activation of TREM-1 protected monocytic cells from apoptosis through activation of both extracellular signal–regulated kinase and v-akt murine thymoma viral oncogene homologue pathways and increased expression of myeloid cell leukemia-1 protein. These findings provide a novel additional mechanism for TREM-1–mediated hyperinflammatory response in monocytes.
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Molad Y, Pokroy-Shapira E, Carmon V. CpG-oligodeoxynucleotide-induced TLR9 activation regulates macrophage TREM-1 expression and shedding. Innate Immun 2013; 19:623-30. [PMID: 23475790 DOI: 10.1177/1753425913476970] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
CpG-oligonucleotide (ODN)-induced TLR9 activation exerts anti-inflammatory effects. TREM-1 is a DAP12-associated receptor, which is up-regulated in response to LPS-mediated TLR4 activation, and plays an essential role in innate immune response by augmenting the production of pro-inflammatory chemokines and cytokines. TREM-1 up-regulation resulted in a grave outcome in animal models, and in patients with sepsis and rheumatoid arthritis, while its soluble form (sTREM-1) exerted anti-inflammatory effects. We hypothesized that CpG-ODN regulates membrane TREM-1 expression and sTREM-1 shedding. The effect of CpG-ODN-induced TLR9 activation on TREM-1 expression and shedding was studied in mouse peritoneal macrophages and the mouse macrophage cell line RAW 264.7. While TREM-1 expression was not altered by CpG-ODN alone, stimulation with both LPS and CpG-ODN significantly abrogated TREM-1 LPS-induced up-regulation. Moreover, CpG-ODN-induced TLR9 activation either alone or in combination with LPS resulted in a significant increase of supernatant sTREM-1. The release of sTREM-1 was correlated positively with MMP-9 activity and was inhibited by chloroquine. These results suggest (i) a novel CpG-ODN-induced TLR9 pathway for the regulation of macrophage TREM-1 expression and MMP-9-mediated TREM-1 shedding; and (ii) a novel mechanism for an anti-inflammatory effect of CpG-ODN through abrogation of LPS-induced membrane TREM-1 up-regulation and increased MMP-9-mediated TREM-1 shedding.
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Affiliation(s)
- Yair Molad
- 1Laboratory of Inflammation Research, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Israel
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Aziz M, Jacob A, Yang WL, Matsuda A, Wang P. Current trends in inflammatory and immunomodulatory mediators in sepsis. J Leukoc Biol 2013; 93:329-42. [PMID: 23136259 PMCID: PMC3579020 DOI: 10.1189/jlb.0912437] [Citation(s) in RCA: 238] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Revised: 10/09/2012] [Accepted: 10/16/2012] [Indexed: 12/22/2022] Open
Abstract
Sepsis refers to severe systemic inflammation in response to invading pathogens. An overwhelming immune response, as mediated by the release of various inflammatory mediators, can lead to shock, multiple organ damage, and even death. Cytokines, proteases, lipid mediators, gaseous substances, vasoactive peptides, and cell stress markers play key roles in sepsis pathophysiology. Various adhesion molecules and chemokines sequester and activate neutrophils into the target organs, further augmenting inflammation and tissue damage. Although the anti-inflammatory substances counterbalance proinflammatory mediators, prolonged immune modulation may cause host susceptibility to concurrent infections, thus reflecting enormous challenge toward developing effective clinical therapy against sepsis. To understand the complex interplay between pro- and anti-inflammatory phenomenon in sepsis, there is still an unmet need to study newly characterized mediators. In addition, revealing the current trends of novel mediators will upgrade our understanding on their signal transduction, cross-talk, and synergistic and immunomodulating roles during sepsis. This review highlights the latest discoveries of the mediators in sepsis linking to innate and adaptive immune systems, which may lead to resolution of many unexplored queries.
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Affiliation(s)
- Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, and Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, USA
| | - Asha Jacob
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, and Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, USA
| | - Weng-Lang Yang
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, and Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, USA
| | - Akihisa Matsuda
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, and Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, USA
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, and Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, USA
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