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1.
Adv Exp Med Biol ; 1197: 165-178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31732941

RESUMO

Periodontitis is a multifactorial chronic inflammatory infectious disease that compromises the integrity of tooth-supporting tissues. The disease progression depends on the disruption of host-microbe homeostasis in the periodontal tissue. This disruption is marked by a shift in the composition of the polymicrobial oral community from a symbiotic to a dysbiotic, more complex community that is capable of evading killing while promoting inflammation. Neutrophils are the main phagocytic cell in the periodontal pocket, and the outcome of the interaction with the oral microbiota is an important determinant of oral health. Novel culture-independent techniques have facilitated the identification of new bacterial species at periodontal lesions and induced a reappraisal of the microbial etiology of periodontitis. In this chapter, we discuss how neutrophils interact with two emerging oral pathogens, Filifactor alocis and Peptoanaerobacter stomatis, and the different strategies deploy by these organisms to modulate neutrophil effector functions, with the goal to outline a new paradigm in our knowledge about neutrophil responses to putative periodontal pathogens and their contribution to disease progression.


Assuntos
Neutrófilos , Periodontite , Clostridiales/imunologia , Disbiose , Humanos , Microbiota/imunologia , Neutrófilos/imunologia , Neutrófilos/microbiologia , Periodontite/imunologia , Periodontite/microbiologia , Periodonto/microbiologia
2.
Zhongguo Zhen Jiu ; 39(11): 1169-72, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31724351

RESUMO

OBJECTIVE: To observe the effect of grain-moxibustion at Zusanli (ST 36) and Weishu (BL 21) on neutrophil to lymphocyte ratio (NLR) and quality of life (QOL) in patients with advanced gastric cancer. METHODS: Sixty patients with advanced gastric cancer were randomly divided into an observation group and a control group, 30 cases in each one. In the control group, conventional chemotherapy regimen combined with symptomatic treatment,such as antiemetic, acid-suppressive, liver-protecting drugs. On the basis of the treatment in the control group, grain-moxibustion was applied at Zusanli (ST 36) and Weishu (BL 21) in the observation group, 9 cones for each acupoint, once a day for a total of 90 days. The levels of NLR were observed before and after treatment, and the clinical efficacy and quality of life were evaluated in the two groups. RESULTS: After treatment, the value of NLR in the observation group was significantly lower than before treatment (P<0.05), there was no significant difference before and after treatment in the control group (P>0.05), and the descend range of observation group was larger than the control group (P<0.05). The effective rates (RR) were 33.3% (10/30) in the observation group and 36.7% (11/30) in the control group, there was no significant difference between the two groups (P>0.05). After treatment, the QOL in the observation group was improved in diarrhea, loss of appetite, fatigue, nausea and vomiting, general health states (P<0.05), there was no significant difference in the control group before and after treatment in varions scores (P>0.05), and the observation group was superior to the control group in fatigue, sleep disorder, loss of appetite, diarrhea and general health states after treatment (P<0.05). CONCLUSION: Grain-moxibustion at Zusanli (ST 36) and Weishu (BL 21) can decrease NLR and improve QOL of patients with advanced gastric cancer.


Assuntos
Linfócitos/imunologia , Moxibustão , Neutrófilos/imunologia , Qualidade de Vida , Neoplasias Gástricas , Pontos de Acupuntura , Humanos , Moxibustão/métodos , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/psicologia , Neoplasias Gástricas/terapia
3.
Exp Parasitol ; 207: 107770, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31586454

RESUMO

Neutrophils respond differently to violations of the body's physiological barriers during infections. Extracellular traps comprise one of the mechanisms used by these cells to reduce the spread of pathogens to neighboring tissues, as well as ensure a high concentration of antimicrobial agents at the site of infection. To date, this innate defense mechanism has not been previously demonstrated in neutrophils of cats exposed to Toxoplasma gondii. The aim of this study was to characterize the in vitro release of neutrophil extracellular traps (NETs) when neutrophils isolated from cats were exposed to T. gondii. First, cellular viability was tested at different time points after parasite exposure. The production of reactive oxygen species (ROS) and lactate dehydrogenase and the amount of extracellular DNA were quantified. In addition, the number of parasites associated with neutrophils was determined, and the observed NETs formed were microscopically characterized. Results showed that (i) in culture, neutrophils isolated from cats presented diminished cellular viability after 4 h of incubation, and when neutrophils were incubated with T. gondii, they displayed cytotoxic effects after 3 h of interaction; (ii) neutrophils were able to release structures composed of DNA and histones, characterized as NETs under optical, immunofluorescence, and electron scanning microscopy, when stimulated with T. gondii; (iii) only 11.4% of neutrophils were able to discharge NETs during 3 h of incubation; however, it was observed through extracellular quantification of DNA that this small number of cells were able to display different behavior compared to a negative control (no parasite) group; (iv) significant differences in ROS production were observed in neutrophils exposed to T. gondii. In conclusion, our results showed that neutrophils isolated from cats exposed to T. gondii release structures composed of DNA and histones, similar to what has already been described in other neutrophil species infected with the parasite.


Assuntos
Armadilhas Extracelulares/metabolismo , Neutrófilos/parasitologia , Toxoplasma/imunologia , Animais , Gatos , Sobrevivência Celular , Cercopithecus aethiops , DNA/análise , Formazans/metabolismo , L-Lactato Desidrogenase/metabolismo , Microscopia Eletrônica de Varredura , Microscopia de Fluorescência , Neutrófilos/imunologia , Neutrófilos/ultraestrutura , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/análise , Sais de Tetrazólio/metabolismo , Células Vero
4.
Nature ; 574(7776): 57-62, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31534221

RESUMO

The causative agent of plague, Yersinia pestis, uses a type III secretion system to selectively destroy immune cells in humans, thus enabling Y. pestis to reproduce in the bloodstream and be transmitted to new hosts through fleabites. The host factors that are responsible for the selective destruction of immune cells by plague bacteria are unknown. Here we show that LcrV, the needle cap protein of the Y. pestis type III secretion system, binds to the N-formylpeptide receptor (FPR1) on human immune cells to promote the translocation of bacterial effectors. Plague infection in mice is characterized by high mortality; however, Fpr1-deficient mice have increased survival and antibody responses that are protective against plague. We identified FPR1R190W as a candidate resistance allele in humans that protects neutrophils from destruction by the Y. pestis type III secretion system. Thus, FPR1 is a plague receptor on immune cells in both humans and mice, and its absence or mutation provides protection against Y. pestis. Furthermore, plague selection of FPR1 alleles appears to have shaped human immune responses towards other infectious diseases and malignant neoplasms.


Assuntos
Macrófagos/metabolismo , Neutrófilos/metabolismo , Peste/microbiologia , Receptores de Formil Peptídeo/metabolismo , Yersinia pestis/metabolismo , Alelos , Animais , Antígenos de Bactérias/metabolismo , Aderência Bacteriana , Sistemas CRISPR-Cas , Quimiotaxia/imunologia , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Neutrófilos/imunologia , Neutrófilos/microbiologia , Peste/imunologia , Peste/prevenção & controle , Polimorfismo de Nucleotídeo Único/genética , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Receptores de Formil Peptídeo/antagonistas & inibidores , Receptores de Formil Peptídeo/deficiência , Receptores de Formil Peptídeo/genética , Sistemas de Secreção Tipo III/efeitos dos fármacos , Células U937 , Yersinia pestis/química , Yersinia pestis/imunologia , Yersinia pestis/patogenicidade
5.
J Agric Food Chem ; 67(40): 11230-11235, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31523955

RESUMO

Ochratoxin A (OTA) is a mycotoxin which could cause strong immunosuppressive toxicological effects in animals and humans. Heterophil extracellular traps (HETs) as a novel defense of chicken heterophils play an important role against pathogen infection. It has been reported that OTA can weaken the phagocytosis function of neutrophils. However, whether or not OTA shows immunosuppressive effects on HET release remains unclear. In the present study, we aim to first investigate the effects of OTA on HET release and then try to clarify the mechanisms in this process. OTA-induced HET structures were observed and analyzed by fluorescence confocal microscopy. The quantitative determination of OTA-induced HETs was measured by PicoGreen and a fluorescence microplate. The results clearly showed that OTA obviously induced the release of HET-like structures in heterophils, and these extracellular networks were composed by chromatin decorated with histones and neutrophil elastase. Reactive oxygen species (ROS) production was also increased in the process of OTA-induced HET formation. Furthermore, the inhibitors of NADPH oxidase, ERK [Formula: see text], and p38 MAPK signaling pathways significantly decreased OTA-induced HET formation. The abovementioned results suggest that OTA-induced HET formation is related to ROS production dependent on the activation of NADPH oxidase, ERK [Formula: see text], and p38 MAPK signaling pathways. Taken together, this study first shows that OTA possesses the ability to trigger HET formation, which provides our understanding of the host that continuously suffered OTA exposure leading to the hyporeactivity of the immune system against infection.


Assuntos
Galinhas/imunologia , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Armadilhas Extracelulares/imunologia , NADPH Oxidases/imunologia , Neutrófilos/efeitos dos fármacos , Ocratoxinas/toxicidade , Espécies Reativas de Oxigênio/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Animais , Galinhas/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Armadilhas Extracelulares/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , NADPH Oxidases/genética , Neutrófilos/enzimologia , Neutrófilos/imunologia , Fagocitose , Proteínas Quinases p38 Ativadas por Mitógeno/genética
6.
Anticancer Res ; 39(9): 5009-5018, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519608

RESUMO

BACKGROUND/AIM: Interleukin (IL)-18, which belongs to the IL-1 superfamily of cytokines, is a known interferon-gamma (IFN-γ)-inducing factor. Since IFN-γ plays an essential role in anticancer immunity mediated through cytotoxic T cells, IL-18 may also contribute to the function of immunosurveillance. The aim of the study was to examine the association of IL-18 with the outcomes of patients with breast cancer. PATIENTS AND METHODS: Serum IL-18 levels were determined at baseline in 270 patients operated for breast cancer, and the relapse-free survival (RFS) was compared between IL-18-high and -low groups. The relationships between IL-18 and tumor-infiltrating lymphocytes (TILs) or the neutrophil-to-lymphocyte ratio (NLR) were also investigated. RESULTS: The RFS of patients was significantly better in the IL-18-low group than in the IL-18-high group (p=0.032). According to the multivariate analysis, IL-18 was a significant and independent predictive factor for RFS (hazard ratio(HR)=0.336; 95% confidence interval(CI)=0.147-0.727; p=0.0053). No association was observed between the IL-18 levels and TILs or NLRs. CONCLUSION: IL-18 levels may be useful for predicting the prognosis of patients who have received surgical treatment for breast cancer.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Interleucina-18/sangue , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Citocinas/sangue , Citocinas/metabolismo , Feminino , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Neutrófilos/imunologia , Neutrófilos/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Valores de Referência , Estudos Retrospectivos , Carga Tumoral
8.
Nat Cell Biol ; 21(9): 1113-1126, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31451770

RESUMO

Cancer-induced immune responses affect tumour progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages that define 'immune subtypes' of triple-negative breast cancer (TNBC), including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumour-intrinsic pathways and mutual regulation between macrophages (or monocytes) and neutrophils contribute to the development of a dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells), is resistant to ICB, and contains a minority of macrophages that seem to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.


Assuntos
Imunoterapia , Células Mieloides/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Microambiente Tumoral/imunologia , Animais , Modelos Animais de Doenças , Feminino , Granulócitos/imunologia , Imunoterapia/métodos , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Neutrófilos/imunologia , Neutrófilos/patologia , Neoplasias de Mama Triplo Negativas/patologia
9.
Nat Immunol ; 20(9): 1196-1207, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31406379

RESUMO

The response to systemic infection and injury requires the rapid adaptation of hematopoietic stem cells (HSCs), which proliferate and divert their differentiation toward the myeloid lineage. Significant interest has emerged in understanding the signals that trigger the emergency hematopoietic program. However, the mechanisms that halt this response of HSCs, which is critical to restore homeostasis, remain unknown. Here we reveal that the E3 ubiquitin ligase Speckle-type BTB-POZ protein (SPOP) restrains the inflammatory activation of HSCs. In the absence of Spop, systemic inflammation proceeded in an unresolved manner, and the sustained response in the HSCs resulted in a lethal phenotype reminiscent of hyper-inflammatory syndrome or sepsis. Our proteomic studies decipher that SPOP restricted inflammation by ubiquitinating the innate signal transducer myeloid differentiation primary response protein 88 (MYD88). These findings unearth an HSC-intrinsic post-translational mechanism that is essential for reestablishing homeostasis after emergency hematopoiesis.


Assuntos
Inflamação/imunologia , Leucocitose/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Neutrófilos/imunologia , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Animais , Linhagem Celular , Feminino , Células HEK293 , Hematopoese/imunologia , Humanos , Masculino , Camundongos , Neutrófilos/citologia , Ubiquitina-Proteína Ligases/metabolismo
10.
J Cancer Res Clin Oncol ; 145(10): 2541-2546, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31367835

RESUMO

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with advanced cancers treated with immune checkpoint inhibitors (ICI), but has generally been evaluated as a single threshold value at baseline. We evaluated NLR at baseline and within first month during treatment in patients who received ICI for advanced cancer to evaluate the prognostic value of baseline and of changes from baseline to on-treatment NLR. METHODS: A retrospective review of patients with advanced cancer treated with ICI from 2011 to 2017 at the Ohio State University was performed. NLR was calculated at the initiation of ICI and repeated at median of 21 days. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Significance of Cox proportional hazards models were evaluated by log-rank test. Calculations were performed using the survival and survminer packages in R, and SPSS. RESULTS: 509 patients were identified and included in the analysis. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (P < 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with P < 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8-33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1-16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9-9.1). CONCLUSIONS: We confirmed the prognostic value of NLR in patients with advanced cancer treated with ICIs. We found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. To our knowledge, this is the first study to demonstrate a non-linear change in NLR over time that correlates with survival.


Assuntos
Contagem de Leucócitos , Contagem de Linfócitos , Linfócitos , Neoplasias/sangue , Neoplasias/mortalidade , Neutrófilos , Adulto , Idoso , Biomarcadores , Feminino , Humanos , Imunoterapia , Estimativa de Kaplan-Meier , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/terapia , Neutrófilos/imunologia , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
11.
Artigo em Inglês | MEDLINE | ID: mdl-31300124

RESUMO

S. Choleraesuis (Choleraesuis) and S. Typhimurium (Typhimurium) cause salmonellosis in pigs and humans. The effects of vaccine strains pSV-less Typhimurium OU5048 and Choleraesuis OU7266 and SPI-2-mutant Choleraesuis SC2284 on the immune responses of pigs against Typhimurium, Choleraesuis, and S. Enteritidis (Enteritidis) with or without the virulence plasmid (pSV) were determined. After oral vaccination of three vaccine groups and challenge with Choleraesuis CN36, the level of Salmonella-specific IgG in sera and the bactericidal effects and superoxide generation of peripheral blood mononuclear cells (PBMCs) and polymorphonuclear leukocytes (PMNs) against the above strains were determined using ELISA and NBT assay, respectively. Among three vaccine strains tested, OU7266 stimulated the highest Salmonella-specific IgG levels. Complement inactivation increased IgG concentration, while E. coli absorption reduced IgG levels. The pSV-containing strains were less resistant to serum killing than the pSV-less strains, and Enteritidis exhibited the lowest resistance to serum killing. Serovars tested, vaccine strains, and timeline periods postvaccination and challenge were important factors affecting superoxide production. The two Choleraesuis vaccine strains stimulated greater levels of superoxide from PMNs and PBMCs than the Typhimurium strains. The PMNs and PBMCs in challenged and vaccinated pigs reduced more superoxide than those in challenged hosts. In vaccinated hosts, pSV-less Salmonella strains triggered lower levels of PMN/PBMC-generated superoxide upon challenge than strains with pSV against Enteritidis and Choleraesuis. Overall, Choleraesuis OU7266 may be better than the other vaccine strains in generating the greatest IgG levels, serum bactericidal activity and superoxide levels. The pSV likely influences the immune responses.


Assuntos
Imunoglobulina G/sangue , Salmonelose Animal/prevenção & controle , Vacinas contra Salmonella/uso terapêutico , Doenças dos Suínos/prevenção & controle , Animais , Anticorpos Antibacterianos/sangue , Proteínas do Sistema Complemento/imunologia , Escherichia coli/imunologia , Escherichia coli/metabolismo , Feminino , Leucócitos Mononucleares/imunologia , Neutrófilos/imunologia , Espécies Reativas de Oxigênio/imunologia , Salmonella , Salmonelose Animal/imunologia , Vacinas contra Salmonella/imunologia , Salmonella typhimurium , Ensaios de Anticorpos Bactericidas Séricos , Suínos , Vacinação/veterinária , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/uso terapêutico
12.
J Anim Sci ; 97(8): 3326-3336, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31299068

RESUMO

Hypocalcemia in dairy cows is often associated with inflammation-related disorders such as metritis and mastitis. The protein encoded by the Ca2+ release-activated calcium modulator 1 (ORAI1) gene is a membrane Ca2+ channel subunit that is activated when Ca2+ stores are depleted. Polymorphonuclear neutrophils (PMNL) have a crucial role in the defense against infection through migration, adhesion, chemotaxis, phagocytosis, and reactive oxygen species (ROS) production in response to pathogens. Whether hypocalcemia affects the activity of PMNL and if ORAI1 is involved remains unknown. To address this, PMNL were isolated at 3 d of calving from dairy cows diagnosed as clinically healthy (n = 20, CONTROL) or with plasma concentration of calcium < 2.0 mmol/L as a criterion for diagnosis of subclinical hypocalcemia (n = 20, HYPOCAL). PMNL isolated from both groups of cows were treated with or without the sarcoendoplasmic Ca2+ ATPase inhibitor thapsigargin, Ca2+ ionophore Ionomycin, and ORAI1 blocker 2APB. The intracellular Ca2+ concentration, ORAI1 abundance, ROS, phagocytosis rate, migration, and adhering capacity of treated PMNL were evaluated. Some of the in vitro assays also included use of small interfering ORAI1 RNA (siORAI1), 100 nM 1,25(OH)2D3, or 100 nM parathyroid hormone (PTH). Intracellular Ca2+ concentration was markedly lower in HYPOCAL. In addition, ORAI1 was detected in PMNL plasma membrane via FACS and was markedly lower in cows with HYPOCAL. Migration, adhesion capacity, and phagocytosis rate of PMNL were lower in response to HYPOCAL. Furthermore, plasma and PMNL concentration of nucleosome assembly protein (NAP2) and pro-platelet basic protein (CXCL7) was markedly lower with HYPOCAL. All these changes were associated with lower ROS production by PMNL. Thapsigargin and ionomycin treatment in vitro increased ORAI1 expression, migration of PMNL, adhering capacity, phagocytosis rate, and ROS production; conversely, those effects were abrogated by siORAI1 and ORAI1 inhibitor 2APB treatment. Also cytosolic Ca2+ concentration and ORAI1 abundance were increased by 1,25(OH)2D3 and PTH supplementation. Overall, the data indicate that failure of PMNL to uptake Ca2+ due to downregulation of ORAI1 during subclinical hypocalcemia is a factor contributing to impaired PMNL function. In addition, plasma PTH or 1,25(OH)2D3 could regulate ORAI1 and also participate in the regulation of PMNL activity.


Assuntos
Cálcio/metabolismo , Bovinos/genética , Regulação da Expressão Gênica , Hipocalcemia/veterinária , Proteína ORAI1/metabolismo , Animais , Bovinos/imunologia , Bovinos/fisiologia , Indústria de Laticínios , Feminino , Hipocalcemia/imunologia , Inflamação/veterinária , Neutrófilos/imunologia , Proteína ORAI1/genética , Hormônio Paratireóideo/metabolismo , Fagocitose , Período Pós-Parto , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/metabolismo
13.
Cancer Invest ; 37(6): 265-274, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31304800

RESUMO

A meta-analysis of 14 studies (16 cohorts) incorporating 1751 participants was performed to evaluate the correlation between baseline neutrophil-to-lymphocyte ratio (NLR) and outcome of immune checkpoint inhibitors (ICI). The pooled hazard ratio (HR) suggested elevated pretreatment NLR was associated with poor OS (HR: 2.61, 95% confidence intervals (CI): 1.77-3.86, p < 0.00001) and PFS (HR: 1.74, 95% CI: 1.34-2.27, p < 0.0001). Stratified analyses on tumor types, ICI agents, the cutoff value of NLR and study regions exhibited the similar outcomes. This study demonstrated that elevated NLR was a predictor of poor OS and PFS for ICI.


Assuntos
Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Linfócitos/imunologia , Neutrófilos/imunologia , Feminino , Humanos , Imunoterapia/métodos , Contagem de Linfócitos , Linfócitos/efeitos dos fármacos , Masculino , Neutrófilos/efeitos dos fármacos , Prognóstico
14.
J Dairy Sci ; 102(9): 8343-8351, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301830

RESUMO

Methionine (Met) is one of the 2 most limiting amino acids for milk production in dairy cow diets. The accepted "ideal" ratio of lysine (Lys) to Met (L:M) when formulating diets is 3:1. However, blood from cows fed corn silage-based diets without supplemental rumen-protected Met averages approximately 3.6:1 L:M. Recent in vivo research on cattle immunonutrition has revealed that the immune system could benefit from greater Met supply. To study more closely the effects of different L:M ratios, blood polymorphonuclear cells (PMN) were isolated from 5 Holstein cows in mid-lactation (238 ± 20 d postpartum, 33.8 ± 3.8 kg of milk/d; mean ± SD). The PMN were incubated at 3 different levels of L:M (3.6:1, 2.9:1, or 2.4:1) and stimulated with lipopolysaccharide (LPS) at either 0 or 50 µg/mL for 2 h at 37°C. Target genes were associated with cytokines, pathogen recognition, nuclear receptors, killing mechanisms, and Met and glutathione metabolism. Data were subjected to ANOVA using PROC MIXED in SAS, with L:M, LPS, and their interaction as fixed effects. Stimulation with LPS upregulated genes related to cytokines (IL1B, TNF, IL10 and IL6) and nuclear receptors, including nuclear factor kappa B (NFKB1) and glucocorticoid receptor (NR3C1), and downregulated the mRNA abundance of chemokine receptor 1 (CXCR1), lysozyme (LYZ) and glutathione reductase (GSR). A linear decrease was observed in the mRNA abundance of TNF when L:M was decreased. A similar response was observed for interleukin-1 receptor-associated kinase 1 (IRAK1) and NFKB1 abundance in cells stimulated with LPS (linear effect). A linear increase of LYZ mRNA expression as L:M decreased was detected in unstimulated cells. Furthermore, a decrease in L:M led to a linear decrease of superoxide dismutase 1 (SOD1) mRNA abundance in cells challenged with LPS. Overall, LPS challenge triggered the activation of isolated PMN from mid-lactation cows. However, data suggest the use of a shorter incubation time to capture the peak response and not the resolution of the inflammatory response as in the present study. Our results indicate a possible involvement of Met in modulating PMN inflammatory and oxidative stress status and in helping the resolution of inflammation after initial stimulation.


Assuntos
Bovinos/imunologia , Redes Reguladoras de Genes , Imunidade/genética , Metionina/farmacologia , Neutrófilos/imunologia , Animais , Bovinos/genética , Células Cultivadas , Dieta/veterinária , Suplementos Nutricionais , Feminino , Lactação/fisiologia , Lipopolissacarídeos/imunologia , Metionina/administração & dosagem , Leite/química , Rúmen/metabolismo
15.
Nat Immunol ; 20(8): 1023-1034, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263278

RESUMO

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.


Assuntos
Encéfalo/imunologia , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Acidente Vascular Cerebral/patologia , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Animais , Encéfalo/citologia , Linhagem Celular , Imunidade Inata/imunologia , Inflamação/patologia , Mucosa Intestinal/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7
17.
PLoS Pathog ; 15(6): e1007833, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31220182

RESUMO

Rift Valley fever virus (RVFV) causes severe disease in livestock concurrent with zoonotic transmission to humans. A subset of people infected with RVFV develop encephalitis, and significant gaps remain in our knowledge of how RVFV causes pathology in the brain. We previously found that, in Lewis rats, subcutaneous inoculation with RVFV resulted in subclinical disease while inhalation of RVFV in a small particle aerosol caused fatal encephalitis. Here, we compared the disease course of RVFV in Lewis rats after each different route of inoculation in order to understand more about pathogenic mechanisms of fatal RVFV encephalitis. In aerosol-infected rats with lethal encephalitis, neutrophils and macrophages were the major cell types infiltrating the CNS, and this was concomitant with microglia activation and extensive cytokine inflammation. Despite this, prevention of neutrophil infiltration into the brain did not ameliorate disease. Unexpectedly, in subcutaneously-inoculated rats with subclinical disease, detectable viral RNA was found in the brain along with T-cell infiltration. This study sheds new light on the pathogenic mechanisms of RVFV encephalitis.


Assuntos
Encéfalo/imunologia , Encefalite Viral/imunologia , Macrófagos/imunologia , Infiltração de Neutrófilos , Neutrófilos/imunologia , Febre do Vale de Rift/imunologia , Vírus da Febre do Vale do Rift/imunologia , Aerossóis , Animais , Encéfalo/patologia , Encéfalo/virologia , Linhagem Celular , Citocinas/imunologia , Encefalite Viral/patologia , Feminino , Humanos , Macrófagos/patologia , Neutrófilos/patologia , Ratos , Ratos Endogâmicos Lew , Febre do Vale de Rift/patologia
18.
PLoS Pathog ; 15(6): e1007877, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31226163

RESUMO

Rapid bone destruction often leads to permanent joint dysfunction in patients with septic arthritis, which is mainly caused by Staphylococcus aureus (S. aureus). Staphylococcal cell wall components are known to induce joint inflammation and bone destruction. Here, we show that a single intra-articular injection of S. aureus lipoproteins (Lpps) into mouse knee joints induced chronic destructive macroscopic arthritis through TLR2. Arthritis was characterized by rapid infiltration of neutrophils and monocytes. The arthritogenic effect was mediated mainly by macrophages/monocytes and partially via TNF-α but not by neutrophils. Surprisingly, a S. aureus mutant lacking Lpp diacylglyceryl transferase (lgt) caused more severe joint inflammation, which coincided with higher bacterial loads of the lgt mutant in local joints than those of its parental strain. Coinjection of pathogenic S. aureus LS-1 with staphylococcal Lpps into mouse knee joints caused improved bacterial elimination and diminished bone erosion. The protective effect of the Lpps was mediated by their lipid moiety and was fully dependent on TLR2 and neutrophils. The blocking of CXCR2 on neutrophils resulted in total abrogation of the protective effect of the Lpps. Our data demonstrate that S. aureus Lpps elicit innate immune responses, resulting in a double-edged effect. On the one hand, staphylococcal Lpps boost septic arthritis. On the other hand, Lpps act as adjuvants and activate innate immunity, which could be useful for combating infections with multiple drug-resistant strains.


Assuntos
Artrite/imunologia , Proteínas de Bactérias/imunologia , Lipoproteínas/imunologia , Neutrófilos/imunologia , Staphylococcus aureus/imunologia , Animais , Artrite/genética , Artrite/microbiologia , Artrite/patologia , Proteínas de Bactérias/genética , Feminino , Lipoproteínas/genética , Camundongos , Neutrófilos/patologia , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/imunologia , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidade , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
20.
Nat Commun ; 10(1): 2402, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160588

RESUMO

Platelet-leukocyte interactions amplify inflammatory reactions, but the underlying mechanism is still unclear. CLEC5A and CLEC2 are spleen tyrosine kinase (Syk)-coupled C-type lectin receptors, abundantly expressed by leukocytes and platelets, respectively. Whereas CLEC5A is a pattern recognition receptor (PRR) to flaviviruses and bacteria, CLEC2 is the receptor for platelet-activating snake venom aggretin. Here we show that dengue virus (DV) activates platelets via CLEC2 to release extracellular vesicles (EVs), including exosomes (EXOs) and microvesicles (MVs). DV-induced EXOs (DV-EXOs) and MVs (DV-MVs) further activate CLEC5A and TLR2 on neutrophils and macrophages, thereby induce neutrophil extracellular trap (NET) formation and proinflammatory cytokine release. Compared to  stat1-/- mice, simultaneous blockade of CLEC5A and TLR2 effectively attenuates DV-induced inflammatory response and increases survival rate from 30 to 90%. The identification of critical roles of CLEC2 and CLEC5A/TLR2 in platelet-leukocyte interactions will support the development of novel strategies to treat acute viral infection in the future.


Assuntos
Plaquetas/metabolismo , Vírus da Dengue/imunologia , Dengue/imunologia , Vesículas Extracelulares/imunologia , Lectinas Tipo C/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Receptores de Superfície Celular/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Micropartículas Derivadas de Células/imunologia , Micropartículas Derivadas de Células/metabolismo , Citocinas/imunologia , Dengue/virologia , Exossomos/imunologia , Exossomos/metabolismo , Armadilhas Extracelulares/imunologia , Vesículas Extracelulares/metabolismo , Humanos , Inflamação , Lectinas Tipo C/genética , Camundongos , Camundongos Knockout , Ativação Plaquetária , Receptores de Superfície Celular/genética , Fator de Transcrição STAT1/genética , Taxa de Sobrevida
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