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1.
EMBO Rep ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38783164

RESUMO

Neutrophil extracellular traps (NETs) are a key antimicrobial feature of cellular innate immunity mediated by polymorphonuclear neutrophils (PMNs). NETs counteract microbes but are also linked to inflammation in atherosclerosis, arthritis, or psoriasis by unknown mechanisms. Here, we report that NET-associated RNA (naRNA) stimulates further NET formation in naive PMNs via a unique TLR8-NLRP3 inflammasome-dependent pathway. Keratinocytes respond to naRNA with expression of psoriasis-related genes (e.g., IL17, IL36) via atypical NOD2-RIPK signaling. In vivo, naRNA drives temporary skin inflammation, which is drastically ameliorated by genetic ablation of RNA sensing. Unexpectedly, the naRNA-LL37 'composite damage-associated molecular pattern (DAMP)' is pre-stored in resting neutrophil granules, defining sterile NETs as inflammatory webs that amplify neutrophil activation. However, the activity of the naRNA-LL37 DAMP is transient and hence supposedly self-limiting under physiological conditions. Collectively, upon dysregulated NET release like in psoriasis, naRNA sensing may represent both a potential cause of disease and a new intervention target.

2.
Cell Death Dis ; 11(8): 701, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839432

RESUMO

Soft tissue sarcomas (STS) are a heterogeneous group of malignancies predominantly affecting children and young adults. Despite improvements in multimodal therapies, 5-year survival rates are only 50% and new treatment options in STS are urgently needed. To develop a rational combination therapy for the treatment of STS we focused on ABT-199 (Venetoclax), a BCL-2 specific BH3-mimetic, in combination with the proteasome inhibitor bortezomib (BZB). Simultaneous inhibition of BCL-2 and the proteasome resulted in strongly synergistic apoptosis induction. Mechanistically, ABT-199 mainly affected the multidomain effector BAX by liberating it from BCL-2 inhibition. The combination with BZB additionally resulted in the accumulation of BOK, a BAX/BAK homologue, and of the BH3-only protein NOXA, which inhibits the anti-apoptotic protein MCL-1. Thus, the combination of ABT-199 and BZB sensitizes STS cells to apoptosis by simultaneously releasing several defined apoptotic restraints. This synergistic mechanism of action was verified by CRISPR/Cas9 knock-out, showing that both BAX and NOXA are crucial for ABT-199/BZB-induced apoptosis. Noteworthy, efficient induction of apoptosis by ABT-199/BZB was not affected by the p53 status and invariably detected in cell lines and patient-derived tumor cells of several sarcoma types, including rhabdomyo-, leiomyo-, lipo-, chondro-, osteo-, or synovial sarcomas. Hence, we propose the combination of ABT-199 and BZB as a promising strategy for the treatment of STS, which should warrant further clinical investigation.


Assuntos
Bortezomib/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Sarcoma/tratamento farmacológico , Sulfonamidas/farmacologia , Adulto , Idoso , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Compostos de Bifenilo/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Nitrofenóis/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sarcoma/metabolismo , Sulfonamidas/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo
3.
Exp Biol Med (Maywood) ; 245(14): 1254-1259, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32515223

RESUMO

IMPACT STATEMENT: In our present study, we investigated the impact of LPS on neutrophil homeostasis and found that oral intake is sufficient to induce hematopoietic stem and progenitor cell fate decisions towards the neutrophil lineage independent of G-CSF. In addition, TLR4 has been identified as the indispensable sensor for oral LPS-modulated steady-state granulopoiesis. We provide evidence that the gastrointestinal microbiome is critical for neutrophil homeostasis, which has implications for patients being treated with chemotherapy or antimicrobial therapy, since both are significantly influencing the composition of the intestinal microbiome.


Assuntos
Granulócitos/efeitos dos fármacos , Granulócitos/metabolismo , Lipopolissacarídeos/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Administração Oral , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutropenia/tratamento farmacológico , Neutropenia/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Rhodobacter sphaeroides/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
4.
Nat Commun ; 8(1): 755, 2017 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-28970470

RESUMO

Chronic lymphocytic leukaemia (CLL) is a clonal disorder of mature B cells. Most patients are characterised by an indolent disease course and an anergic phenotype of their leukaemia cells, which refers to a state of unresponsiveness to B cell receptor stimulation. Up to 10% of CLL patients transform from an indolent subtype to an aggressive form of B cell lymphoma over time (Richter´s syndrome) and show a significantly worse treatment outcome. Here we show that B cell-specific ablation of Nfat2 leads to the loss of the anergic phenotype culminating in a significantly compromised life expectancy and transformation to aggressive disease. We further define a gene expression signature of anergic CLL cells consisting of several NFAT2-dependent genes including Cbl-b, Grail, Egr2 and Lck. In summary, this study identifies NFAT2 as a crucial regulator of the anergic phenotype in CLL.NFAT2 is a transcription factor that has been linked with chronic lymphocytic leukaemia (CLL), but its functions in CLL manifestation are still unclear. Here the authors show, by analysing mouse CLL models and characterising biopsies from CLL patients, that NFAT2 is an important regulator for the anergic phenotype of CLL.


Assuntos
Anergia Clonal/genética , Leucemia Linfocítica Crônica de Células B/genética , Fatores de Transcrição NFATC/genética , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteína 2 de Resposta de Crescimento Precoce , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica , Camundongos , Fenótipo , Proteínas Proto-Oncogênicas c-cbl , Ubiquitina-Proteína Ligases
5.
BMC Res Notes ; 7: 313, 2014 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-24885681

RESUMO

BACKGROUND: While paraneoplastic leukocytosis is a common phenomenon in solid tumors, extreme elevations of white blood counts (WBC) in the range of more than 100,000/µl are uncommon in patients with non-hematologic malignancies. Leukocytosis with mature neutrophils due to a granulocyte colony-stimulating factor (G-CSF) producing tumor is only seen on rare occasions. CASE PRESENTATION: Massive neutrophil leukocytosis of approximately 100,000/µl was diagnosed in a 57-year-old Caucasian woman with metastatic undifferentiated endometrial sarcoma. A bone marrow trephine biopsy revealed massively increased granulopoiesis, but no evidence of monoclonal myeloproliferative disease. After the primary tumor had been resected, white blood count (WBC) plummeted and went back to nearly normal levels within one week. With progressive metastatic disease, granulocyte colony-stimulating factor (G-CSF) plasma levels were found to be increased by 10-fold. White blood count (WBC) strictly correlated with tumor burden and response to chemotherapy. In the final stage of treatment resistent disease, white blood count (WBC) approximated 300,000/µl. CONCLUSION: We report on a granulocyte colony-stimulating factor (G-CSF) secreting undifferentiated endometrial sarcoma, which was associated with extreme neutrophil counts. White blood count (WBC) were closely correlated with tumor burden and associated with an aggressive clinical course. We suggest that paraneoplastic neutrophilia represents a poor prognostic sign in soft tissue sarcoma. In patients with similar constellations, antitumor therapy must not be delayed.


Assuntos
Neoplasias da Medula Óssea/diagnóstico , Fator Estimulador de Colônias de Granulócitos/metabolismo , Síndromes Paraneoplásicas/complicações , Síndromes Paraneoplásicas/diagnóstico , Sarcoma/complicações , Sarcoma/diagnóstico , Sarcoma/metabolismo , Contagem de Células Sanguíneas , Medula Óssea/patologia , Medula Óssea/cirurgia , Neoplasias da Medula Óssea/sangue , Neoplasias da Medula Óssea/diagnóstico por imagem , Neoplasias da Medula Óssea/cirurgia , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Síndromes Paraneoplásicas/sangue , Síndromes Paraneoplásicas/diagnóstico por imagem , Síndromes Paraneoplásicas/cirurgia , Radiografia Torácica , Sarcoma/cirurgia , Tomografia Computadorizada por Raios X
6.
Blood ; 123(23): 3563-6, 2014 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-24778154

RESUMO

Hematopoiesis in general is demand driven and adaptive, but in contrast to erythropoiesis or thrombocytopoiesis, our knowledge on how neutrophil production is adapted to individual needs remains incomplete. Recently, neutrophil homeostasis has been shown to depend on danger receptors, macrophages, and even circadian rhythms. Puzzle pieces for a broader view of neutrophil homeostasis accumulate, and we will herein try to put seemingly contradictory evidence in a perspective of neutrophil homeostasis and emergency granulopoiesis determined by innate immunologic signaling.


Assuntos
Homeostase/imunologia , Imunidade Inata/fisiologia , Neutrófilos/fisiologia , Animais , Retroalimentação Fisiológica , Fator Estimulador de Colônias de Granulócitos/fisiologia , Hematopoese/genética , Humanos , Camundongos , Microbiota/fisiologia , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/fisiologia
8.
Blood ; 121(5): 723-33, 2013 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-23223360

RESUMO

UNLABELLED: Polymorphonuclear neutrophil granulocytes (neutrophils) are tightly controlled by an incompletely understood homeostatic feedback loop adjusting the marrow's supply to peripheral needs. Although it has long been known that marrow cellularity is inversely correlated with G-CSF levels, the mechanism linking peripheral clearance to production remains unknown. Herein, the feedback response to antibody induced neutropenia is characterized to consist of G-CSF­dependent shifts of marrow hematopoietic progenitor populations including expansion of the lin-/Sca-1/c-kit (LSK) and granulocyte macrophage progenitor (GMP) compartments at the expense of thrombopoietic and red cell precursors. Evidence is provided that positive feedback regulation is independent from commensal germs as well as T, B, and NK cells. However, in vivo feedback is impaired in TLR4-/- and TRIF-/-, but not MyD88-/- animals. In conclusion, steady-state neutrophil homeostasis is G-CSF­dependent and regulated through pattern-recognition receptors,thereby directly linking TLR-triggering to granulopoiesis. KEY POINTS: Steady-state and emergency granulopoiesis are both dependent on TLR signaling.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/imunologia , Células Precursoras de Granulócitos/imunologia , Homeostase/imunologia , Neutrófilos/imunologia , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Fator Estimulador de Colônias de Granulócitos/genética , Fator Estimulador de Colônias de Granulócitos/imunologia , Células Precursoras de Granulócitos/citologia , Homeostase/genética , Linfócitos/imunologia , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Neutrófilos/citologia , Transdução de Sinais/genética , Receptor 4 Toll-Like/genética
9.
Ann N Y Acad Sci ; 1266: 171-8, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22901268

RESUMO

Neutrophil granulocytes represent the first immunologic barrier against invading pathogens, and neutropenia predisposes to infection. However, neutrophils may also cause significant collateral inflammatory damage. Therefore, neutrophil numbers are tightly regulated by an incompletely understood homeostatic feedback loop adjusting the marrow's supply to peripheral needs. Granulocyte colony-stimulating factor (G-CSF) is accepted to be the major determinant of neutrophil production, and G-CSF levels have, soon after its discovery, been described to be inversely correlated with neutrophil counts. A neutrophil sensor, or "neutrostat," has, therefore, been postulated. The prevailing feedback hypothesis was established in adhesion molecule-deficient mice; it includes macrophages and Th17 cells, which determine G-CSF levels in response to the number of peripherally transmigrated, apoptosing neutrophils. Recent work has deepened our understanding of homeostatic regulation of neutrophil granulopoiesis, but there are still inconsistent findings and unresolved questions when it comes to a plausible hypothesis, similar to the feedback control models of red cell or platelet homeostasis.


Assuntos
Neutrófilos/citologia , Neutrófilos/fisiologia , Animais , Diferenciação Celular , Retroalimentação Fisiológica , Fator Estimulador de Colônias de Granulócitos/fisiologia , Homeostase , Humanos , Camundongos , Camundongos Knockout , Mielopoese , Neutrófilos/imunologia , Receptores de Fator Estimulador de Colônias de Granulócitos/fisiologia , Células Estromais/citologia , Células Estromais/fisiologia
10.
Clin Exp Metastasis ; 27(3): 141-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20182908

RESUMO

Data from animal studies indicate that platelets play a key role in tumor dissemination and metastasis. We therefore hypothesized that metastastic cancer patients may display a specific platelet phenotype. Percentage of activated, p-selectin positive platelets as well as platelet contents (i.e., plasma and platelet count-corrected serum levels of VEGF-A, CXCL12, CXCL4, and thrombospondin-1) were analyzed in 43 patients with newly diagnosed metastatic disease prior to treatment. Tumor patients had increased platelet counts and significantly elevated percentages of activated platelets. Moreover, the platelet content of VEGF-A in cancer patients was significantly increased compared to healthy controls, while thrombospondin-1, CXCL12 and CXCL4 were significantly decreased. Our data contain several unexpected results: firstly, CXCL12 was found in minute quantities in the serum as compared with murine studies. Secondly, CXCL4, which was found by mass spectrometry to be the single massively upregulated intraplatelet chemokine in mice after tumor xenotransplantation, was decreased in tumor patient platelets. While increased contents of VEGF-A have been attributed to platelet scavenger activity, the differential decrease of specific platelet contents may be due to differential secretion or altered megakaryopoiesis in metastatic cancer patients.


Assuntos
Plaquetas/metabolismo , Quimiocina CXCL12/sangue , Metástase Neoplásica/patologia , Fator Plaquetário 4/sangue , Trombospondina 1/sangue , Fatores de Crescimento do Endotélio Vascular/sangue , Animais , Biomarcadores Tumorais/análise , Plaquetas/patologia , Estudos de Casos e Controles , Quimiocina CXCL12/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Espectrometria de Massas , Megacariócitos/metabolismo , Megacariócitos/patologia , Camundongos , Estadiamento de Neoplasias , Contagem de Plaquetas , Fator Plaquetário 4/metabolismo , Trombospondina 1/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo
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