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1.
J Exp Med ; 219(2)2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35015026

RESUMO

Inflammatory monocytes are key mediators of acute and chronic inflammation; yet, their functional diversity remains obscure. Single-cell transcriptome analyses of human inflammatory monocytes from COVID-19 and rheumatoid arthritis patients revealed a subset of cells positive for CD127, an IL-7 receptor subunit, and such positivity rendered otherwise inert monocytes responsive to IL-7. Active IL-7 signaling engaged epigenetically coupled, STAT5-coordinated transcriptional programs to restrain inflammatory gene expression, resulting in inverse correlation between CD127 expression and inflammatory phenotypes in a seemingly homogeneous monocyte population. In COVID-19 and rheumatoid arthritis, CD127 marked a subset of monocytes/macrophages that retained hypoinflammatory phenotypes within the highly inflammatory tissue environments. Furthermore, generation of an integrated expression atlas revealed unified features of human inflammatory monocytes across different diseases and different tissues, exemplified by those of the CD127high subset. Overall, we phenotypically and molecularly characterized CD127-imprinted functional heterogeneity of human inflammatory monocytes with direct relevance for inflammatory diseases.


Assuntos
Artrite Reumatoide/imunologia , COVID-19/imunologia , Epigênese Genética/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Monócitos/imunologia , SARS-CoV-2/imunologia , Feminino , Humanos , Inflamação/imunologia , Interleucina-7/imunologia , Masculino
2.
BMC Infect Dis ; 22(1): 27, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983404

RESUMO

BACKGROUND: The severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a highly transmittable virus which causes the novel coronavirus disease (COVID-19). Monocyte distribution width (MDW) is an in-vitro hematological parameter which describes the changes in monocyte size distribution and can indicate progression from localized infection to systemic infection. In this study we evaluated the correlation between the laboratory parameters and available clinical data in different quartiles of MDW to predict the progression and severity of COVID-19 infection. METHODS: A retrospective analysis of clinical data collected in the Emergency Department of Rashid Hospital Trauma Center-DHA from adult individuals tested for SARS-CoV-2 between January and June 2020. The patients (n = 2454) were assigned into quartiles based on their MDW value on admission. The four groups were analyzed to determine if MDW was an indicator to identify patients who are at increased risk for progression to sepsis. RESULTS: Our data showed a significant positive correlation between MDW and various laboratory parameters associated with SARS-CoV-2 infection. The study also revealed that MDW ≥ 24.685 has a strong correlation with poor prognosis of COVID-19. CONCLUSIONS: Monitoring of monocytes provides a window into the systemic inflammation caused by infection and can aid in evaluating the progression and severity of COVID-19 infection.


Assuntos
COVID-19 , Sepse , Adulto , Biomarcadores , Humanos , Monócitos , Estudos Retrospectivos , SARS-CoV-2 , Sepse/diagnóstico
3.
BMC Infect Dis ; 22(1): 26, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983430

RESUMO

BACKGROUND: Early diagnosis and treatment of patients with sepsis reduce mortality significantly. In terms of exploring new diagnostic tools of sepsis, monocyte distribution width (MDW), as part of the white blood cell (WBC) differential count, was first reported in 2017. MDW greater than 20 and abnormal WBC count together provided a satisfactory accuracy and was proposed as a novel diagnostic tool of sepsis. This study aimed to compare MDW and procalcitonin (PCT)'s diagnostic accuracy on sepsis in the emergency department. METHODS: This was a single-center prospective cohort study. Laboratory examinations including complete blood cell and differentiation count (CBC/DC), MDW, PCT were obtained while arriving at the ED. We divided patients into non-infection, infection without systemic inflammatory response syndrome (SIRS), infection with SIRS, and sepsis-3 groups. This study's primary outcome is the sensitivity and specificity of MDW, PCT, and MDW + WBC in differentiating septic and non-septic patients. In addition, the cut-off value for MDW was established to maximize sensitivity at an optimal level of specificity. RESULTS: From May 2019 to September 2020, 402 patients were enrolled for data analysis. Patient number in each group was: non-infection 64 (15.9%), infection without SIRS 82 (20.4%), infection with SIRS 202 (50.2%), sepsis-3 15 (7.6%). The AUC of MDW, PCT, and MDW + WBC to predict infection with SIRS was 0.753, 0.704, and 0.784, respectively (p < 0.01). The sensitivity, specificity, PPV, and NPV of MDW using 20 as the cutoff were 86.4%, 54.2%, 76.4%, and 70%, compared to 32.9%, 88%, 82.5%, and 43.4% using 0.5 ng/mL as the PCT cutoff value. On combing MDW and WBC count, the sensitivity and NPV further increased to 93.4% and 80.3%, respectively. In terms of predicting sepsis-3, the AUC of MDW, PCT, and MDW + WBC was 0.72, 0.73, and 0.70, respectively. MDW, using 20 as cutoff, exhibited sensitivity, specificity, PPV, and NPV of 90.6%, 37.1%, 18.7%, and 96.1%, respectively, compared to 49.1%, 78.6%, 26.8%, and 90.6% when 0.5 ng/mL PCT was used as cutoff. CONCLUSIONS: In conclusion, MDW is a more sensitive biomarker than PCT in predicting infection-related SIRS and sepsis-3 in the ED. MDW < 20 shows a higher NPV to exclude sepsis-3. Combining MDW and WBC count further improves the accuracy in predicting infection with SIRS but not sepsis-3. Trial registration The study was retrospectively registered to the ClinicalTrial.gov (NCT04322942) on March 26th, 2020.


Assuntos
Pró-Calcitonina , Sepse , Biomarcadores , Proteína C-Reativa/análise , Serviço Hospitalar de Emergência , Humanos , Monócitos , Estudos Prospectivos , Sepse/diagnóstico
4.
Theranostics ; 12(1): 290-306, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34987646

RESUMO

Coronavirus disease 2019 (COVID19), caused by SARS-CoV-2, is a complex disease, with a variety of clinical manifestations ranging from asymptomatic infection or mild cold-like symptoms to more severe cases requiring hospitalization and critical care. The most severe presentations seem to be related with a delayed, deregulated immune response leading to exacerbated inflammation and organ damage with close similarities to sepsis. Methods: In order to improve the understanding on the relation between host immune response and disease course, we have studied the differences in the cellular (monocytes, CD8+ T and NK cells) and soluble (cytokines, chemokines and immunoregulatory ligands) immune response in blood between Healthy Donors (HD), COVID19 and a group of patients with non-COVID19 respiratory tract infections (NON-COV-RTI). In addition, the immune response profile has been analyzed in COVID19 patients according to disease severity. Results: In comparison to HDs and patients with NON-COV-RTI, COVID19 patients show a heterogeneous immune response with the presence of both activated and exhausted CD8+ T and NK cells characterised by the expression of the immune checkpoint LAG3 and the presence of the adaptive NK cell subset. An increased frequency of adaptive NK cells and a reduction of NK cells expressing the activating receptors NKp30 and NKp46 correlated with disease severity. Although both activated and exhausted NK cells expressing LAG3 were increased in moderate/severe cases, unsupervised cell clustering analyses revealed a more complex scenario with single NK cells expressing more than one immune checkpoint (PD1, TIM3 and/or LAG3). A general increased level of inflammatory cytokines and chemokines was found in COVID19 patients, some of which like IL18, IL1RA, IL36B and IL31, IL2, IFNα and TNFα, CXCL10, CCL2 and CCL8 were able to differentiate between COVID19 and NON-COV-RTI and correlated with bad prognosis (IL2, TNFα, IL1RA, CCL2, CXCL10 and CXCL9). Notably, we found that soluble NKG2D ligands from the MIC and ULBPs families were increased in COVID19 compared to NON-COV-RTI and correlated with disease severity. Conclusions: Our results provide a detailed comprehensive analysis of the presence of activated and exhausted CD8+T, NK and monocyte cell subsets as well as extracellular inflammatory factors beyond cytokines/chemokines, specifically associated to COVID19. Importantly, multivariate analysis including clinical, demographical and immunological experimental variables have allowed us to reveal specific immune signatures to i) differentiate COVID19 from other infections and ii) predict disease severity and the risk of death.


Assuntos
COVID-19/sangue , COVID-19/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Linfócitos T CD8-Positivos/virologia , COVID-19/mortalidade , Estudos de Casos e Controles , Quimiocinas/sangue , Citocinas/sangue , Feminino , Hospitalização , Humanos , Células Matadoras Naturais/virologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Monócitos/virologia , Estudos Prospectivos , Infecções Respiratórias/sangue , Infecções Respiratórias/imunologia , Índice de Gravidade de Doença
5.
Nat Commun ; 13(1): 14, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013241

RESUMO

Type I interferons (IFNs) are critical for anti-viral responses, and also drive autoimmunity when dysregulated. Upon viral sensing, monocytes elicit a sequential cascade of IFNß and IFNα production involving feedback amplification, but how exactly this cascade is regulated in human cells is incompletely understood. Here we show that the PYHIN protein myeloid cell nuclear differentiation antigen (MNDA) is required for IFNα induction in monocytes. Unlike other PYHINs, this is not due to a pathogen sensing role, but rather MNDA regulated expression of IRF7, a transcription factor essential for IFNα induction. Mechanistically, MNDA is required for recruitment of STAT2 and RNA polymerase II to the IRF7 gene promoter, and in fact MNDA is itself recruited to the IRF7 promoter after type I IFN stimulation. These data implicate MNDA as a critical regulator of the type I IFN cascade in human myeloid cells and reveal a new role for human PYHINs in innate immune gene induction.


Assuntos
Antígenos de Diferenciação Mielomonocítica/metabolismo , Imunidade Inata , Interferon Tipo I/metabolismo , Células Mieloides/metabolismo , Fatores de Transcrição/metabolismo , Linhagem Celular , Regulação da Expressão Gênica , Humanos , Imunidade Inata/genética , Imunidade Inata/fisiologia , Monócitos/metabolismo
7.
J Exp Med ; 219(2)2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34914824

RESUMO

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRß repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.


Assuntos
COVID-19/complicações , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Monócitos/metabolismo , Receptores de IgG/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Linfócitos T/imunologia , Adolescente , Células Epiteliais Alveolares/patologia , Linfócitos B/imunologia , Vasos Sanguíneos/patologia , COVID-19/imunologia , COVID-19/patologia , Proliferação de Células , Criança , Estudos de Coortes , Ativação do Complemento , Citocinas/metabolismo , Enterócitos/patologia , Feminino , Humanos , Imunidade Humoral , Inflamação/patologia , Interferon Tipo I/metabolismo , Interleucina-15/metabolismo , Ativação Linfocitária/imunologia , Masculino , Receptores de Antígenos de Linfócitos T/metabolismo , SARS-CoV-2/imunologia , Superantígenos/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/patologia
8.
Proc Natl Acad Sci U S A ; 119(1)2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34969849

RESUMO

Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes a potentially fatal pneumonia with multiorgan failure, and high systemic inflammation. To gain mechanistic insight and ferret out the root of this immune dysregulation, we modeled, by in vitro coculture, the interactions between infected epithelial cells and immunocytes. A strong response was induced in monocytes and B cells, with a SARS-CoV-2-specific inflammatory gene cluster distinct from that seen in influenza A or Ebola virus-infected cocultures, and which reproduced deviations reported in blood or lung myeloid cells from COVID-19 patients. A substantial fraction of the effect could be reproduced after individual transfection of several SARS-CoV-2 proteins (Spike and some nonstructural proteins), mediated by soluble factors, but not via transcriptional induction. This response was greatly muted in monocytes from healthy children, perhaps a clue to the age dependency of COVID-19. These results suggest that the inflammatory malfunction in COVID-19 is rooted in the earliest perturbations that SARS-CoV-2 induces in epithelia.


Assuntos
COVID-19/imunologia , Células Epiteliais/imunologia , Monócitos/imunologia , SARS-CoV-2/patogenicidade , Adulto , Linfócitos B/imunologia , COVID-19/patologia , Criança , Técnicas de Cocultura , Ebolavirus/patogenicidade , Células Epiteliais/virologia , Perfilação da Expressão Gênica , Humanos , Inflamação , Vírus da Influenza A/patogenicidade , Pulmão/imunologia , Células Mieloides/imunologia , Especificidade da Espécie , Proteínas Virais/imunologia
9.
Exp Neurol ; 347: 113901, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34688600

RESUMO

BACKGROUND AND PURPOSE: Stroke therapy still lacks successful measures to improve post stroke recovery. Neurotrophin-3 (NT-3) is one promising candidate which has proven therapeutic benefit in motor recovery in acute experimental stroke. Post stroke, the immune system has opposing pathophysiological roles: pro-inflammatory cascades and immune cell infiltration into the brain exacerbate cell death while the peripheral immune response has only limited capabilities to fight infections during the acute and subacute phase. With time, anti-inflammatory mechanisms are supposed to support recovery of the ischemic damage within the brain parenchyma. However, interestingly, NT-3 can improve recovery in chronic neurological injury when combined with the pro-inflammatory stimulus lipopolysaccharide (LPS). AIM: We elucidated the impact of NT-3 on human monocyte and T cell activation as well as cytokine production ex vivo after stroke. In addition, we investigated the age-dependent availability of the high affinity NT-3 receptor TrkC upon LPS stimulation. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from acute stroke patients and controls and incubated with different dosages of NT-3 (10 and 100 ng/mL) and with or without LPS or anti-CD3/CD28 for 48 h. Total TrkC expression and cell activation (CD25, CD69 and HLA-DR) were assessed by FACS staining. IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21 and IL-22 were quantified by cytometric bead array. RESULTS: Most monocytes and only a small proportion of T cells expressed TrkC in blood from humans without stroke. Activation of cells from young humans (without strokes) using anti-CD3/CD28 or LPS partially reduced the proportion of monocytes expressing TrkC whilst they increased the proportion of T cells expressing TrkC. In contrast, activation of cells from elderly humans (without strokes) did not affect the proportion of monocytes expressing TrkC and only anti-CD3/CD28 led to an increase in the proportion of CD4+ T cells expressing TrkC. In blood from stroke patients or controls, NT-3 treatment reduced the percentage of monocytes and CD4+ and CD8+ T cells that were activated and reduced all cytokines investigated besides IL-21. CONCLUSIONS: NT-3 attenuated immune responses in cells from stroke patients and controls. The mechanism whereby human immune cells respond to NT-3 may be via TrkC receptors whose levels are regulated by stimulation. Further work is required to determine whether the induction of sensorimotor recovery in rodents by NT-3 after CNS injury is caused by this attenuation of the immune response.


Assuntos
Citocinas/imunologia , Imunidade Celular/imunologia , Monócitos/imunologia , Neurotrofina 3/farmacologia , Acidente Vascular Cerebral/imunologia , Linfócitos T/imunologia , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Citocinas/sangue , Feminino , Humanos , Imunidade Celular/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Neurotrofina 3/uso terapêutico , Método Simples-Cego , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Adulto Jovem
10.
Endocrinology ; 163(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34734245

RESUMO

Polycyclic aromatic hydrocarbons like benzo[a]pyrene (BaP) are generated during incomplete combustion of organic materials. Prior research has demonstrated that BaP is a prenatal ovarian toxicant and carcinogen. However, the metabolic pathways active in the embryo and its developing gonads and the mechanisms by which prenatal exposure to BaP predisposes to ovarian tumors later in life remain to be fully elucidated. To address these data gaps, we orally dosed pregnant female mice with BaP from embryonic day (E) 6.5 to E11.5 (0, 0.2, or 2 mg/kg/day) for metabolite measurement or E9.5 to E11.5 (0 or 3.33 mg/kg/day) for embryonic gonad RNA sequencing. Embryos were harvested at E13.5 for both experiments. The sum of BaP metabolite concentrations increased significantly with dose in the embryos and placentas, and concentrations were significantly higher in female than male embryos and in embryos than placentas. RNA sequencing revealed that enzymes involved in metabolic activation of BaP are expressed at moderate to high levels in embryonic gonads and that greater transcriptomic changes occurred in the ovaries in response to BaP than in the testes. We identified 490 differentially expressed genes (DEGs) with false discovery rate P-values < 0.05 when comparing BaP-exposed to control ovaries but no statistically significant DEGs between BaP-exposed and control testes. Genes related to monocyte/macrophage recruitment and activity, prolactin family genes, and several keratin genes were among the most upregulated genes in the BaP-exposed ovaries. Results show that developing ovaries are more sensitive than testes to prenatal BaP exposure, which may be related to higher concentrations of BaP metabolites in female embryos.


Assuntos
Benzo(a)pireno/metabolismo , Gônadas/metabolismo , Placenta/metabolismo , Prenhez , Transcriptoma , Animais , Cromatografia Líquida de Alta Pressão , Biologia Computacional , Feminino , Inflamação , Queratinas/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Ovário/metabolismo , Gravidez , RNA-Seq , Fatores Sexuais , Testículo/metabolismo , Fatores de Tempo
11.
J Fish Dis ; 45(1): 19-33, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34549432

RESUMO

To date, the mechanisms of inflammation have been poorly studied in fish of commercial interest, due to the lack of development of appropriate experimental models. The current study evaluated a local inflammation triggered by a polymeric carrageenin mixture (a mucopolysaccharide derived from the red seaweed Chondrus crispus) in the skin of gilthead seabream (Sparus aurata). Fish were injected subcutaneously with phosphate-buffered saline (as control) or λ/κ-carrageenin (1%), and skin samples from the injection sites were collected 1.5, 3 and 6 hr post-injection, processed for inclusion in paraplast and stained with haematoxylin-eosin, Alcian blue or periodic acid-Schiff. Furthermore, immunohistochemistry and expression analyses of several cells' markers and proinflammatory genes were also analysed in samples of the injected sites. Microscopic results indicated an increased number of skin mucus-secreting cells and acidophilic granulocytes in the skin of fish studied at 1.5 hr and 3 hr post-injection with carrageenin, respectively, with respect to the data obtained in control fish. Otherwise, both the gene expression of the non-specific cytotoxic cell marker (granzyme B, grb) and the proinflammatory cytokine (interleukin-1ß, il-1ß) were up-regulated at 1.5 hr in the skin of fish injected with carrageenin compared with the control fish, whilst the gene expression of acidophilic granulocyte markers (NADPH oxidase subunit Phox22 and Phox40, phox22 and phox40) was up-regulated at 3 and 6 hr in the carrageenin group, compared with the control group. In addition, the gene expression of myeloperoxidase (mpo) was also up-regulated at 6 hr in the skin of fish injected with carrageenin in comparison with control samples. The present results indicate the chronological participation of two important immune cells involved in the resolution of the inflammation in the skin of gilthead seabream.


Assuntos
Doenças dos Peixes , Dourada , Animais , Carragenina , Doenças dos Peixes/induzido quimicamente , Granulócitos , Inflamação/induzido quimicamente , Inflamação/veterinária , Injeções Subcutâneas , Macrófagos , Monócitos , Muco
12.
Methods Mol Biol ; 2409: 223-234, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34709645

RESUMO

Despite many advances on the understanding of dengue pathogenesis in the last decades, some questions remained to be clarified. The virulence of the pathogen and the host immune response are the main factors involved in pathogenesis of dengue infection. In addition, skin dendritic cells (DCs) are one of the primary targets for dengue virus infection. After infection, DCs process and present antigens to T cells and also secrete cytokines that shape the immune response. Although relevant for the development of antiviral immune response, an imbalance in the cytokine production by immune cells could lead to cytokine storm observed in severe dengue fever cases. Therefore, this chapter will describe the protocols for the in vitro differentiation of human monocytes into human monocyte-derived dendritic cells (mdDCs), followed by dengue virus infection, as well as the cytokine quantification produced by mdDCs using a cytometric bead array method.


Assuntos
Vírus da Dengue , Dengue , Citocinas , Células Dendríticas , Humanos , Monócitos , Replicação Viral
13.
Nat Immunol ; 23(1): 23-32, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34937933

RESUMO

Systemic immune cell dynamics during coronavirus disease 2019 (COVID-19) are extensively documented, but these are less well studied in the (upper) respiratory tract, where severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates1-6. Here, we characterized nasal and systemic immune cells in individuals with COVID-19 who were hospitalized or convalescent and compared the immune cells to those seen in healthy donors. We observed increased nasal granulocytes, monocytes, CD11c+ natural killer (NK) cells and CD4+ T effector cells during acute COVID-19. The mucosal proinflammatory populations positively associated with peripheral blood human leukocyte antigen (HLA)-DRlow monocytes, CD38+PD1+CD4+ T effector (Teff) cells and plasmablasts. However, there was no general lymphopenia in nasal mucosa, unlike in peripheral blood. Moreover, nasal neutrophils negatively associated with oxygen saturation levels in blood. Following convalescence, nasal immune cells mostly normalized, except for CD127+ granulocytes and CD38+CD8+ tissue-resident memory T cells (TRM). SARS-CoV-2-specific CD8+ T cells persisted at least 2 months after viral clearance in the nasal mucosa, indicating that COVID-19 has both transient and long-term effects on upper respiratory tract immune responses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Nasofaringe/imunologia , Nariz/citologia , Mucosa Respiratória/imunologia , SARS-CoV-2/imunologia , Anticorpos Antivirais/sangue , COVID-19/imunologia , COVID-19/patologia , Granulócitos/imunologia , Antígenos HLA-DR/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Monócitos/imunologia , Nasofaringe/citologia , Nasofaringe/virologia , Neutrófilos/imunologia , Nariz/imunologia , Nariz/virologia , Estudos Prospectivos , Mucosa Respiratória/citologia , Mucosa Respiratória/virologia
14.
Methods Mol Biol ; 2373: 253-266, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34520017

RESUMO

Microfluidics allows for recapitulating organotypic environments in miniaturized cell culture platforms. This ability paves the way to the investigation of complex biological processes in a relevant milieu. Here we describe the protocols to generate an organotypic model including a vascularized compartment mimicking the synovial membrane and designed for the study of monocyte extravasation during osteoarthritis.


Assuntos
Cartilagem , Membrana Sinovial , Cartilagem Articular , Humanos , Dispositivos Lab-On-A-Chip , Monócitos , Osteoartrite
15.
Methods Mol Biol ; 2375: 13-19, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34591295

RESUMO

A major limitation in engineering vascular grafts is the lack of proper endothelium to prevent thrombosis and subsequent graft failure. Obtaining endothelial cells from patients' vasculature is intrusive and requires extensive culture time. Here we present an alternative strategy wherein abundant and easily accessible monocytes from peripheral blood are cultured and differentiated towards an endothelial-like state capable of preventing thrombosis through production of nitric oxide and formation of endothelial adherens junctions. Considering the plethora of monocytes present within peripheral blood, this method provides a robust alternative to generating endothelial cells required for vascular graft production.


Assuntos
Monócitos , Células Cultivadas , Células Endoteliais , Humanos , Óxido Nítrico , Trombose
16.
Virology ; 565: 73-81, 2022 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-34742127

RESUMO

Bacillus Calmette-Guérin (BCG) vaccine is currently used to prevent tuberculosis infection. The vaccine was found to enhance resistance to certain types of infection including positive sense RNA viruses. The current COVID-19 pandemic is caused by positive sense RNA, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A higher mortality rate of COVID-19 patients was reported in countries where BCG vaccination is not routinely administered, when compared to the vaccinated ones. We hypothesized that BCG vaccine may control SARS-CoV2 infection via modulating the monocyte immune response. We analyzed GSE104149 dataset to investigate whether human monocytes of BCG-vaccinated individuals acquire resistance to SARS-CoV-2 infection. Differentially expressed genes obtained from the dataset were used to determine enriched pathways, biological processes, and molecular functions for monocytes post BCG vaccination. Our data show that BCG vaccine promotes a more effective immune response of monocytes against SARS-CoV2, but probably not sufficient to prevent the infection.


Assuntos
Vacina BCG/imunologia , COVID-19/epidemiologia , Vacinação/estatística & dados numéricos , Vacina BCG/administração & dosagem , COVID-19/prevenção & controle , Perfilação da Expressão Gênica , Humanos , Inflamação , Monócitos/imunologia , Monócitos/virologia , SARS-CoV-2/fisiologia
17.
Methods Mol Biol ; 2410: 627-647, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34914073

RESUMO

We recently developed a monocyte-based cellular vaccine platform for cancer treatment. In contrast to the traditional utilization of monocytes as precursors to generate dendritic cells (DC) for vaccination purposes, we find that freshly isolated monocytes with no differentiation process can be loaded with tumor antigens (Ag) and trigger robust antitumor cytotoxic T lymphocyte (CTL) responses. In this chapter, we describe methods to prepare, administer, and evaluate murine Ly-6Chi monocyte-based cellular vaccines for their therapeutic efficacy. This includes procedures for isolation, purity determination, Ag loading, administration of bone marrow (BM)-derived monocytes, as well as methods to determine vaccine efficacy through the examination of Ag-specific CD8+ T cell expansion and antitumor responses in murine melanoma models. As a vaccine platform, undifferentiated monocytes can be easily adapted to different tumor models with a multitude of target antigens. The method described here seeks to facilitate preclinical research of monocyte-based vaccination as a strategy for cancer immunotherapy.


Assuntos
Vacinas Anticâncer , Monócitos , Animais , Antígenos de Neoplasias , Células Dendríticas/imunologia , Camundongos , Monócitos/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinas
18.
Arq Gastroenterol ; 58(4): 439-442, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34909847

RESUMO

BACKGROUND: Non-alcoholic hepatic steatosis (NAS) is characterized by excess fat accumulation in hepatocytes, causing portal and lobular inflammation and hepatocyte injury. OBJECTIVE: We aimed to evaluate the alterations in monocyte count to high-density lipoprotein cholesterol ratio (MHR) in patients with grade 2 or 3 fatty liver disease and the association of this marker with liver function tests and insulin resistance. METHODS: In this retrospective analysis; patients diagnosed and followed for the grade 2 or 3 fatty liver disease were included in the patient group and the patients who had undergone abdominal ultrasound for any reason and who were not having any fatty liver disease were included in the control group. RESULTS: Totally 409 cases were included in the study. Among participants, 201 were in the control group, and 208 were in the NAS group (111 were having grade 2 and 97 were having grade 3 steatosis). The monocyte/HDL ratio was significantly higher in the NAS group compared with the healthy controls (P=0.001). There was a significant positive correlation between the monocyte/HDL ratio and age (r=0.109; P=0.028), ALT (r=0.123, P=0.014) and HOMA-IR (r=0.325, P=0.001) values. CONCLUSION: In conclusion, the monocyte to high-density lipoprotein ratio significantly increases in fatty liver disease and correlates with insulin resistance. Since it was suggested as a prognostic marker in atherosclerotic diseases, elevated MHR values in fatty liver disease should be evaluated cautiously.


Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Índice de Massa Corporal , Humanos , Monócitos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Estudos Retrospectivos
19.
Bratisl Lek Listy ; 122(12): 880-883, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34904850

RESUMO

BACKGROUND: The aim of this study is to determine the role of hematological parameters - neutrophil/lymphocyte, platelet/lymphocyte, and monocyte/lymphocyte ratios - in the diagnosis of aseptic loosening after total knee arthroplasty. METHODS: This study retrospectively analyzed the data of 244 patients who had primary total knee arthroplasty and 66 patients with aseptic loosening developed after total knee arthroplasty. The white blood cell counts, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, monocyte/lymphocyte ratio and c-reactive protein levels in both groups were determined using the results of venous blood samples collected during preoperative preparation and compared between the groups. RESULTS: Our study findings reveal that the monocyte/lymphocyte ratio of the group with aseptic loosening was statistically significantly different from that of the patient group who had primary total knee arthroplasty (p=0.02). Furthermore, although c-reactive protein levels are not high enough to suggest systemic inflammation, the difference between the groups is statistically significant (p=0.01). CONCLUSIONS: No hematological parameter that could be used in the diagnosis of aseptic loosening has been defined in the literature so far. This study demonstrated that the monocyte/lymphocyte ratio could be a helpful parameter in the diagnosis of aseptic loosening (Tab. 1, Fig. 1, Ref. 28).


Assuntos
Artroplastia do Joelho , Artroplastia do Joelho/efeitos adversos , Humanos , Linfócitos , Monócitos , Neutrófilos , Falha de Prótese , Reoperação , Estudos Retrospectivos
20.
Nat Commun ; 12(1): 7294, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34911964

RESUMO

Recruitment of bone marrow derived monocytes via bloodstream and their subsequent conversion to CX3CR1+ macrophages in response to intestinal injury is dependent on CCR2, Nr4a1, and the microbiome. This process is critical for proper tissue repair; however, GATA6+ peritoneal cavity macrophages might represent an alternative, more readily available source of mature and functional myeloid cells at the damaged intestinal locations. Here we show, using spinning-disk confocal microscopy, that large F4/80hiGATA6+ peritoneal cavity macrophages promptly accumulate at damaged intestinal sites upon intestinal thermal injury and upon dextran sodium sulfate induced colitis in mice via a direct route from the peritoneal cavity. In contrast to bloodstream derived monocytes/macrophages, cavity macrophages do not depend on CCR2, Nr4a1 or the microbiome for recruitment, but rather on the ATP-release and exposed hyaluronan at the site of injury. They participate in the removal of necrotic cells, revascularization and collagen deposition and thus resolution of tissue damage. In summary, peritoneal cavity macrophages represent a rapid alternative route of intestinal tissue repair to traditional monocyte-derived macrophages.


Assuntos
Fator de Transcrição GATA6/imunologia , Doenças Inflamatórias Intestinais/imunologia , Macrófagos Peritoneais/imunologia , Peritônio/imunologia , Animais , Fator de Transcrição GATA6/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/fisiopatologia , Intestinos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Receptores CCR2/genética , Receptores CCR2/imunologia , Regeneração
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