Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.461
Filtrar
1.
Chemotherapy ; 64(2): 62-80, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31387102

RESUMO

BACKGROUND: Immune checkpoints are critical regulatory pathways of the immune system which finely tune the response to biological threats. Among them, the CD-28/CTLA-4 and PD-1/PD-L1 axes play a key role in tumour immune escape and are well-established targets of cancer immunotherapy. SUMMARY: The clinical experience accumulated to date provides unequivocal evidence that anti-CTLA-4, PD-1, or PD-L1 monoclonal antibodies, used as monotherapy or in combination regimes, are effective in a variety of advanced/metastatic types of cancer, with improved clinical outcomes compared to conventional chemotherapy. However, the therapeutic success is currently restricted to a limited subset of patients and reliable predictive biomarkers are still lacking. Key Message: The identification and characterization of additional co-inhibitory pathways as novel pharmacological targets to improve the clinical response in refractory patients has led to the development of different immune checkpoint inhibitors, the activities of which are currently under investigation. In this review, we discuss recent literature data concerning the mechanisms of action of next-generation monoclonal antibodies targeting LAG-3, TIM-3, and TIGIT co-inhibitory molecules that are being explored in clinical trials, as single agents or in combination with other immune-stimulating agents.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias/tratamento farmacológico , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Ensaios Clínicos como Assunto , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Microambiente Tumoral
2.
DNA Cell Biol ; 38(10): 1155-1165, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433201

RESUMO

Our previous genome-wide association study has identified a suggestive association at rs11264799 within FCRL3 (Fc receptor-like 3) locus on 1q23.1 for IgA nephropathy (IgAN) in a Chinese Han population. This study aims to investigate the association of FCRL3 variants with the susceptibility, clinicopathological phenotypes and prognosis of IgAN. Eleven FCRL3 single-nucleotide polymorphisms (SNPs) were selected and analyzed in this two-stage case/control study with a total of 1750 IgAN cases and 2500 healthy controls in a Chinese Han population. Unconditional logistic regression models were used to estimate odds ratios and 95% confidence intervals (CIs) as implemented in the PLINK software. Luciferase assays were applied to detect the allelic effect of rs11264794 on gene expression regulation. We found that four SNPs (rs11264794, rs7865684, rs11264799, and rs6691569) were significantly associated with IgAN susceptibility after Bonferroni correction in the combined samples. Genotype/phenotype association analysis observed that two SNPs (rs11264794 and rs11264793) were associated with less disease severity. After adjusting for confounders, rs11264794 was independently correlated with renal outcome in IgAN patients (hazard ratio = 0.64, 95% CI = 0.43-0.97, p = 0.033). In addition, the protective allele A of rs11264794 was significantly associated with higher FCRL3 gene expression. Furthermore, luciferase reporter gene assays demonstrated that the minor allele of rs11264794 obviously reduced the specific binding between miR-183-5p.1 and FCRL3 3'-untranslated region. Our results indicate that FCRL3 gene polymorphisms are associated with the development and progression of IgAN, and the rs11264794-A allele showed a protective role for IgAN.


Assuntos
Predisposição Genética para Doença , Glomerulonefrite por IGA/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Receptores Imunológicos/genética , Regiões 3' não Traduzidas , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Feminino , Expressão Gênica , Genes Reporter , Estudos de Associação Genética , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/etnologia , Glomerulonefrite por IGA/patologia , Humanos , Modelos Logísticos , Luciferases/genética , Luciferases/metabolismo , Masculino , MicroRNAs/metabolismo , Razão de Chances , Fenótipo , Prognóstico , Receptores Imunológicos/metabolismo , Índice de Gravidade de Doença
3.
Medicine (Baltimore) ; 98(30): e16534, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348270

RESUMO

BACKGROUND: High-grade prostate cancer (PCa) has a poor prognosis, and up to 15% of patients worldwide experience lymph node invasion (LNI). To further improve the prediction lymph node invasion in prostate cancer, we adopted risk scores of the genes expression based on the nomogram in guidelines. METHODS: We analyzed clinical data from 320 PCa patients from the Cancer Genome Atlas database. Weighted gene coexpression network analysis was used to identify the genes that were significantly associated with LNI in PCa (n = 390). Analyses using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were performed to identify the activated signaling pathways. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors for the presence of LNI. RESULTS: We found that patients with actual LNI and predicted LNI had the worst survival outcomes. The 7 most significant genes (CTNNAL1, ENSA, MAP6D1, MBD4, PRCC, SF3B2, TREML1) were selected for further analysis. Pathways in the cell cycle, DNA replication, oocyte meiosis, and 9 other pathways were dramatically activated during LNI in PCa. Multivariate analyses identified that the risk score (odds ratio [OR] = 1.05 for 1% increase, 95% confidence interval [CI]: 1.04-1.07, P < .001), serum PSA level, clinical stage, primary biopsy Gleason grade (OR = 2.52 for a grade increase, 95% CI: 1.27-5.22, P = .096), and secondary biopsy Gleason grade were independent predictors of LNI. A nomogram built using these predictive variables showed good calibration and a net clinical benefit, with an area under the curve (AUC) value of 90.2%. CONCLUSIONS: In clinical practice, the application of our nomogram might contribute significantly to the selection of patients who are good candidates for surgery with extended pelvic lymph node dissection.


Assuntos
Biomarcadores Tumorais/genética , Metástase Linfática/genética , Nomogramas , Neoplasias da Próstata/genética , Idoso , Área Sob a Curva , Proteínas de Ciclo Celular/metabolismo , Bases de Dados Genéticas , Endodesoxirribonucleases/metabolismo , Humanos , Modelos Logísticos , Linfonodos/patologia , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Proteínas de Neoplasias/metabolismo , Razão de Chances , Peptídeos/metabolismo , Valor Preditivo dos Testes , Neoplasias da Próstata/patologia , Fatores de Processamento de RNA/metabolismo , Receptores Imunológicos/metabolismo , Reprodutibilidade dos Testes , Fatores de Risco , alfa Catenina/metabolismo
4.
Cancer Immunol Immunother ; 68(8): 1223-1233, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201473

RESUMO

Plasmacytoid dendritic cells (pDCs) are present in various primary and metastatic human neoplasms; however, their clinical significance in hepatocellular carcinoma (HCC) is unclear. In this study, we investigated the distribution, prognostic value, and potential function of pDCs in HCC patients undergoing curative resection. We performed immunohistochemical analyses of whole tumor sections from 224 patients to assess the expression of BDCA2, CD3, CD4, CD8, Foxp3, granzyme B, IL-17, and CD34. The findings were validated using tissue microarrays from another two independent cohorts totaling 841 HCC patients undergoing curative resection. Our results demonstrated that high numbers of BDCA2+ pDCs within tumors correlated with high alpha-fetoprotein levels, greater vascular invasion, advanced tumor-node-metastasis stage, shorter overall survival, and a higher recurrence rate. However, patient outcomes were not associated with pDCs in peritumoral stromal or nontumor tissues. Furthermore, an increase in intratumoral pDCs was associated with increased intratumoral infiltration of Foxp3+ regulatory T cells and IL-17-producing cells and correlated with tumor vascular density. Univariate and multivariate analyses revealed that the presence of intratumoral pDCs alone or in combination with regulatory T and/or IL-17-producing cells was an independent predictor of time to recurrence and overall survival. In conclusion, our study demonstrated that intratumoral infiltration by pDCs is a novel indicator for poor prognosis in patients with HCC, possibly through the induction of an immune tolerogenic and inflammatory tumor microenvironment comprising regulatory T and IL-17-producing cells. An assessment of the combination of these cells represents a superior predictor of patient outcome.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Células Dendríticas/imunologia , Interleucina-17/metabolismo , Neoplasias Hepáticas/diagnóstico , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Progressão da Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/metabolismo , Hepatectomia , Humanos , Lectinas Tipo C/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Receptores Imunológicos/metabolismo , Análise de Sobrevida , alfa-Fetoproteínas/metabolismo
5.
Nat Neurosci ; 22(8): 1217-1222, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31235932

RESUMO

Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for sporadic, late-onset Alzheimer's disease. Here we show that germline knockout of Trem2 or the TREM2R47H variant reduces microgliosis around amyloid-ß plaques and facilitates the seeding and spreading of neuritic plaque tau aggregates. These findings demonstrate a key role for TREM2 and microglia in limiting the development of peri-plaque tau pathologies.


Assuntos
Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Placa Amiloide/genética , Placa Amiloide/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Tauopatias/genética , Tauopatias/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo , Animais , Córtex Cerebral/patologia , Camundongos , Camundongos Knockout , Microglia/patologia
6.
Nat Commun ; 10(1): 2350, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138815

RESUMO

Endothelial cell migration, proliferation and survival are triggered by VEGF-A activation of VEGFR2. However, how these cell behaviors are regulated individually is still unknown. Here we identify Endophilin-A2 (ENDOA2), a BAR-domain protein that orchestrates CLATHRIN-independent internalization, as a critical mediator of endothelial cell migration and sprouting angiogenesis. We show that EndoA2 knockout mice exhibit postnatal angiogenesis defects and impaired front-rear polarization of sprouting tip cells. ENDOA2 deficiency reduces VEGFR2 internalization and inhibits downstream activation of the signaling effector PAK but not ERK, thereby affecting front-rear polarity and migration but not proliferation or survival. Mechanistically, VEGFR2 is directed towards ENDOA2-mediated endocytosis by the SLIT2-ROBO pathway via SLIT-ROBO-GAP1 bridging of ENDOA2 and ROBO1. Blocking ENDOA2-mediated endothelial cell migration attenuates pathological angiogenesis in oxygen-induced retinopathy models. This work identifies a specific endocytic pathway controlling a subset of VEGFR2 mediated responses that could be targeted to prevent excessive sprouting angiogenesis in pathological conditions.


Assuntos
Aciltransferases/genética , Células Endoteliais/metabolismo , Neovascularização Fisiológica/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Movimento Celular/genética , Polaridade Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Endocitose/genética , Células Endoteliais/citologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Receptores Imunológicos/metabolismo , Vasos Retinianos/citologia , Vasos Retinianos/crescimento & desenvolvimento , Quinases Ativadas por p21/metabolismo
7.
Fish Shellfish Immunol ; 90: 215-222, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31039438

RESUMO

The zebrafish has unique advantages for understanding the evolution of vertebrate immunity and to model human diseases. In this review, we will firstly give an overview of the current knowledge on vertebrate innate immune receptors with special emphasis on the inflammasome and then summarize the main contribution of the zebrafish model to this field, including to the identification of novel inflammasome components and to the mechanisms involved in its activation, assembly and clearance of intracellular bacteria.


Assuntos
Evolução Biológica , Proteínas de Peixes/genética , Imunidade Inata , Receptores Imunológicos/genética , Peixe-Zebra/imunologia , Animais , Modelos Animais de Doenças , Evolução Molecular , Proteínas de Peixes/metabolismo , Imunidade Inata/genética , Modelos Animais , Receptores Imunológicos/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
8.
Med Sci Monit ; 25: 3495-3502, 2019 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-31077581

RESUMO

BACKGROUND The use of adoptive T cell therapy has proven to be effective in some advanced malignancies. This study aimed to investigate the effects of lymphocyte-activation gene 3 (LAG-3) immune checkpoint receptor in the enrichment of tumor antigen-specific CD8⁺ T lymphocytes derived from peripheral blood mononuclear cells (PBMCs) in patients with colorectal cancer. MATERIAL AND METHODS Peripheral blood samples were obtained from 20 patients with colorectal cancer and apheresis was performed with enrichment and cell sorting to obtain CD8⁺LAG-3⁺ T cells, which were expanded using high-dose interleukin-2 (IL-2). T cell subsets were detected using fluorescence-activated cell sorting (FACS), and T cell receptor (TCR) sequencing was used to determine specific clone types. Interferon-γ (IFN-γ) enzyme-linked immunospot (ELISpot) and cell counting kit-8 (CCK-8) assays were used to measure cell avidity and cytotoxicity. RESULTS The cultured cells increased in number over time and had the greatest proliferative activity at 15 days, at which time the percentage of CD3⁺, CD3⁺CD8⁺, and CD8⁺CD28⁺ reached maximal levels. High purity CD8⁺LAG-3⁺ T cells were isolated by FACS and at 15 days. TCR sequencing showed that CD8⁺LAG-3⁺ T cells were oligoclonal, ELISpot identified increased production of tumor-specific IFN-γ, and the CCK-8 assay showed increased cytotoxicity when compared with pre-cultured CD8⁺LAG-3⁻ T cells. CONCLUSIONS In patients with colorectal cancer, CD8⁺LAG-3⁺ T cells showed more specific anti-tumor activity following cell culture in vitro, which supported the potential role for the LAG-3 immune checkpoint receptor in enriching tumor-specific T cells in patients with cancer.


Assuntos
Antígenos CD/genética , Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/genética , Adulto , Idoso , Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Antígenos CD28/imunologia , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , China , Neoplasias Colorretais/metabolismo , Feminino , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T , Receptores Imunológicos/metabolismo
9.
PLoS Pathog ; 15(5): e1007785, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31083700

RESUMO

Memory T cell inflation is a process in which a subset of cytomegalovirus (CMV) specific CD8 T cells continuously expands mainly during latent infection and establishes a large and stable population of effector memory cells in peripheral tissues. Here we set out to identify in vivo parameters that promote and limit CD8 T cell inflation in the context of MCMV infection. We found that the inflationary T cell pool comprised mainly high avidity CD8 T cells, outcompeting lower avidity CD8 T cells. Furthermore, the size of the inflationary T cell pool was not restricted by the availability of specific tissue niches, but it was directly related to the number of virus-specific CD8 T cells that were activated during priming. In particular, the amount of early-primed KLRG1- cells and the number of inflationary cells with a central memory phenotype were a critical determinant for the overall magnitude of the inflationary T cell pool. Inflationary memory CD8 T cells provided protection from a Vaccinia virus challenge and this protection directly correlated with the size of the inflationary memory T cell pool in peripheral tissues. These results highlight the remarkable protective potential of inflationary CD8 T cells that can be harnessed for CMV-based T cell vaccine approaches.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Memória Imunológica/imunologia , Muromegalovirus/imunologia , Receptores Imunológicos/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/virologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Imunológicos/metabolismo
10.
J Frailty Aging ; 8(2): 54-56, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30997915

RESUMO

Alzheimer's disease (AD) is a common neurodegenerative disorder, strongly related with age. It has been reported that genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2), a cell-surface receptor expressed in microglial cells, greatly increase the risk of AD, thus suggesting an involvement of the microglia in the AD pathogenesis. The aim of this report is to provide an overview of the TREM2 and of its possible implication in the pathogenesis of AD.


Assuntos
Doença de Alzheimer/patologia , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Receptores Imunológicos/metabolismo , Doença de Alzheimer/metabolismo , Biomarcadores/metabolismo , Humanos , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genética , Risco
11.
PLoS Pathog ; 15(4): e1007658, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30947296

RESUMO

Throughout evolution, cytomegaloviruses (CMVs) have been capturing genes from their hosts, employing the derived proteins to evade host immune defenses. We have recently reported the presence of a number of CD48 homologs (vCD48s) encoded by different pathogenic viruses, including several CMVs. However, their properties and biological relevance remain as yet unexplored. CD48, a cosignaling molecule expressed on the surface of most hematopoietic cells, modulates the function of natural killer (NK) and other cytotoxic cells by binding to its natural ligand 2B4 (CD244). Here, we have characterized A43, the vCD48 exhibiting the highest amino acid sequence identity with host CD48. A43, which is encoded by owl monkey CMV, is a soluble molecule released from the cell after being proteolytically processed through its membrane proximal region. A43 is expressed with immediate-early kinetics, yielding a protein that is rapidly detected in the supernatant of infected cells. Remarkably, surface plasmon resonance assays revealed that this viral protein binds to host 2B4 with high affinity and slow dissociation rates. We demonstrate that soluble A43 is capable to abrogate host CD48:2B4 interactions. Moreover, A43 strongly binds to human 2B4 and prevents 2B4-mediated NK-cell adhesion to target cells, therefore reducing the formation of conjugates and the establishment of immunological synapses between human NK cells and CD48-expressing target cells. Furthermore, in the presence of this viral protein, 2B4-mediated cytotoxicity and IFN-γ production by NK cells are severely impaired. In summary, we propose that A43 may serve as a functional soluble CD48 decoy receptor by binding and masking 2B4, thereby impeding effective NK cell immune control during viral infections. Thus, our findings provide a novel example of the immune evasion strategies developed by viruses.


Assuntos
Antígeno CD48/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Citotoxicidade Imunológica/imunologia , Células Matadoras Naturais/imunologia , Receptores Imunológicos/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Antígeno CD48/metabolismo , Células Cultivadas , Infecções por Citomegalovirus/virologia , Humanos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/virologia , Ativação Linfocitária , Receptores Imunológicos/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo
12.
Toxicol Lett ; 311: 1-10, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31028789

RESUMO

Pulmonary fibrosis induced by prolonged exposure to silica particles is a chronic and irreversible lung disease without effective treatment till now. Our previous study has shown that early intervention with MARCO antagonist PolyG could alleviate pulmonary fibrosis in silica-exposed rats. However, the therapeutic effects of PolyG on silica-induced pulmonary fibrosis have rarely been reported. In this study, we explored the effects of administration (on the 28th day after silica exposure) of PolyG (MARCO inhibitor) on an established rat silicosis model. The lungs were analyzed histopathologically in rats using HE and Masson staining. The silica-induced ERS-related apoptosis, EMT and fibrosis were evaluated using western blotting, qRT-PCR and immunohistochemical analyses. The results suggested that silica exposure could increase the MARCO activity, and induce ERS and EMT in lung tissues. Pharmacological targeting of MARCO with PolyG attenuated the development of pulmonary fibrosis in silica-exposed rats. Further study indicated that PolyG could inhibit silica-induced ERS-related apoptosis and EMT process. Together, our findings reveal an essential function of ERS-related apoptosis and EMT in the processes of pulmonary fibrosis caused by silica, and identify MARCO as a potential therapeutic pharmacological target for silicosis.


Assuntos
Pulmão/efeitos dos fármacos , Poli G/farmacologia , Fibrose Pulmonar/prevenção & controle , Receptores Imunológicos/antagonistas & inibidores , Fármacos do Sistema Respiratório/farmacologia , Dióxido de Silício , Silicose/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ligantes , Pulmão/metabolismo , Pulmão/patologia , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos Sprague-Dawley , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Silicose/metabolismo , Silicose/patologia
13.
Mediators Inflamm ; 2019: 1208086, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944544

RESUMO

In acute pulmonary inflammation, polymorphonuclear cells (PMNs) pass a transendothelial barrier from the circulation into the lung interstitium followed by a transepithelial migration into the alveolar space. These migration steps are regulated differentially by a concept of adhesion molecules and remain-despite decades of research-incompletely understood. Current knowledge of changes in the expression pattern of adhesion molecules mainly derives from in vitro studies or from studies in extrapulmonary organ systems, where regulation of adhesion molecules differs significantly. In a murine model of lung inflammation, we determined the expression pattern of nine relevant neutrophilic adhesion molecules on their way through the different compartments of the lung. We used a flow cytometry-based technique that allowed describing spatial distribution of the adhesion molecules expressed on PMNs during their migration through the lung in detail. For example, the highest expression of CD29 was found in the intravascular compartment, highlighting its impact on the initial adhesion to the endothelium. CD47 showed its peak of expression on the later phase of transendothelial migration, whereas CD11b and CD54 expression peaked interstitial. A pivotal role for transepithelial migration was found for the adhesion molecule CD172a. Thereby, expression may correlate with functional impact for specific migration steps. In vitro studies further confirmed our in vivo findings. In conclusion, we are the first to determine the changes in expression patterns of relevant adhesion molecules on their migration through the different compartments of the lung. These findings may help to further understand the regulation of neutrophil trafficking in the lung.


Assuntos
Moléculas de Adesão Celular/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Neutrófilos/metabolismo , Pneumonia/metabolismo , Lesão Pulmonar Aguda/metabolismo , Animais , Antígeno CD11b/metabolismo , Antígeno CD47/metabolismo , Adesão Celular/efeitos dos fármacos , Citometria de Fluxo , Inflamação/imunologia , Inflamação/metabolismo , Integrina beta1/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Receptores Imunológicos/metabolismo
14.
Microb Pathog ; 131: 234-238, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30986450

RESUMO

C1q, as a LAIR-1 ligand, maintains monocytes quiescence and possess immunosuppressive properties. To understand the roles and molecular mechanisms, C1q mediated inflammation cytokines and several pivotal proteins in THP-1 cells after H. pylori infection were detected. The results showed that the expression of IL-8, IL-10, LAIR-1, phosphorylated/total JNK, phosphorylated/total p38-MAPK, phosphorylated/total AKT and phosphorylated/total NF-κB were up-regulated significantly in THP-1 cells after H. pylori infection. There was significant upregulation in IL-10 concentration, phosphorylated/total p38-MAPK and phosphorylated/total AKT, and downregulation in phosphorylated/total JNK in non-H. pylori infected THP-1 cells pretreated with C1q. C1q was also able to increase IL-8 and IL-10 production, and reduce LAIR-1 and phosphorylated/total p38-MAPK expression in pretreatment-C1q THP-1 cells after H. pylori infection. These results together indicated that H. pylori might induce IL-8 and IL-10 production through JNK, p38-MAPK, PI3K/AKT and NF-κB signaling pathway. C1q manipulate LAIR-1 to regulation IL-8 and IL-10 secretion in THP-1 cells after H. pylori infection through the p38-MAPK signaling pathway. This information is helpful to further understand the role and mechanisms of C1q on inflammation cytokines secretion in monocytes after H. pylori infection.


Assuntos
Complemento C1q/metabolismo , Complemento C1q/farmacologia , Citocinas/metabolismo , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Células THP-1/efeitos dos fármacos , Células THP-1/metabolismo , Humanos , Interleucina-10/metabolismo , Interleucina-8/metabolismo , Sistema de Sinalização das MAP Quinases , Monócitos/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases , Fosforilação , Receptores Imunológicos/metabolismo , Transdução de Sinais , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Int J Oncol ; 54(6): 1943-1954, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942436

RESUMO

Immunoglobulin­like transcript (ILT) 4, a negative regulator of immune response in allograft rejection, autoimmunity and infectious diseases, has recently been determined to serve important roles in tumor development. In the present study, the co­expression of ILT4 and human leukocyte antigen­G (HLA­G) in tissues of human primary colorectal cancer (CRC) was revealed, and its association with older age, advanced stage, regional lymph node involvement and poor overall survival time was identified. In CRC cell lines, ILT4 and HLA­G co­expression and their autocrine regulation was demonstrated. ILT4 interference affected HLA­G expression and regulated the cell proliferation, invasion and migration of CRC. HLA­G fusion protein treatment also increased ILT4 expression in a dose­dependent manner, thereby activating protein kinase B (AKT) and extracellular signal­regulated kinase (ERK) signaling, and facilitating the proliferation, migration and invasion of CRC cells. Additionally, the AKT and ERK activation, and CRC cell malignant characteristics induced by HLA­G may be suppressed by blocking ILT4. The present results indicated that the interaction of ILT4 and its ligand HLA­G promotes CRC progression through AKT and ERK signal activation, providing a novel strategy of blocking ILT4/HLA­G for the treatment of CRC.


Assuntos
Neoplasias Colorretais/patologia , Antígenos HLA-G/metabolismo , Metástase Linfática/patologia , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Colo/patologia , Neoplasias Colorretais/mortalidade , Progressão da Doença , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reto/patologia , Transdução de Sinais , Análise de Sobrevida , Fatores de Tempo , Adulto Jovem
16.
Ann Clin Lab Sci ; 49(2): 249-256, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31028072

RESUMO

OBJECTIVE: This study aims to explore the effect of triggering a receptor expressed on myeloid cells 2 (TREM2) in lipopolysaccharide (LPS)-stimulated primary microglia cells and its mechanisms. METHODS: We isolated mouse primary microglia cells in this study. The levels of TREM2, IL-6, and TNF-α in peripheral blood of SCI patients were examined by ELISA assay. The qRT-PCR and western blotting assays were performed to investigate the effects of TREM2 in LPS-induced primary microglia cells. RESULTS: The levels of TREM2, IL-6, and TNF-α significantly increased in peripheral blood of SCI patients and in LPS-stimulated primary microglia cells. Down-regulation of TREM2 significantly reduced the expression of p-NF-κB and the production of IL-6 and TNF-α. In addition, PDTC (a NF-κB inhibitor) treatment inhibited TREM2 overexpression induced-production of IL-6 and TNF-α. CONCLUSIONS: Downregulating the expression of TREM2 can inhibit the release of inflammatory factors from LPS-stimulated microglia by inhibiting NF-κB signaling pathway activity, which may be beneficial for the treatment of SCI.


Assuntos
Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Receptores Imunológicos/metabolismo , Animais , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Humanos , Interleucina-6/sangue , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Traumatismos da Medula Espinal/sangue , Fator de Necrose Tumoral alfa/sangue , Regulação para Cima/efeitos dos fármacos
17.
Anticancer Res ; 39(3): 1267-1273, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30842157

RESUMO

BACKGROUND: The members of the slit homolog (SLIT) and roundabout homolog (ROBO) families have emerged as important signaling molecules in tumor metastasis. This study analyzed their role in regulating breast cancer (BC) cell motility and chemotaxis and assessed expression of ROBO1 in brain metastases (BMs) of breast, lung, and colon cancer, and in peritoneal metastases (PMs) of ovarian cancer. MATERIALS AND METHODS: The BC cell line MDA-MB231 was subjected to scratch, motility, and chemotaxis assays using heparin and a purified recombinant N-terminal SLIT2 fragment. Protein expression was assessed in primary tumors and metastases by immunohistochemistry. RESULTS: Exposure to SLIT2 induced MDA-MB231 cell motility, but no significant chemotaxis without the presence of heparin. ROBO1 was expressed in 4/5 primary BC and in 18/21 BC-derived BM samples; 7/9 BM primary lung cancer samples also stained positive. In contrast, BMs from colorectal cancer were negative for ROBO1. Primary ovarian cancer and ovarian PM showed ROBO1 expression in 0/6 and in only 2/6 samples, respectively, whereas SLIT2 was observed in 1/6 primary cancer and in 6/6 PMs samples. CONCLUSION: SLIT2 can induce BC cell motility and chemotaxis, but the latter requires the presence of heparin. BM expression of ROBO1 is a common feature of some, but not all cancer types. SLIT2 expression appears to be a general feature of ovarian cancer-derived PMs.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptores Imunológicos/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Heparitina Sulfato/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas do Tecido Nervoso/farmacologia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/secundário
18.
Nat Commun ; 10(1): 1365, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30911003

RESUMO

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer's disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aß. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.


Assuntos
Doença de Alzheimer/terapia , Potenciação de Longa Duração/efeitos dos fármacos , Glicoproteínas de Membrana/genética , Microglia/efeitos dos fármacos , Placa Amiloide/terapia , Receptores Imunológicos/genética , Memória Espacial/efeitos dos fármacos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Injeções Intraventriculares , Potenciação de Longa Duração/fisiologia , Masculino , Glicoproteínas de Membrana/administração & dosagem , Glicoproteínas de Membrana/metabolismo , Camundongos , Microglia/metabolismo , Microglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Fenótipo , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Cultura Primária de Células , Proteólise , Receptores Imunológicos/administração & dosagem , Receptores Imunológicos/metabolismo , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Memória Espacial/fisiologia , Técnicas Estereotáxicas
19.
Arch Immunol Ther Exp (Warsz) ; 67(2): 109-123, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30820596

RESUMO

INTRODUCTION: SLIT-ROBO is a ligand-receptor family of neuronal guidance cues that has been involved in pathological and physiological angiogenesis. SLIT-ROBO expression is altered in many tumours. However, no data exist about the role of the whole family in acute myelogenous myeloid leukemia (AML). PURPOSE: Herein, we assessed the expression of all SLIT-ROBO family in bone marrow (BM) biopsy of AML patients and control group on both protein and RNA levels. METHODS: The paraffin-embedded tissue blocks were subjected to immunohistochemistry for SLIT1, SLIT2, SLIT3, ROBO1, ROBO2, ROBO3, and ROBO4. Microvessel density (MVD) was evaluated by CD34 immunohistochemistry. An in silico analysis using The Cancer Genome Atlas data repository was conducted for assessment of RNA level. RESULTS: Acute myeloid leukemia patients were generally high expressers of ROBO1 and ROBO2 compared to the controls (p < 0.0001, p < 0.001, respectively). In contrast, low expression of SLIT1, SLIT2, and SLIT3 ligands has been noted more commonly in AML than in control BM samples (p < 0.0001, p = 0.003, and p = 0.001, respectively). ROBO4 expression correlated with MVD. The in silico analysis showed a poor prognostic value of high ROBO3 and low SLIT2 RNA levels (p = 0.0003 and p = 0.0008, respectively), as well as high ROBO3 and ROBO4 RNA levels in cytogenetic poor risk groups of patients (p = 0.0029 and p = 0.0003, respectively). CONCLUSIONS: These data indicate that SLIT-ROBO family members play a role in the biology of AML. Low expression of SLIT in BM of AML patients may suggest its expression alterations in AML. Increased expression of ROBO1 and ROBO2 in AML patients suggests their participation in AML pathogenesis.


Assuntos
Leucemia Mieloide Aguda/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Orientação de Axônios , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Neovascularização Patológica , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Adulto Jovem
20.
Ann Clin Lab Sci ; 49(1): 23-30, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30814074

RESUMO

OBJECTIVE: This study aims to explore the effect of TREM2 modified BMSCs on hippocampus of AD mice. METHODS: Mouse bone marrow mesenchymal stem cells were isolated and identified. APP/PS1 double transgenic mice were confirmed to be AD model and divided into 4 groups: control group, MSCs group, MSCs+vector group and MSCs+pEGFP-TREM2 group. RESULTS: The incubation period and the number of errors in the MSCs+pEGFP-TREM2 group were significantly decreased than that of control group after 3 days. The quantity and area of Aß deposition in MSCs+pEGFP-TREM2 group were significantly smaller than that of control group. Aß40 and Aß42 levels were significantly decreased most in MSCs+pEGFP-TREM2 group. The expression levels of TREM2 and DAP12 significantly increased in the MSCs+pEGFP-TREM2 group. CONCLUSIONS: TREM2 modified bone marrow MSCs affected the ability of learning and memory of AD model mice and this mechanism may be related to the expression of TREM2 and DAP12 genes.


Assuntos
Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/fisiologia , Modelos Animais de Doenças , Glicoproteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/patologia , Presenilina-1/fisiologia , Receptores Imunológicos/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Comportamento Animal , Células Cultivadas , Humanos , Masculino , Glicoproteínas de Membrana/genética , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores Imunológicos/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA