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1.
Front Immunol ; 12: 654998, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531848

RESUMO

HCV core protein is the first structural protein synthesized during hepatitis C virus (HCV) infection and replication. It is released from virus infected liver cells and mediates multiple functions to affect host cell response. The innate immune response is the first line of defense against viral infection. After HCV infection, Kupffer cells (KCs) which are liver macrophages play an important role in host innate immune response. Kupffer cells act as phagocytes and release different cytokines and chemokines to counter viral infection and regulate inflammation and fibrosis in liver. Earlier, we have demonstrated that HCV core protein interacts with gC1qR and activates MAPK, NF-κB and PI3K/AKT pathways in macrophages. In this study, we explored the effect of HCV core protein on CCL2 and CXCL10 expression in macrophages and the signaling pathways involved. Upon silencing of gC1qR, we observed a significant decrease expression of CCL2 and CXCL10 in macrophages in the presence of HCV core protein. Inhibiting NF-κB pathway, but not P38, JNK, ERK and AKT pathways greatly reduced the expression of CCL2 and CXCL10. Therefore, our results indicate that interaction of HCV core protein with gC1qR could induce CCL2 and CXCL10 secretion in macrophages via NF-κB signaling pathway. These findings may shed light on the understanding of how leukocytes migrate into the liver and exaggerate host-derived immune responses and may provide novel therapeutic targets in HCV chronic inflammation.


Assuntos
Quimiocina CCL2/imunologia , Quimiocina CXCL10/imunologia , Hepacivirus/imunologia , Macrófagos/imunologia , NF-kappa B/imunologia , Transdução de Sinais/imunologia , Proteínas do Core Viral/imunologia , Animais , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Expressão Gênica/imunologia , Hepacivirus/metabolismo , Hepacivirus/fisiologia , Hepatite C/imunologia , Hepatite C/metabolismo , Hepatite C/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Macrófagos do Fígado/imunologia , Macrófagos do Fígado/metabolismo , Macrófagos do Fígado/virologia , Macrófagos/metabolismo , Macrófagos/virologia , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Células THP-1 , Proteínas do Core Viral/metabolismo
2.
Cell Rep ; 37(1): 109773, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34587479

RESUMO

SARS-CoV-2 infection in children is less severe than it is in adults. We perform a longitudinal analysis of the early innate responses in children and adults with mild infection within household clusters. Children display fewer symptoms than adults do, despite similar initial viral load, and mount a robust anti-viral immune signature typical of the SARS-CoV-2 infection and characterized by early interferon gene responses; increases in cytokines, such as CXCL10 and GM-CSF; and changes in blood cell numbers. When compared with adults, the antiviral response resolves faster (within a week of symptoms), monocytes and dendritic cells are more transiently activated, and genes associated with B cell activation appear earlier in children. Nonetheless, these differences do not have major effects on the quality of SARS-CoV-2-specific antibody responses. Our findings reveal that better early control of inflammation as observed in children may be key for rapidly controlling infection and limiting the disease course.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/genética , COVID-19/imunologia , Citocinas/metabolismo , Imunidade Inata , SARS-CoV-2/imunologia , Transcriptoma , Imunidade Adaptativa , Adolescente , Adulto , Linfócitos B/metabolismo , COVID-19/virologia , Quimiocina CXCL10/metabolismo , Criança , Pré-Escolar , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Lactente , Inflamação/virologia , Interferons/metabolismo , Estudos Longitudinais , Pessoa de Meia-Idade , Monócitos/metabolismo , Análise de Sequência de RNA , Carga Viral , Adulto Jovem
3.
Medicine (Baltimore) ; 100(38): e27365, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559160

RESUMO

ABSTRACT: Although several studies have attempted to investigate the etiology of and mechanism underlying psoriasis, the precise molecular mechanism remains unclear. Our study aimed to explore the molecular mechanism underlying psoriasis based on bioinformatics.GSE30999, GSE34248, GSE41662, and GSE50790 datasets were obtained from the Gene Expression Omnibus database. The Gene Expression Omnibus profiles were integrated to obtain differentially expressed genes in R software. Then a series of analyses was performed, such as Gene Ontology annotation, Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein-protein interaction network analysis, among others. The key genes were obtained by CytoHubba, and validated by real-time quantitative polymerase chain reaction.A total of 359 differentially expressed genes were identified between 270 paired lesional and non-lesional skin groups. The common enriched pathways were nucleotide-binding and oligomerization domain-like receptor signaling pathway, and cytokine-cytokine receptor interaction. Seven key genes were identified, including CXCL1, ISG15, CXCL10, STAT1, OASL, IFIT1, and IFIT3. These key genes were validated as upregulated in the 4 datasets and M5-induced HaCaT cells.Our study identified 7 key genes, namely CXCL1, ISG15, CXCL10, STAT1, OASL, IFIT1, and IFIT3, and 2 mostly enriched pathways (nucleotide-binding and oligomerization domain-like receptor signaling pathway, and cytokine-cytokine receptor interaction) involved in psoriatic pathogenesis. More importantly, CXCL1, ISG15, STAT1, OASL, IFIT1, IFIT3, and especially CXCL10 may be potential biomarkers. Therefore, our findings may bring a new perspective to the molecular mechanism underlying psoriasis and suggest potential biomarkers.


Assuntos
Biomarcadores/metabolismo , Quimiocina CXCL10/metabolismo , Psoríase/metabolismo , Estudos de Casos e Controles , Biologia Computacional , Células HaCaT , Humanos , Mapas de Interação de Proteínas , Psoríase/genética , Pele/metabolismo
4.
Nat Commun ; 12(1): 4851, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381047

RESUMO

Pathogens are thought to use host molecular cues to control when to initiate life-cycle transitions, but these signals are mostly unknown, particularly for the parasitic disease malaria caused by Plasmodium falciparum. The chemokine CXCL10 is present at high levels in fatal cases of cerebral malaria patients, but is reduced in patients who survive and do not have complications. Here we show a Pf 'decision-sensing-system' controlled by CXCL10 concentration. High CXCL10 expression prompts P. falciparum to initiate a survival strategy via growth acceleration. Remarkably, P. falciparum inhibits CXCL10 synthesis in monocytes by disrupting the association of host ribosomes with CXCL10 transcripts. The underlying inhibition cascade involves RNA cargo delivery into monocytes that triggers RIG-I, which leads to HUR1 binding to an AU-rich domain of the CXCL10 3'UTR. These data indicate that when the parasite can no longer keep CXCL10 at low levels, it can exploit the chemokine as a cue to shift tactics and escape.


Assuntos
Quimiocina CXCL10/metabolismo , Malária Falciparum/parasitologia , Plasmodium falciparum/fisiologia , Regiões 3' não Traduzidas , Quimiocina CXCL10/genética , Proteína DEAD-box 58/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Vesículas Extracelulares/metabolismo , Interações Hospedeiro-Parasita , Humanos , Estágios do Ciclo de Vida , Malária Falciparum/imunologia , Monócitos/metabolismo , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/metabolismo , Biossíntese de Proteínas , RNA de Protozoário/metabolismo , Receptores Imunológicos/metabolismo , Ribossomos/metabolismo , Células THP-1
5.
J Immunol ; 207(5): 1229-1238, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34348975

RESUMO

Infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or seasonal influenza may lead to respiratory failure requiring intubation and mechanical ventilation. The pathophysiology of this respiratory failure is attributed to local immune dysregulation, but how the immune response to viral infection in the lower airways of the human lung differs between individuals with respiratory failure and those without is not well understood. We used quantitative multiparameter flow cytometry and multiplex cytokine assays to evaluate matched blood and bronchoalveolar lavage (BAL) samples from control human subjects, subjects with symptomatic seasonal influenza who did not have respiratory failure, and subjects with severe seasonal influenza or SARS-CoV-2 infection with respiratory failure. We find that severe cases are associated with an influx of nonclassical monocytes, activated T cells, and plasmablast B cells into the lower airways. Cytokine concentrations were not elevated in the lower airways of moderate influenza patients compared with controls; however, 28 of 35 measured cytokines were significantly elevated in severe influenza, severe SARS-CoV-2 infection, or both. We noted the largest elevations in IL-6, IP-10, MCP-1, and IL-8. IL-1 family cytokines and RANTES were higher in severe influenza infection than severe SARS-CoV-2 infection. Interestingly, only the concentration of IP-10-correlated between blood and BAL during severe infection. Our results demonstrate inflammatory immune dysregulation in the lower airways during severe viral pneumonia that is distinct from lower airway responses seen in human patients with symptomatic, but not severe, illness and suggest that measurement of blood IP-10 concentration may predict this unique dysregulation.


Assuntos
COVID-19/imunologia , Vírus da Influenza A/fisiologia , Pneumonia Viral/imunologia , Sistema Respiratório/imunologia , SARS-CoV-2/fisiologia , Adulto , Idoso , Proteínas Sanguíneas/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19/diagnóstico , Quimiocina CXCL10/metabolismo , Estudos de Coortes , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Influenza Humana/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Respiratória , Índice de Gravidade de Doença
6.
Sci Rep ; 11(1): 16891, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413454

RESUMO

Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody-drug conjugate with a topoisomerase I inhibitor deruxtecan (DXd), exhibits an excellent anti-tumor effect in previously treated HER2-positive tumors. A recent study demonstrated that T-DXd not only suppressed tumor growth but also enhanced anti-tumor immunity through increasing the number of tumor-infiltrating CD8+ T cells and enhancement of major-histocompatibility-complex class I expression on tumor cells in a mouse model. However, the effect of T-DXd on anti-tumor immune responses in human cancers is largely unknown. We investigated the effect of T-DXd on the expression of HLA class I and CXCL9/10/11, T-cell chemoattractants, in HER2-positive human gastric cancer (GC) cells. We found that T-DXd significantly inhibited GC cell proliferation in a HER2-dependent manner, while it slightly increased the expression of HLA class I in HER2-positive GC cells. Moreover, we revealed that T-DXd significantly induced mRNA expression of CXCL9/10/11 in HER2-positive GC cells. T-DXd-triggered up-regulation of these chemokines was mediated through the activation of DNA damage signaling pathways. These results suggest that T-DXd triggers anti-tumor immune responses at least in part through induction of the expression of HLA class I and CXCL9/10/11 on HER2-positive GC cells, resulting in the enhancement of anti-tumor immunity in human GC.


Assuntos
Camptotecina/análogos & derivados , Quimiocina CXCL10/genética , Quimiocina CXCL11/genética , Quimiocina CXCL9/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunoconjugados/uso terapêutico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/imunologia , Trastuzumab/uso terapêutico , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/metabolismo , Quimiocina CXCL9/metabolismo , Fatores Quimiotáticos/farmacologia , Dano ao DNA , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoconjugados/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genética , Trastuzumab/farmacologia , Regulação para Cima/efeitos dos fármacos
7.
Elife ; 102021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34328416

RESUMO

The development of pancreatic cancer requires recruitment and activation of different macrophage populations. However, little is known about how macrophages are attracted to the pancreas after injury or an oncogenic event, and how they crosstalk with lesion cells or other cells of the lesion microenvironment. Here, we delineate the importance of CXCL10/CXCR3 signaling during the early phase of murine pancreatic cancer. We show that CXCL10 is produced by pancreatic precancerous lesion cells in response to IFNγ signaling and that inflammatory macrophages are recipients for this chemokine. CXCL10/CXCR3 signaling in macrophages mediates their chemoattraction to the pancreas, enhances their proliferation, and maintains their inflammatory identity. Blocking of CXCL10/CXCR3 signaling in vivo shifts macrophage populations to a tumor-promoting (Ym1+, Fizz+, Arg1+) phenotype, increases fibrosis, and mediates progression of lesions, highlighting the importance of this pathway in PDA development. This is reversed when CXCL10 is overexpressed in PanIN cells.


Assuntos
Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Inflamação/etiologia , Neoplasias Pancreáticas/fisiopatologia , Receptores CXCR3/imunologia , Receptores CXCR3/metabolismo , Microambiente Tumoral/imunologia , Animais , Células Cultivadas , Quimiocina CXCL10/antagonistas & inibidores , Quimiocina CXCL10/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Inflamação/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Pâncreas/citologia , Pâncreas/imunologia , Pâncreas/patologia , Neoplasias Pancreáticas/imunologia , Receptores CXCR3/antagonistas & inibidores , Receptores CXCR3/genética , Transdução de Sinais
8.
Front Immunol ; 12: 690201, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220848

RESUMO

Ovarian carcinomas (OCs) are poorly immunogenic and immune checkpoint inhibitors (ICIs) have offered a modest benefit. In this study, high CD3+ T-cells and CD163+ tumor-associated macrophages (TAMs) densities identify a subgroup of immune infiltrated high-grade serous carcinomas (HGSCs) with better outcomes and superior response to platinum-based therapies. On the contrary, in most clear cell carcinomas (CCCs) showing poor prognosis and refractory to platinum, a high TAM density is associated with low T cell frequency. Immune infiltrated HGSC are characterized by the 30-genes signature (OC-IS30) covering immune activation and IFNγ polarization and predicting good prognosis (n = 312, TCGA). Immune infiltrated HGSC contain CXCL10 producing M1-type TAM (IRF1+pSTAT1Y701+) in close proximity to T-cells. A fraction of these M1-type TAM also co-expresses TREM2. M1-polarized TAM were barely detectable in T-cell poor CCC, but identifiable across various immunogenic human cancers. Single cell RNA sequencing data confirm the existence of a tumor-infiltrating CXCL10+IRF1+STAT1+ M1-type TAM overexpressing antigen processing and presentation gene programs. Overall, this study highlights the clinical relevance of the CXCL10+IRF1+STAT1+ macrophage subset as biomarker for intratumoral T-cell activation and therefore offers a new tool to select patients more likely to respond to T-cell or macrophage-targeted immunotherapies.


Assuntos
Carcinoma/metabolismo , Quimiocina CXCL10/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Císticas, Mucinosas e Serosas/metabolismo , Neoplasias Ovarianas/metabolismo , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismo , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Complexo CD3/metabolismo , Carcinoma/tratamento farmacológico , Carcinoma/genética , Carcinoma/imunologia , Células Cultivadas , Quimiocina CXCL10/genética , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Císticas, Mucinosas e Serosas/imunologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Fenótipo , Prognóstico , Receptores de Superfície Celular/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Macrófagos Associados a Tumor/imunologia
9.
Front Immunol ; 12: 688753, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276678

RESUMO

Objectives: Type I interferons (IFNs) are central and reflective of disease activity in systemic lupus erythematosus (SLE). However, IFN-α levels are notoriously difficult to measure and the type I IFN gene signature (IGS) is not yet available in clinical routine. This study evaluates galectin-9 and an array of chemokines/cytokines in their potential as surrogate markers of type I IFN and/or SLE disease activity. Methods: Healthy controls and well-characterized Swedish SLE patients from two cross-sectional cohorts (n=181; n=59) were included, and a subgroup (n=21) was longitudinally followed. Chemokine/cytokine responses in immune complex triggered IFN-α activity was studied in healthy donor peripheral blood mononuclear cells (PBMC). Levels of chemokines/cytokines and galectin-9 were measured by immunoassays. Gene expression was quantified by qPCR. Results: The IGS was significantly (p<0.01) correlated with galectin-9 (rho=0.54) and CXCL10 (rho=0.37) levels whereas serum IFN-α correlated with galectin-9 (rho=0.36), CXCL10 (rho=0.39), CCL19 (rho=0.26) and CCL2 (rho=0.19). The strongest correlation was observed between galectin-9 and TNF (rho=0.56). IFN-α and disease activity (SLEDAI-2K) were correlated (rho=0.20) at cross-sectional analysis, but no significant associations were found between SLEDAI-2K and galectin-9 or chemokines. Several inflammatory mediators increased at disease exacerbation although CCL19, CXCL11, CXCL10, IL-10 and IL-1 receptor antagonist were most pronounced. Immune complex-stimulation of PBMC increased the production of CCL2, CXCL8 and TNF. Conclusion: Galectin-9 and CXCL10 were associated with type I IFN in SLE but correlated stronger with TNF. None of the investigated biomarkers showed a convincing association with disease activity, although CXCL10 and CCL19 performed best in this regard.


Assuntos
Interferon-alfa/sangue , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/diagnóstico , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Quimiocina CCL19/metabolismo , Quimiocina CXCL10/metabolismo , Quimiocinas/metabolismo , Estudos Transversais , Proteínas do Citoesqueleto/genética , Feminino , Galectinas/metabolismo , Perfilação da Expressão Gênica , Humanos , Imunoensaio , Leucócitos Mononucleares/imunologia , Estudos Longitudinais , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Proteínas/genética , Suécia , Proteínas Supressoras de Tumor/genética , Adulto Jovem
10.
Eur J Immunol ; 51(9): 2317-2329, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34272885

RESUMO

Endothelial cells are key regulators of transendothelial migration and their secretion of chemokines and expression of adhesion molecules facilitates lymphocyte entry into tissues. Previously, we demonstrated that Tregs can reduce transendothelial migration of T cells into tumors by decreasing endothelial CXCL10 secretion, but the mechanism by which this occurs is still not known. In this study, we aimed to define how Tregs decrease transendothelial migration into tumors. mRNA sequencing of intestinal tumor endothelial cells from Treg depleted mice identified neutral sphingomyelinase 2 (nSMase2) as a gene downregulated in the presence of Tregs. nSMase2 is expressed in human umbilical vein endothelial cells (HUVECs) and was decreased after coculture with Tregs. Furthermore, blocking of nSMase2 activity in vitro decreased VCAM1, CX3CL1, and CXCL10 expression in HUVECs, mirroring the same decrease found in Treg cocultures. In the APCmin/+ mouse model of intestinal cancer, nSMase2 is lower in tumor endothelial cells than in unaffected small intestine and chronic treatment with a nSMase2 inhibitor suppressed the increased migration that is otherwise seen in the absence of Tregs. We conclude that nSMase2 is an important mediator in endothelial cells supporting transendothelial migration, which may be targeted by Tregs to reduce T-cell migration into tumors.


Assuntos
Quimiocina CXCL10/metabolismo , Neoplasias do Colo/patologia , Linfócitos do Interstício Tumoral/imunologia , Esfingomielina Fosfodiesterase/metabolismo , Linfócitos T Reguladores/imunologia , Migração Transendotelial e Transepitelial/fisiologia , Animais , Moléculas de Adesão Celular/biossíntese , Linhagem Celular , Quimiocina CX3CL1/biossíntese , Quimiocina CXCL10/biossíntese , Neoplasias do Colo/imunologia , Regulação para Baixo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Subpopulações de Linfócitos T/imunologia , Versicanas/biossíntese
11.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34128960

RESUMO

Initial replication of SARS-CoV-2 in the upper respiratory tract is required to establish infection, and the replication level correlates with the likelihood of viral transmission. Here, we examined the role of host innate immune defenses in restricting early SARS-CoV-2 infection using transcriptomics and biomarker-based tracking in serial patient nasopharyngeal samples and experiments with airway epithelial organoids. SARS-CoV-2 initially replicated exponentially, with a doubling time of ∼6 h, and induced interferon-stimulated genes (ISGs) in the upper respiratory tract, which rose with viral replication and peaked just as viral load began to decline. Rhinovirus infection before SARS-CoV-2 exposure accelerated ISG responses and prevented SARS-CoV-2 replication. Conversely, blocking ISG induction during SARS-CoV-2 infection enhanced viral replication from a low infectious dose. These results show that the activity of ISG-mediated defenses at the time of SARS-CoV-2 exposure impacts infection progression and that the heterologous antiviral response induced by a different virus can protect against SARS-CoV-2.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Imunidade Inata/fisiologia , Nasofaringe/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Enzima de Conversão de Angiotensina 2/genética , Estudos de Casos e Controles , Quimiocina CXCL10/metabolismo , Suscetibilidade a Doenças/imunologia , Feminino , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Interferons/genética , Interferons/imunologia , Interferons/metabolismo , Masculino , Pessoa de Meia-Idade , Infecções por Picornaviridae/imunologia , Infecções por Picornaviridae/virologia , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Carga Viral , Replicação Viral
12.
Am J Respir Cell Mol Biol ; 65(5): 513-520, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34166603

RESUMO

Smoking and human immunodeficiency virus 1 (HIV-1) infection are risk factors for chronic obstructive pulmonary disease (COPD), which is among the most common comorbid conditions in people living with HIV-1. HIV-1 infection leads to persistent expansion of CD8+ T cells, and CD8+ T cell-mediated inflammation has been implicated in COPD pathogenesis. In this study, we investigated the effects of HIV-1 infection and smoking on T-cell dynamics in patients at risk of COPD. BAL fluid, endobronchial brushings, and blood from HIV-1 infected and uninfected nonsmokers and smokers were analyzed by flow cytometry, and lungs were imaged by computed tomography. Chemokines were measured in BAL fluid, and CD8+ T-cell chemotaxis in the presence of cigarette smoke extract was assessed in vitro. HIV-1 infection increased CD8+ T cells in the BAL fluid, but this increase was abrogated by smoking. Smokers had reduced BAL fluid concentrations of the T cell-recruiting chemokines CXCL10 and CCL5, and cigarette smoke extract inhibited CXCL10 and CCL5 production by macrophages and CD8+ T-cell transmigration in vitro. In contrast to the T cells in BAL fluid, CD8+ T cells in endobronchial brushings were increased in HIV-1-infected smokers, which was driven by an accumulation of effector memory T cells in the airway mucosa and an increase in tissue-resident memory T cells. Mucosal CD8+ T-cell numbers inversely correlated with lung aeration, suggesting an association with inflammation and remodeling. HIV-1 infection and smoking lead to retention of CD8+ T cells within the airway mucosa.


Assuntos
Linfócitos T CD8-Positivos/patologia , Infecções por HIV/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/patologia , Fumar/efeitos adversos , Adulto , Líquido da Lavagem Broncoalveolar , Linfócitos T CD8-Positivos/virologia , Quimiocina CCL5/metabolismo , Quimiocina CXCL10/metabolismo , Quimiotaxia , Feminino , HIV-1/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/patologia , Membrana Mucosa/virologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Receptores CCR5/metabolismo , Receptores CXCR3/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/virologia , Fatores de Risco , Tomografia Computadorizada por Raios X , Carga Viral
13.
Cell Death Dis ; 12(5): 489, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990548

RESUMO

Tumor recurrence is the major obstacle for pushing the envelope of liver transplantation for hepatocellular carcinoma (HCC) patients. The inflammatory cascades activated by acute liver graft injury promote tumor recurrence. We aimed to explore the role and mechanism of myeloid-derived suppressor cell (MDSC) mobilization induced by liver graft injury on tumor recurrence. By analyzing 331 HCC patients who received liver transplantation, the patients with graft weight ratio (GWR, the weight of liver graft divided by the estimated standard liver weight of recipient) <60% had higher tumor recurrence than GWR ≥60% ones. MDSCs and CXCL10/TLR4 levels were significantly increased in patients with GWR <60% or tumor recurrence. These findings were further validated in our rat orthotopic liver transplantation model. In CXCL10-/- and TLR4-/- mice of hepatic ischemia/reperfusion injury plus major hepatectomy (IRH) model, monocytic MDSCs, instead of granulocytic MDSCs, were significantly decreased. Importantly, CXCL10 deficiency reduced the accumulation of TLR4+ monocytic MDSCs, and CXCL10 increased MDSC mobilization in the presence of TLR4. Moreover, MMP14 was identified as the key molecule bridging CXCL10/TLR4 signaling and MDSC mobilization. Knockout or inhibition of CXCL10/TLR4 signaling significantly reduced the tumor growth with decreased monocytic MDSCs and MMP14 in the mouse tumor recurrent model. Our data indicated that monocytic MDSCs were mobilized and recruited to liver graft during acute phase injury, and to promote HCC recurrence after transplantation. Targeting MDSC mobilization via CXCL10/TLR4/MMP14 signaling may represent the therapeutic potential in decreasing post-transplant liver tumor recurrence.


Assuntos
Quimiocina CXCL10/metabolismo , Transplante de Fígado/métodos , Células Supressoras Mieloides/metabolismo , Animais , Humanos , Masculino , Camundongos , Ratos , Transdução de Sinais
14.
Viruses ; 13(3)2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799906

RESUMO

Mayaro virus (MAYV) and chikungunya virus (CHIKV) are known for their arthrotropism, but accumulating evidence shows that CHIKV infections are occasionally associated with serious neurological complications. However, little is known about the capacity of MAYV to invade the central nervous system (CNS). We show that human neural progenitors (hNPCs), pericytes and astrocytes are susceptible to MAYV infection, resulting in the production of infectious viral particles. In primary astrocytes, MAYV, and to a lesser extent CHIKV, elicited a strong antiviral response, as demonstrated by an increased expression of several interferon-stimulated genes, including ISG15, MX1 and OAS2. Infection with either virus led to an enhanced expression of inflammatory chemokines, such as CCL5, CXCL10 and CXCL11, whereas MAYV induced higher levels of IL-6, IL-12 and IL-15 in these cells. Moreover, MAYV was more susceptible than CHIKV to the antiviral effects of both type I and type II interferons. Taken together, this study shows that although MAYV and CHIKV are phylogenetically related, they induce different types of antiviral responses in astrocytes. This work is the first to evaluate the potential neurotropism of MAYV and shows that brain cells and particularly astrocytes and hNPCs are permissive to MAYV, which, consequently, could lead to MAYV-induced neuropathology.


Assuntos
Infecções por Alphavirus/imunologia , Alphavirus/imunologia , Astrócitos/imunologia , Astrócitos/virologia , Encéfalo/imunologia , 2',5'-Oligoadenilato Sintetase/metabolismo , Infecções por Alphavirus/patologia , Animais , Encéfalo/virologia , Linhagem Celular , Quimiocina CCL5/metabolismo , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/metabolismo , Febre de Chikungunya/imunologia , Vírus Chikungunya/imunologia , Chlorocebus aethiops , Citocinas/metabolismo , Humanos , Interferon Tipo I/imunologia , Interferon gama/imunologia , Proteínas de Resistência a Myxovirus/metabolismo , Células-Tronco Neurais/virologia , Pericitos/virologia , Ubiquitinas/metabolismo , Células Vero
15.
Cells ; 10(4)2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807462

RESUMO

Chronic hepatitis C virus (HCV) infection is closely associated with a plethora of diseases, including cancers and autoimmune disorders. However, the distinct triggers and cellular networks leading to such HCV-derived diseases are poorly understood. Around 8% of the human genome consists of human endogenous retroviruses. They are usually silenced but can be reactivated by environmental conditions, including viral infections. Our current understanding indicates that the activation of one specific family-namely, HERV-K(HML-2)-is linked to distinct pathologies, including cancer and autoimmunity. In this study, we analyzed the transcription levels of HERV-K(HML-2) in 42 HCV-infected patients receiving direct-acting antiviral therapies. Samples from the start of treatment until 12 weeks post-treatment were investigated. Our results show increased HERV-K(HML-2) transcript levels in patients with HCV-derived liver cirrhosis throughout the observation period. Several clinical parameters specifying poor liver function are positively correlated with HERV-K(HML-2) expression. Of note, patients without a sustained viral clearance showed a drastic increase in HERV-K(HML-2) transcript levels. Together, our data suggest that increased HERV-K(HML-2) expression is correlated with reduced liver function as well as therapy success in HCV-infected patients.


Assuntos
Retrovirus Endógenos/genética , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Fígado/patologia , Proteínas do Envelope Viral/genética , Adulto , Idoso , Albuminas/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , Quimiocina CXCL10/metabolismo , Estudos de Coortes , Feminino , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/patologia , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/genética , Resposta Viral Sustentada , Resultado do Tratamento , Proteínas do Envelope Viral/metabolismo
16.
J Endocrinol ; 249(3): 163-175, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33764312

RESUMO

The ß-cell response to injury may be as critical for the development of diabetes as the specific insult. In the current study, we used streptozotocin (STZ) to injure the ß-cell in order to study the response with a focus on NFκB. MIN6 cells were exposed to STZ (0.5-8 mM, 0-24h) ±TNFα (100 ng/mL) and ±IκBß siRNA to lower the threshold to NFκB activation. Cell viability was determined by trypan blue exclusion. NFκB activation was determined by the expression of the target genes Nos2 and Cxcl10, localization of the NFκB proteins p65 and p50, and expression and localization of the NFκB inhibitors, IκBß and IκBα. There was no NFκB activation in MIN6 cell exposed to STZ (2 mM) alone. However, knocking down IκBß expression using siRNA resulted in STZ-induced expression of NFκB target genes and increased cell death, while co-incubation with STZ and TNFα enhanced cell death compared to either exposure alone. Adult male IκBß-/- and WT mice were exposed to STZ and monitored for diabetes. The IκBß-/- mice developed hyperglycemia and diabetes more frequently than controls following STZ exposure. Based on these results we conclude that STZ exposure alone does not induce NFκB activity. However, lowering the threshold to NFκB activation by co-incubation with TNFα or lowering IκBß levels by siRNA sensitizes the NFκB response to STZ and results in a higher likelihood of developing diabetes in vivo. Therefore, increasing the threshold to NFκB activation through stabilizing NFκB inhibitory proteins may prevent ß-cell injury and the development of diabetes.


Assuntos
Células Secretoras de Insulina/efeitos dos fármacos , NF-kappa B/metabolismo , Estreptozocina/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Diabetes Mellitus Experimental , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Células Secretoras de Insulina/metabolismo , Insulinoma/metabolismo , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
17.
Nat Immunol ; 22(4): 434-448, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33649580

RESUMO

T cells dynamically interact with multiple, distinct cellular subsets to determine effector and memory differentiation. Here, we developed a platform to quantify cell location in three dimensions to determine the spatial requirements that direct T cell fate. After viral infection, we demonstrated that CD8+ effector T cell differentiation is associated with positioning at the lymph node periphery. This was instructed by CXCR3 signaling since, in its absence, T cells are confined to the lymph node center and alternatively differentiate into stem-like memory cell precursors. By mapping the cellular sources of CXCR3 ligands, we demonstrated that CXCL9 and CXCL10 are expressed by spatially distinct dendritic and stromal cell subsets. Unlike effector cells, retention of stem-like memory precursors in the paracortex is associated with CCR7 expression. Finally, we demonstrated that T cell location can be tuned, through deficiency in CXCL10 or type I interferon signaling, to promote effector or stem-like memory fates.


Assuntos
Infecções por Arenaviridae/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Memória Imunológica , Linfonodos/metabolismo , Células Precursoras de Linfócitos T/metabolismo , Receptores CXCR3/metabolismo , Animais , Infecções por Arenaviridae/genética , Infecções por Arenaviridae/imunologia , Infecções por Arenaviridae/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Linhagem da Célula , Células Cultivadas , Quimiocina CXCL10/genética , Quimiocina CXCL9/genética , Quimiotaxia de Leucócito , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Interferon Tipo I/metabolismo , Ligantes , Linfonodos/imunologia , Linfonodos/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/patogenicidade , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Células Precursoras de Linfócitos T/imunologia , Células Precursoras de Linfócitos T/virologia , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores CCR7/metabolismo , Receptores CXCR3/genética , Transdução de Sinais , Nicho de Células-Tronco , Células Estromais/imunologia , Células Estromais/metabolismo
18.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33786610

RESUMO

Thoracic radiotherapy is an effective treatment for many types of cancer; however it is also associated with an increased risk of developing cardiovascular disease (CVD), appearing mainly ≥10 years after radiation exposure. The present study investigated acute and early term physiological and molecular changes in the cardiovascular system after ionizing radiation exposure. Female and male ApoE­/­ mice received a single exposure of low or high dose X­ray thoracic irradiation (0.1 and 10 Gy). The level of cholesterol and triglycerides, as well as a large panel of inflammatory markers, were analyzed in serum samples obtained at 24 h and 1 month after irradiation. The secretion of inflammatory markers was further verified in vitro in coronary artery and microvascular endothelial cell lines after exposure to low and high dose of ionizing radiation (0.1 and 5 Gy). Local thoracic irradiation of ApoE­/­ mice increased serum growth differentiation factor­15 (GDF­15) and C­X­C motif chemokine ligand 10 (CXCL10) levels in both female and male mice 24 h after high dose irradiation, which were also secreted from coronary artery and microvascular endothelial cells in vitro. Sex­specific responses were observed for triglyceride and cholesterol levels, and some of the assessed inflammatory markers as detailed below. Male ApoE­/­ mice demonstrated elevated intercellular adhesion molecule­1 and P­selectin at 24 h, and adiponectin and plasminogen activator inhibitor­1 at 1 month after irradiation, while female ApoE­/­ mice exhibited decreased monocyte chemoattractant protein­1 and urokinase­type plasminogen activator receptor at 24 h, and basic fibroblast growth factor 1 month after irradiation. The inflammatory responses were mainly significant following high dose irradiation, but certain markers showed significant changes after low dose exposure. The present study revealed that acute/early inflammatory responses occurred after low and high dose thoracic irradiation. However, further research is required to elucidate early asymptomatic changes in the cardiovascular system post thoracic X­irradiation and to investigate whether GDF­15 and CXCL10 could be considered as potential biomarkers for the early detection of CVD risk in thoracic radiotherapy­treated patients.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/metabolismo , Quimiocina CXCL10/metabolismo , Endotélio Vascular/efeitos da radiação , Fator 15 de Diferenciação de Crescimento/metabolismo , Raios X , Animais , Apolipoproteínas E/deficiência , Aterosclerose/genética , Molécula 1 de Adesão Celular/genética , Molécula 1 de Adesão Celular/metabolismo , Linhagem Celular , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CXCL10/genética , Células Endoteliais/metabolismo , Células Endoteliais/efeitos da radiação , Endotélio Vascular/citologia , Feminino , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 15 de Diferenciação de Crescimento/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Selectina-P/genética , Selectina-P/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
19.
Front Immunol ; 12: 584414, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717066

RESUMO

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE). Our previous studies demonstrated increased serum and renal Interleukin (IL)-22 in LN patients and MRL/lpr mice. This study investigated the role of IL-22 and its mechanism in LN. Here, we found that IL-22 was mainly produced by type 3 innate lymphoid cells (ILC3) in kidney of MRL/lpr mice. The systemic illness and local renal lesion were significantly alleviated in IL-22 or IL-22R gene knockout (KO) mice (IL-22 KO or IL-22R KO MRL/lpr mice) than control mice (MRL/lpr mice). IL-22 KO or IL-22R KO MRL/lpr mice had significantly slighter infiltration of macrophage in kidney than MRL/lpr mice. Consistently, by RNA-Seq, the expression of (CC motif) ligand 2 (CCL2) and (CXC motif) ligand 10 (CXCL10) was decreased in kidney of KO mice compared with control mice. By immunoblotting, significantly increased levels of STAT3 phosphorylation were found in the kidney of control mice compared to KO mice. In vitro, primary kidney epithelial cells from control mouse stimulated with recombinant IL-22 (rIL-22) expressed higher levels of CCL2, CXCL10, and phosphorylated STAT3. At the same time, when primary kidney epithelial cells were treated with rIL-22, transwell assay demonstrated their supernatant recruited more macrophages. In human kidney epithelial cell line (HK2) cells, when treated with rIL-22, we observed similar results with primary mouse kidney epithelial cells. Moreover, when cells were stimulated with rIL-22 following pre-treatment with STAT3 pathway inhibitor, the expression of CCL2 and CXCL10 were significantly reversed. Our findings demonstrate that IL-22 binding to IL-22R in kidney epithelial cells activated the STAT3 signaling pathway, enhanced the chemokine secretion and then promoted macrophage infiltration to the kidney of MRL/lpr mice, thus aggravated LN in lupus-prone mice. These findings indicate that IL-22 may play a pathogenic role in LN and may provide a promising novel therapeutic target for LN.


Assuntos
Imunidade Inata , Interleucinas/metabolismo , Nefrite Lúpica/etiologia , Nefrite Lúpica/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Animais , Autoanticorpos/imunologia , Biomarcadores , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Proteínas do Sistema Complemento/imunologia , Células Epiteliais/metabolismo , Feminino , Humanos , Imunofenotipagem , Interleucinas/genética , Rim/imunologia , Rim/metabolismo , Rim/patologia , Nefrite Lúpica/patologia , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Receptores de Interleucina/metabolismo , Fator de Transcrição STAT3 , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Baço/patologia
20.
J Mol Histol ; 52(3): 611-620, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33709190

RESUMO

This study aimed to annotate the role of long intergenic non-coding RNA 152 (LINC00152) in CD8+ T cells mediated immune responses in gastric cancer (GC) and the underlying mechanism. LINC00152 expression levels were detected through RT-PCR. For tumor engraftment, HGC-27 cells that received LINC00152 shRNA, LINC00152 overexpression vectors, enhancer of zeste homolog 2 (EZH2) shRNA or combination transfection were injected into mice. Chromatin immunoprecipitation (ChIP) assay was used to explore the interaction between LINC00152, Cys-X-cys ligand 9 (CXCL9) and Cys-X-cys ligand 10 (CXCL10). Flow cytometry was adopted to measure the CD8+ T-cell infiltration in tumor issue. In this study, we found increased LINC00152 expression levels are positively associated with the poor prognosis of GC patients and negatively associated with the CD8 levels. ChIP assay verified that LINC00152 recruits EZH2 to the promoters of CXCL9 and CXCL10, thus the silencing of LINC00152 promoted the production of CXCL9 and CXCL10. Knockdown of LINC00152 suppressed tumor cells growth in vivo and in vitro, increased tumor-infiltrating CD8+ T cells numbers and promoted the expression of CXCL9, CXCL10 and C-X-C Motif Chemokine Receptor 3 (CXCR3) in xenograft tumors. While CD8+ T cell depletion reversed the tumor suppression effect of LINC00152 silence. Besides, the silencing of EZH2 partly inhibited the promotion effect LINC00152 on tumor growth. Our study indicated that LINC00152 inhibition suppressed the tumor progress may through promoting CD8+ T-cell infiltration.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Linfócitos do Interstício Tumoral/imunologia , RNA Longo não Codificante/metabolismo , Receptores CXCR3/metabolismo , Neoplasias Gástricas/imunologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Quimiocina CXCL9/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , RNA Longo não Codificante/sangue , RNA Longo não Codificante/genética , Receptores CXCR3/genética , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética
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