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1.
Medicine (Baltimore) ; 99(18): e18755, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32358341

RESUMO

Many inflammation indicators have been reported to be related with patient outcomes in various cancers. Previous studies have evaluated the combination of platelet (PLT) and lymphocyte to monocyte ratio (COP-LMR) as a systemic inflammatory marker for prognostication in lung cancer, yet its prognostic role among breast cancer patients remains unclear.In the present study, a total of 409 breast cancer patients with surgical resection were retrospectively investigated. The receiver operating characteristic (ROC) curve was used to choose the optimal cut-off value of PLT and lymphocyte to monocyte ratio (LMR). Patients were classified into 3 groups according to the score of COP-LMR, and its relationship with various clinicopathological factors and breast cancer prognosis were further evaluated.The ROC curve analysis showed that COP-LMR had a higher area under the ROC curve for the prediction of 5-year disease-free survival and overall survival than PLT or LMR alone. Multivariable analysis showed that an elevated COP-LMR was an independent predictor of poor disease-free survival (P = .032) and overall survival (P = .005). Subgroup analysis revealed that COP-LMR was still significantly associated with prognosis in both luminal A and luminal B subtypes.Preoperative COP-LMR is a potential prognostic factor in breast cancer patients who underwent surgery.


Assuntos
Neoplasias da Mama/mortalidade , Contagem de Leucócitos/estatística & dados numéricos , Linfócitos , Monócitos , Contagem de Plaquetas/estatística & dados numéricos , Adulto , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Período Pré-Operatório , Prognóstico , Curva ROC , Estudos Retrospectivos
2.
J Biomed Nanotechnol ; 16(2): 212-223, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32252882

RESUMO

Together with the development of new therapeutic agents, innovation in the delivery system of anti-tumor drugs is required to increase tumor-specificity and avoid unexpected toxicity. To achieve higher efficiency, we combined a live cell-mediated drug delivery system with nanotechnology, with the aim to prove that blood monocytes can be a cargo to deliver antitumor drugs encapsulated in Polymeric poly(D, L-lactide-co-glycolide) acid based nanoparticles (PLGA NPs). In this study, we have characterized how isolated purified monocytes efficiently internalize PLGA-NPs and have imaged in vivo their trafficking upon intravenous injection in tumor-bearing mice. Monocytes carrying PLGA-Cy7 NPs were able to reach the tumor site, with superior efficiency than free PLGA-Cy7 NPs, and the bio-distribution analysis confirmed that tumors were the most reached among peripheral tissues. We further demonstrate that monocytes carrying Doxorubicin encapsulated PLGA NPs (PLGA-Doxo) induced strong killing of co-cultured tumor cells. Our studies provide proof-of-concept evidence that monocytes can be exploited in approaches of live cell-mediated drug delivery systems for tumor therapy.


Assuntos
Nanopartículas , Animais , Antineoplásicos , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Camundongos , Monócitos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
3.
Wiad Lek ; 73(2): 401-404, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32248183

RESUMO

Toll-like receptors (TLRs) are signalling pattern-recognition receptors, which play an important part in initiating the immune response in psoriasis. The available literature has little information about study of these receptors in blood. The purpose of the present work was to study the level of expression of TLR2 and TLR4 types on blood monocytes in a psoriasis patient. Within 2016-2018, TLR2 and TLR4 were examined thrice in the blood of a patient with psoriasis during its exacerbation before the beginning of his treatment. The expression of surface receptors CD282 (TLR2) and CD284 (TLR4) on peripheral blood monocytes was studied by the method of flow cytometry with use of monoclonal antibodies. The obtained data show that the expression of TLR2 on peripheral blood monocytes was high, while that of TLR4 was mostly within its reference values of 3.3±0.1 mfi. Hence, the conducted studies have shown that the expression of TLR2 on peripheral blood monocytes in all three studies was high, thereby demonstrating involvement of this factor into the pathogenesis of the above disease. During all three blood examinations, monocytes revealed an extremely high intensity of TLR2 fluorescence on studied cells that exceeded the same intensity in healthy subjects by 1.5-2 times. The expression of TLR4 on peripheral blood monocytes during all three studies was within its reference values, this fact demonstrating absence of any information value of the above factor in the pathogenesis of psoriasis.


Assuntos
Monócitos , Psoríase , Humanos , Receptores Toll-Like
4.
Medicine (Baltimore) ; 99(15): e19580, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282706

RESUMO

INTRODUCTION: Infective endocarditis (IE) and other severe infections induce significant changes in the immune response in a considerable number of affected patients. Numerous IE patients develop a persistent functional immunological phenotype that can best be characterized by a profound anti-inflammation and/ or functional "anergy." This is pronounced in patients with unresolved infectious foci and was previously referred to as "injury-associated immunosuppression" (IAI). IAI can be assessed by measurement of the monocytic human leukocyte antigen-DR (mHLA-DR) expression, a global functional marker of immune competence. Persistence of IAI is associated with prolonged intensive care unit length of stay, increased secondary infection rates, and death. Immunomodulation to reverse IAI was shown beneficial in early immunostimulatory (randomized controlled) clinical trials. METHODS: Prospective 1:1 randomized controlled clinical study to compare the course of mHLA-DR in patients scheduled for cardiac surgery for IE. Patients will receive either best standard of care plus cytokine adsorption during surgery while on cardiopulmonary bypass (protocol A) versus best standard of care alone, that is, surgery without cytokine adsorption (protocol B). A total of 54 patients will be recruited and randomized. The primary endpoint is a change in quantitative expression of mHLA-DR (antibodies per cell on CD14+ monocytes/ macrophages, assessed using a quantitative standardized assay) from baseline (preoperation [pre-OP], visit 1) to day 1 post-OP (visit 4). DISCUSSION: This randomized controlled clinical trial (RECReATE) will compare 2 clinical treatment protocols and will investigate whether cytokine adsorption restores monocytic immune competence (reflected by increased mHLA-DR expression) in patients with IE undergoing cardiac surgery. TRIAL REGISTRATION: This protocol was registered in ClinicalTrials.gov, under number NCT03892174, first listed on March 27, 2019.


Assuntos
Citocinas/isolamento & purificação , Endocardite/terapia , Antígenos HLA-DR/metabolismo , Monócitos/metabolismo , Desintoxicação por Sorção , Protocolos Clínicos , Endocardite/imunologia , Humanos , Cuidados Intraoperatórios , Estudos Prospectivos
5.
Mem Inst Oswaldo Cruz ; 115: e190408, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32321156

RESUMO

BACKGROUND: The mechanism of resistance to SbIII in Leishmania is complex, multifactorial and involves not only biochemical mechanisms, but also other elements, such as the immune system of the host. OBJECTIVES: In this study, putative changes in the immunological profile of human monocytes infected with wild-type (WT) and antimony (SbIII)-resistant Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum lines were evaluated. METHODS: Susceptibility assays WT and SbIII-resistant L. braziliensis and L. infantum were performed using lines THP-1 human monocytic lineage. Phagocytic capacity, cytokine profile, intracellular nitric oxide (NO) production and surface carbohydrate residues profile were performed in peripheral blood monocytes by flow cytometry. FINDINGS: The phagocytic capacity and intracellular NO production by classical (CD14++CD16-) and proinflammatory (CD14++CD16+) monocytes were higher in the presence of L. infantum lines compared to L. braziliensis lines. The results also highlight proinflammatory monocytes as the cellular subpopulation of major relevance in a phagocytosis event and NO expression. It is important to note that L. infantum induced a proinflammatory cytokine profile characterised by higher levels of TNF-α in culture supernatant than L. braziliensis. Conversely, both Leishmania lines induce high levels of IL-6 in culture supernatant. Analysis of the expression profile of surface carbohydrates showed that L. braziliensis presents 4.3-fold higher expression of galactose(ß1,4)N-acetylglucosamine than L. infantum line. Interestingly, the expression level of α-N-acetylgalactosamine residues was 2-fold lower in the SbIII-resistant L. braziliensis line than its counterpart WT line, indicating differences in surface glycoconjugates between these lines. MAIN CONCLUSIONS: Our results showed that L. braziliensis and L. infantum induce different innate immune responses and a highly inflammatory profile, which is characteristic of infection by L. infantum, the species associated with visceral disease.


Assuntos
Antimônio/farmacologia , Antiprotozoários/farmacologia , Leishmania braziliensis/imunologia , Leishmania infantum/imunologia , Monócitos/parasitologia , Óxido Nítrico/biossíntese , Fagocitose/imunologia , Adulto , Resistência a Medicamentos , Feminino , Citometria de Fluxo , Humanos , Imunidade Inata , Leishmania braziliensis/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Masculino , Monócitos/imunologia , Adulto Jovem
6.
Medicine (Baltimore) ; 99(14): e19627, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32243389

RESUMO

Effects of mutations on AML (acute myeloid leukemia) patients have been an area of clinical interest. The aim of this study was to analyze pre-chemotherapy WBC (white blood cell), platelet, monocyte, hemoglobin, and mean platelet volume (MPV) levels in acute myeloid leukemia patients with Wilms tumor 1 (WT1), FMS-like tyrosine kinase 3 (FLT3), or nucleophosmin (NPM) gene mutations, attempting to detect and compare possible differences in these values.The study included 71 patients with acute myeloid leukemia known to have WT1, FLT3, or NPM gene mutations. The patients were divided into 3 groups: FLT3-mutated AML patients without any accompanying known mutations other than WT1 at the time of diagnosis (Group 1), NPM-mutated AML patients without any accompanying known mutations other than WT1 at the time of diagnosis (Group 2), WT1-mutated AML patients with no other accompanying known mutations at the time of diagnosis (Group 3). We carried out intergroup comparisons of WBC, platelet (PLT), monocyte, hemoglobin, and MPV levels before chemotherapy.There was a statistically significant difference between the groups in terms of WBC parameters (P = .001). There were no statistically significant differences between the groups with respect to hemoglobin, platelet, and monocyte levels.Higher white blood cell counts could be observed in patients with FLT3-mutated AML.


Assuntos
Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/sangue , Proteínas WT1/sangue , Tirosina Quinase 3 Semelhante a fms/sangue , Adulto , Feminino , Hemoglobinas/análise , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucócitos , Masculino , Volume Plaquetário Médio , Monócitos/metabolismo , Mutação , Proteínas Nucleares/genética , Contagem de Plaquetas , Proteínas WT1/genética , Tirosina Quinase 3 Semelhante a fms/genética
7.
Medicine (Baltimore) ; 99(14): e19638, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32243392

RESUMO

BACKGROUND: This study aimed to systematically assess the prognostic value of lymphocyte monocyte ratio (LMR) in patients with ovarian cancer through performing a meta-analysis. METHODS: Web of Science, PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure databases were searched for potentially eligible studies. The baseline characteristics and relevant data were extracted. Hazard ratios with 95% confidence intervals (CIs) were combined to assess the prognostic value of LMR in patients with ovarian cancer. RESULTS: Nine studies enrolling 2809 patients were included. The pooled hazard ratios of lower LMR for overall survival and progression free survival in patients with ovarian cancer were 1.71 (95% CI, 1.40-2.09) and 1.68 (95% CI, 1.49-1.88), respectively. Subgroup analysis and sensitivity analysis were also performed. No significant publication bias was found. CONCLUSION: Our results suggested that lower LMR was associated with poorer overall survival and progression free survival in patients with ovarian cancer. The findings may assist prognosis evaluation and future research on therapies based on modulating host immune response in ovarian cancer.


Assuntos
Linfócitos/metabolismo , Monócitos/metabolismo , Neoplasias Ovarianas/mortalidade , Feminino , Humanos , Contagem de Leucócitos , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Taxa de Sobrevida
8.
Mol Immunol ; 120: 179-186, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32169738

RESUMO

BACKGROUND: The NLRP3 inflammasome has been suggested to play a crucial role in host antiviral defense, including against hepatitis B virus (HBV) infection. In the present study, we measured expression of NLRP3 and its related cytokines in patients with different stages of HBV-related acute-on-chronic liver failure (HBV-ACLF), a pattern of end-stage liver disease that occurs frequently in patients with chronic HBV (CHB) infection or HBV-related cirrhosis. METHODS: A total of 75 subjects including 30 HBV-ACLF patients, 30 CHB patients, and 15 healthy controls (HCs) were enrolled. The NLRP3 inflammasome and its components (caspase-1, interleukin (IL)-1ß, and IL-18) were measured in peripheral blood mononuclear cells (PBMCs), macrophages, and liver using flow cytometry, quantitative real-time polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry. The LPS was used to evaluate changes in NLRP3 and its related cytokines in CD14+ monocytes which may reflect immune status. Cytokine expression was measured using RT-PCR. RESULTS: Patients with HBV-ACLF had lower NLRP3 inflammasome expression in peripheral CD14+ monocytes, particularly in the middle-to-late stage, but higher expression in liver macrophages compared to CHB and HCs. Compared with H-LPS or L-LPS alone, L-LPS sequential H-LPS can significantly inhibit the expression of NLRP3 and its related cytokines. CONCLUSION: Differential expression patterns of the NLRP3 inflammasome in the periphery and liver might be related to immune dysfunction and recruitment of monocytes to the injured liver during disease progression. Persistent systemic inflammation is likely a cause of compromised immune status in patients with HBV-ACLF.


Assuntos
Insuficiência Hepática Crônica Agudizada/imunologia , Hepatite B Crônica/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/metabolismo , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Casos e Controles , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Feminino , Hepatite B Crônica/complicações , Hepatite B Crônica/metabolismo , Humanos , Inflamassomos/sangue , Inflamassomos/metabolismo , Fígado/imunologia , Fígado/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/sangue , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
9.
Adv Exp Med Biol ; 1219: 161-185, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130699

RESUMO

The behavior of cancer is undoubtedly affected by stroma. Macrophages belong to this microenvironment and their presence correlates with reduced survival in most cancers. After a tumor-induced "immunoediting", these monocytes/macrophages, originally the first line of defense against tumor cells, undergo a phenotypic switch and become tumor-supportive and immunosuppressive.The influence of these tumor-associated macrophages (TAMs) on cancer is present in all traits of carcinogenesis. These cells participate in tumor initiation and growth, migration, vascularization, invasion and metastasis. Although metastasis is extremely clinically relevant, this step is always reliant on the angiogenic ability of tumors. Therefore, the formation of new blood vessels in tumors assumes particular importance as a limiting step for disease progression.Herein, the once unsuspected roles of macrophages in cancer will be discussed and their importance as a promising strategy to treat this group of diseases will be reminded.


Assuntos
Macrófagos/metabolismo , Monócitos/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Humanos , Macrófagos/imunologia , Monócitos/imunologia , Neoplasias/imunologia , Neovascularização Patológica , Microambiente Tumoral/imunologia
10.
Anticancer Res ; 40(3): 1503-1512, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132050

RESUMO

AIM: We examined whether the perioperative systemic inflammation score (SIS), which describes systemic inflammation and/or malnutrition, affected the tumor recurrence and survival in advanced gastric cancer patients. PATIENTS AND METHODS: The study retrospectively analyzed 160 patients with stage II/III gastric cancer who underwent curative resection at the Kanagawa Cancer Center. The SIS was evaluated before surgery, one week after surgery and one month after surgery, as determined by the serum albumin level (cut-off value=4.0 g/dl) and lymphocyte-to-monocyte ratio (cut-off value=4.44). RESULTS: A high SIS at one month after surgery was identified as an independent predictor for overall survival [hazard ratio (HR)=2.143, p=0.020] and showed a marginal significance for the relapse-free survival (HR=1.814, p=0.053) in multivariate analyses. CONCLUSION: The SIS at one month after surgery is a useful biomarker for predicting the long-term outcome in patients with advanced gastric cancer.


Assuntos
Inflamação/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Gástricas/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/administração & dosagem , Quimioterapia Adjuvante , Humanos , Inflamação/sangue , Linfócitos/patologia , Pessoa de Meia-Idade , Monócitos/patologia , Estadiamento de Neoplasias , Oxaloacetatos/administração & dosagem , Período Perioperatório , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Análise de Sobrevida , Adulto Jovem
11.
Bratisl Lek Listy ; 121(2): 133-136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115966

RESUMO

OBJECTIVE: We aimed to investigate whether a simple and easily calculated parameter such as monocyte/ HDL ratio (MHR) may be used in predicting non-dipper (NDHT)-dipper HT (DHT) end organ damage. METHODS: 70 NDHT and 73 DHT patient groups were included in the study according to ambulatory blood pressure screening results. Basic laboratory parameters and spot urine samples were evaluated. Transthoracic echocardiography and ophthalmological examination were performed for end-organ damages. RESULTS: The MHR among the groups was higher in the NDHT group; which was statistically significant (p≤0.001). In the NDHT group, albumin, creatinine, protein values, protein/creatinine ratio in the spot urine were significantly higher than in the DHT group (p≤0.05). Left ventricular hypertrophy (LVH) and retinopathy were also more frequently observed in the NDHT group (p≤0.001 and p=0.001, respectively). MHR in patients with LVH and retinopathy was significantly higher than in those without these complications (p=0.001). CONCLUSION: Easy to use, non-invasive and simple calculation, MHR can be used to predict end organ damage in hypertensive cases, and can be also used to distinguish between DHT/NDHT groups. This data supports the role of inflammation (Tab. 7, Ref. 14).


Assuntos
Monitorização Ambulatorial da Pressão Arterial , HDL-Colesterol , Hipertensão , Hipertrofia Ventricular Esquerda , Monócitos , Pressão Sanguínea , HDL-Colesterol/sangue , Ecocardiografia , Humanos , Hipertensão/diagnóstico
12.
Bratisl Lek Listy ; 121(2): 151-153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115969

RESUMO

BACKGROUND: Mitral valve prolapse (MVP) is a common disorder, afflicting 2 % to 3 % of the general population. Despite the general belief of a benign disorder, there is an increasing awareness of an association between mitral valve prolapse and sudden cardiac death from arrhythmia and also atherosclerosis. Monocyte to high density lipoprotein ratio (MHR) is a new tool for predicting inflammation, which plays a major role in atherosclerosis. OBJECTIVE:   To evaluate the relationship between MHR and the presence of MVP. METHODS: The study population consisted of 82 patients with MVP and the control group of 78 normal individuals. Transthoracic echocardiograpy was performed for all of the study population and peripheral venous blood samples were drawn for measuring MHR and other haemotological parameters. RESULTS: The patients with MVP were more likely to have higher MHR values (15.82±6.01 in MVP patients and 13.30 ± 6.43 in controls; p=0.011). Monocyte counts and MHR of the MVP group were significantly higher than the control group and MHR values were directly proportional with the regurgitation area. CONCLUSION: The MHR is strongly associated with MVP and regurgitation area and might be a prognostic factor for patients with MVP (Tab. 3, Fig. 1, Ref. 15).


Assuntos
Lipoproteínas HDL , Prolapso da Valva Mitral , Monócitos , Estudos de Casos e Controles , Morte Súbita Cardíaca , Humanos , Lipoproteínas HDL/sangue , Prolapso da Valva Mitral/sangue , Prolapso da Valva Mitral/diagnóstico , Prognóstico
13.
Crit Care ; 24(1): 96, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188504

RESUMO

BACKGROUND: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Numerous studies have explored the complex and dynamic transcriptome modulations observed in sepsis patients, but a large fraction of the transcriptome remains unexplored. This fraction could provide information to better understand sepsis pathophysiology. Multiple levels of interaction between human endogenous retroviruses (HERV) and the immune response have led us to hypothesize that sepsis is associated with HERV transcription and that HERVs may contribute to a signature among septic patients allowing stratification and personalized management. METHODS: We used a high-density microarray and RT-qPCR to evaluate the HERV and Mammalian Apparent Long Terminal Repeat retrotransposons (MaLR) transcriptome in a pilot study that included 20 selected septic shock patients, stratified on mHLA-DR expression, with samples collected on day 1 and day 3 after inclusion. We validated the results in an unselected, independent cohort that included 100 septic shock patients on day 3 after inclusion. We compared septic shock patients, according to their immune status, to describe the transcriptional HERV/MaLR and conventional gene expression. For differential expression analyses, moderated t tests were performed and Wilcoxon signed-rank tests were used to analyze RT-qPCR results. RESULTS: We showed that 6.9% of the HERV/MaLR repertoire was transcribed in the whole blood, and septic shock was associated with an early modulation of a few thousand of these loci, in comparison to healthy volunteers. We provided evidence that a subset of HERV/MaLR and conventional genes were differentially expressed in septic shock patients, according to their immune status, using monocyte HLA-DR (mHLA-DR) expression as a proxy. A group of 193 differentially expressed HERV/MaLR probesets, tested in an independent septic shock cohort, identified two groups of patients with different immune status and severity features. CONCLUSION: We demonstrated that a large, unexplored part of our genome, which codes for HERV/MaLR, may be linked to the host immune response. The identified set of HERV/MaLR probesets should be evaluated on a large scale to assess the relevance of these loci in the stratification of septic shock patients. This may help to address the heterogeneity of these patients.


Assuntos
Retrovirus Endógenos/genética , Choque Séptico , Transcriptoma/genética , Idoso , Feminino , Antígenos HLA-DR , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Projetos Piloto , Retroelementos , Choque Séptico/sangue , Choque Séptico/genética , Choque Séptico/imunologia , Sequências Repetidas Terminais
14.
Crit Care ; 24(1): 110, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32192532

RESUMO

BACKGROUND: Decreased monocytic (m)HLA-DR expression is the most studied biomarker of sepsis-induced immunosuppression. To date, little is known about the relationship between sepsis characteristics, such as the site of infection, causative pathogen, or severity of disease, and mHLA-DR expression kinetics. METHODS: We evaluated mHLA-DR expression kinetics in 241 septic shock patients with different primary sites of infection and pathogens. Furthermore, we used unsupervised clustering analysis to identify mHLA-DR trajectories and evaluated their association with outcome parameters. RESULTS: No differences in mHLA-DR expression kinetics were found between groups of patients with different sites of infection (abdominal vs. respiratory, p = 0.13; abdominal vs. urinary tract, p = 0.53) and between pathogen categories (Gram-positive vs. Gram-negative, p = 0.54; Gram-positive vs. negative cultures, p = 0.84). The mHLA-DR expression kinetics differed between survivors and non-survivors (p < 0.001), with an increase over time in survivors only. Furthermore, we identified three mHLA-DR trajectories ('early improvers', 'delayed or non-improvers' and 'decliners'). The probability for adverse outcome (secondary infection or death) was higher in the delayed or non-improvers and decliners vs. the early improvers (delayed or non-improvers log-rank p = 0.03, adjusted hazard ratio 2.0 [95% CI 1.0-4.0], p = 0.057 and decliners log-rank p = 0.01, adjusted hazard ratio 2.8 [95% CI 1.1-7.1], p = 0.03). CONCLUSION: Sites of primary infection or causative pathogens are not associated with mHLA-DR expression kinetics in septic shock patients. However, patients showing delayed or no improvement in or a declining mHLA-DR expression have a higher risk for adverse outcome compared with patients exhibiting a swift increase in mHLA-DR expression. Our study signifies that changes in mHLA-DR expression over time, and not absolute values or static measurements, are of clinical importance in septic shock patients.


Assuntos
Antígenos HLA-DR/metabolismo , Choque Séptico/imunologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Infecção Hospitalar , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Prognóstico , Fatores de Risco , Choque Séptico/mortalidade
15.
Adv Exp Med Biol ; 1204: 57-73, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32152943

RESUMO

CLEC5A is a spleen tyrosine kinase (Syk)-coupled C-type lectin that is highly expressed by monocytes, macrophages, neutrophils, and dendritic cells and interacts with virions directly, via terminal fucose and mannose moieties of viral glycans. CLEC5A also binds to N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) disaccharides of bacterial cell walls. Compared to other C-type lectins (DC-SIGN and DC-SIGNR) and TLRs, CLEC5A binds its ligands with relatively low affinities. However, CLEC5A forms a multivalent hetero-complex with DC-SIGN and other C-type lectins upon engagement with ligands, and thereby mediates microbe-induced inflammatory responses via activation of Syk. For example, in vivo studies in mouse models have demonstrated that CLEC5A is responsible for flaviviruses-induced hemorrhagic shock and neuroinflammation, and a CLEC5A polymorphism in humans is associated with disease severity following infection with dengue virus. In addition, CLEC5A is co-activated with TLR2 by Listeria and Staphylococcus. Furthermore, CLEC5A-postive myeloid cells are responsible for Concanavilin A-induced aseptic inflammatory reactions. Thus, CLEC5A is a promiscuous pattern recognition receptor in myeloid cells and is a potential therapeutic target for attenuation of both septic and aseptic inflammatory reactions.


Assuntos
Lectinas Tipo C/imunologia , Receptores de Superfície Celular/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Animais , Vírus da Dengue/imunologia , Flavivirus/imunologia , Humanos , Inflamação/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Neutrófilos/imunologia
16.
Nat Commun ; 11(1): 609, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001710

RESUMO

Tumor-associated macrophages affect tumor progression and resistance to immune checkpoint therapy. Here, we identify the chemokine signal regulator FROUNT as a target to control tumor-associated macrophages. The low level FROUNT expression in patients with cancer correlates with better clinical outcomes. Frount-deficiency markedly reduces tumor progression and decreases macrophage tumor-promoting activity. FROUNT is highly expressed in macrophages, and its myeloid-specific deletion impairs tumor growth. Further, the anti-alcoholism drug disulfiram (DSF) acts as a potent inhibitor of FROUNT. DSF interferes with FROUNT-chemokine receptor interactions via direct binding to a specific site of the chemokine receptor-binding domain of FROUNT, leading to inhibition of macrophage responses. DSF monotherapy reduces tumor progression and decreases macrophage tumor-promoting activity, as seen in the case of Frount-deficiency. Moreover, co-treatment with DSF and an immune checkpoint antibody synergistically inhibits tumor growth. Thus, inhibition of FROUNT by DSF represents a promising strategy for macrophage-targeted cancer therapy.


Assuntos
Cadeias Pesadas de Clatrina/metabolismo , Dissulfiram/farmacologia , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Quimiocinas/metabolismo , Progressão da Doença , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imunoterapia , Cinética , Neoplasias Pulmonares/genética , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Metástase Neoplásica , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Prognóstico , Fatores de Risco
17.
Nat Neurosci ; 23(3): 351-362, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32042176

RESUMO

Monocyte-derived and tissue-resident macrophages are ontogenetically distinct components of the innate immune system. Assessment of their respective functions in pathology is complicated by changes to the macrophage phenotype during inflammation. Here we find that Cxcr4-CreER enables permanent genetic labeling of hematopoietic stem cells (HSCs) and distinguishes HSC-derived monocytes from microglia and other tissue-resident macrophages. By combining Cxcr4-CreER-mediated lineage tracing with Cxcr4 inhibition or conditional Cxcr4 ablation in photothrombotic stroke, we find that Cxcr4 promotes initial monocyte infiltration and subsequent territorial restriction of monocyte-derived macrophages to infarct tissue. After transient focal ischemia, Cxcr4 deficiency reduces monocyte infiltration and blunts the expression of pattern recognition and defense response genes in monocyte-derived macrophages. This is associated with an altered microglial response and deteriorated outcomes. Thus, Cxcr4 is essential for an innate-immune-system-mediated defense response after cerebral ischemia. We further propose Cxcr4-CreER as a universal tool to study functions of HSC-derived cells.


Assuntos
Isquemia Encefálica/imunologia , Células-Tronco Hematopoéticas/imunologia , Microglia/imunologia , Monócitos/imunologia , Receptores CXCR4/metabolismo , Acidente Vascular Cerebral/imunologia , Animais , Isquemia Encefálica/patologia , Linhagem da Célula , Infarto Cerebral/imunologia , Infarto Cerebral/patologia , Células-Tronco Hematopoéticas/patologia , Imunidade Inata/genética , Ataque Isquêmico Transitório/imunologia , Ataque Isquêmico Transitório/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/patologia , Monócitos/patologia , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Acidente Vascular Cerebral/patologia , Trombose/patologia , Resultado do Tratamento
18.
Immunology ; 159(3): 243-244, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32043595

RESUMO

The concept of trained immunity refers to remodelling of the monocyte and macrophage metabolic and epigenetic landscape, conferring an amplified inflammatory response upon secondary stimulation. This effect is typically modelled in vitro by stimulating monocytes with either Bacillus Calmette Guerin (BCG) or ß-Glucan for 24 hr, before subsequent stimulation with LPS or Pam-3-Cys (P3C) as a secondary stimulus 6 days later. Here, we focus on a recent paper which interrogated the role of the anti-inflammatory TLR, TLR10, on trained immunity. Using both an in vitro model of trained immunity, and analysis of BCG vaccinated individuals, the authors interestingly demonstrate that, despite its ability to regulate aspects of innate immunity, TLR10 does not have a significant role in this process.


Assuntos
Mycobacterium bovis , Receptor 10 Toll-Like , Humanos , Imunidade Inata , Macrófagos , Monócitos
19.
Nat Commun ; 11(1): 600, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001677

RESUMO

Canonical roles for macrophages in mediating the fibrotic response after a heart attack include extracellular matrix turnover and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal that macrophages directly contribute collagen to the forming post-injury scar. Unbiased transcriptomics shows an upregulation of collagens in both zebrafish and mouse macrophages following heart injury. Adoptive transfer of macrophages, from either collagen-tagged zebrafish or adult mouse GFPtpz-collagen donors, enhances scar formation via cell autonomous production of collagen. In zebrafish, the majority of tagged collagen localises proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-deposited collagen and that predominantly laid-down by myofibroblasts. Macrophage-specific targeting of col4a3bpa and cognate col4a1 in zebrafish significantly reduces scarring in cryoinjured hosts. Our findings contrast with the current model of scarring, whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair.


Assuntos
Cicatriz/metabolismo , Cicatriz/patologia , Colágeno/metabolismo , Coração/fisiopatologia , Macrófagos/patologia , Cicatrização , Peixe-Zebra/fisiologia , Transferência Adotiva , Animais , Embrião de Mamíferos/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Proteínas de Fluorescência Verde/metabolismo , Macrófagos/metabolismo , Camundongos , Monócitos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Baço/patologia , Transcrição Genética , Transcriptoma/genética , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/metabolismo
20.
PLoS One ; 15(2): e0228637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32074122

RESUMO

PURPOSE: Obesity results from excess energy intake over expenditure and is characterized by chronic low-grade inflammation involving circulating monocytes (Mo) and group 2 innate lymphoid cells (ILC2s) imbalance. We analyzed circulating Mo subsets and ILC2s percentages and ß2-adrenergic receptor (ß2AR) expression in lean and obese subjects, and the possible effect of hypocaloric restriction on these innate immune cells. METHODS: In 139 individuals aged 45 to 57 years, classified in 74 lean individuals (>18.9kg/m2 BMI <24.9kg/m2) and 65 with obesity (n = 65), we collected fasting blood samples to detect Mo subsets, ILC2s number, and ß2AR expression by flow cytometry. Lipids, insulin, leptin, and acylated-ghrelin concentrations were quantified. Resting energy expenditure (REE) was estimated by indirect calorimetry. These measurements were repeated in obese subjects after 7-weeks of hypocaloric restriction. RESULTS: Non-classical monocytes (NCM) and ß2AR expression on intermediate Mo (IM) were increased in obese individuals (p<0.001, in both cases), whereas the percent of ILC2s was decreased (p<0.0001). Stepwise regression analysis showed significantly negative associations of ILC2s with caloric intake, ß2AR expression on IM with REE, but a positive relationship between NCM and HOMA-IR. Caloric restriction allowed a significant diminution of NCM and the ß2AR expression on IM, as well as, an increase in the percent of classical Mo (CM), and ILC2s. ΔREE was related to ΔCD16+/CD16- ratio. CONCLUSIONS: These findings show that in obesity occur changes in NCM, ILC2s and ß2AR expression, which contribute to the low-grade inflammation linked to obesity and might revert with caloric restriction.


Assuntos
Restrição Calórica , Monócitos/metabolismo , Obesidade/dietoterapia , Adulto , Feminino , Grelina/sangue , Humanos , Insulina/sangue , Leptina/sangue , Lipídeos/sangue , Subpopulações de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Obesidade/sangue , Obesidade/metabolismo , Receptores Adrenérgicos beta 2/metabolismo
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