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1.
Nutrients ; 13(10)2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34684578

RESUMO

In a previous study, we demonstrated that melatonin prevents kidney damage in a salt-induced hypertension model by decreasing oxidative stress. We hypothesized that this effect involves melatonin's immunomodulatory properties. In vivo Study-Dahl salt-sensitive (DSS) rats were fed normal chow, a high-salt diet (HSD), or a HSD and melatonin (30 mg/kg/day) in their water for eight weeks. Kidneys were harvested for immediate lymphocyte isolation and characterization by Flow cytometry (CD3+CD4+ and CD3+CD8+) and for lymphocyte chemoattractant (mainly CXCL chemokines) gene expression studies. In vitro study-rat mesangial cells (RMC) were cultured in a high-salt medium without and with melatonin. A HSD was associated with significant renal infiltration of CD4+ and CD8+ T lymphocytes compared to control. Melatonin significantly reduced renal lymphocyte infiltration. A HSD significantly increased mRNA expression of CXCL chemokines. Adding melatonin to the HSD abolished this effect. Treating RMC cells with salt increased the expression of CXCL10 and CXCL11 but not CXCL9. Adding melatonin to the culture media prevented this increase. Treating HSD-fed rats with melatonin decreased renal lymphocyte chemoattractant mRNA expression and is associated with significantly reducing renal T lymphocyte infiltration. Salt may have a direct effect on chemokine-producing renal cells, which is blunted by melatonin treatment.


Assuntos
Quimiocinas/metabolismo , Hipertensão/imunologia , Rim/imunologia , Melatonina/farmacologia , Receptores CXCR3/metabolismo , Linfócitos T/imunologia , Animais , Linhagem Celular , Hipertensão/prevenção & controle , Rim/efeitos dos fármacos , Ligantes , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Ratos , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta , Linfócitos T/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
2.
PLoS One ; 16(10): e0258316, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34673799

RESUMO

RORγt is an isoform of RORC, preferentially expressed in Th17 cells, that functions as a critical regulator of type 3 immunity. As murine Th17-driven inflammatory disease models were greatly diminished in RORC knock-out mice, this receptor was prioritised as an attractive therapeutic target for the treatment of several autoimmune diseases. Human genetic studies indicate a significant contributory role for RORC in several human disease conditions. Furthermore, genome-wide association studies (GWAS) report a significant association between inflammatory bowel disease (IBD) and the RORC regulatory variant rs4845604. To investigate if the rs4845604 variant may affect CD4+ T cell differentiation events, naïve CD4+ T cells were isolated from eighteen healthy subjects homozygous for the rs4845604 minor (A) or major (G) allele). Isolated cells from each subject were differentiated into distinct T cell lineages by culturing in either T cell maintenance medium or Th17 driving medium conditions for six days in the presence of an RORC inverse agonist (to prevent constitutive receptor activity) or an inactive diastereomer (control). Our proof of concept study indicated that genotype had no significant effect on the mean number of naïve CD4 T cells isolated, nor the frequency of Th1-like and Th17-like cells following six days of culture in any of the four culture conditions. Analysis of the derived RNA-seq count data identified genotype-driven transcriptional effects in each of the four culture conditions. Subsequent pathway enrichment analysis of these profiles reported perturbation of metabolic signalling networks, with the potential to affect the cellular detoxification response. This investigation reveals that rs4845604 genotype is associated with transcriptional effects in CD4+ T cells that may perturb immune and metabolic pathways. Most significantly, the rs4845604 GG, IBD risk associated, genotype may be associated with a differential detoxification response. This observation justifies further investigation in a larger cohort of both healthy and IBD-affected individuals.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Hipersensibilidade/genética , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Ativação Linfocitária/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Proliferação de Células , Regulação da Expressão Gênica , Predisposição Genética para Doença , Homozigoto , Humanos , Doenças Inflamatórias Intestinais/patologia , Receptores CXCR3/metabolismo
3.
Biochim Biophys Acta Rev Cancer ; 1876(2): 188628, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34560199

RESUMO

Metastasis is a significant cause of the mortality resulting from solid malignancies. The process of metastasis is complex and is regulated by numerous cancer cell-intrinsic and -extrinsic factors. CXCR3 is a chemokine receptor that is frequently expressed by cancer cells, endothelial cells and immune cells. CXCR3A signaling in cancer cells tends to promote the invasive and migratory phenotype of cancer cells. Indirectly, CXCR3 modulates the anti-tumor immune response resulting in variable effects that can permit or inhibit metastatic progression. Finally, the activity of CXCR3B in endothelial cells is generally angiostatic, which limits the access of cancer cells to key conduits to secondary sites. However, the interaction of these activities within a tumor and the presence of opposing CXCR3 splice variants clouds the picture of the role of CXCR3 in metastasis. Consequently, thorough analysis of the contributions of CXCR3 to cancer metastasis is necessary. This review is an in-depth examination of the involvement of CXCR3 in the metastatic process of solid malignancies.


Assuntos
Neoplasias/genética , Receptores CXCR3/metabolismo , Humanos , Metástase Neoplásica , Neoplasias/patologia , Transdução de Sinais
4.
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
5.
J Clin Invest ; 131(18)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34314390

RESUMO

NK cell suppression of T cells is a key determinant of viral pathogenesis and vaccine efficacy. This process involves perforin-dependent elimination of activated CD4+ T cells during the first 3 days of infection. Although this mechanism requires cell-cell contact, NK cells and T cells typically reside in different compartments of lymphoid tissues at steady state. Here, we showed that NK cell suppression of T cells is associated with transient accumulation of NK cells within T cell-rich sites of the spleen during lymphocytic choriomeningitis virus infection. The chemokine receptor CXCR3 was required for this relocation and suppression of antiviral T cells. Accordingly, NK cell migration was mediated by type I IFN-dependent promotion of CXCR3 ligand expression. In contrast, adenoviral vectors that weakly induced type I IFN and did not stimulate NK cell inhibition of T cells also did not promote measurable redistribution of NK cells to T cell zones. Exogenous IFN rescued NK cell migration during adenoviral vector immunization. Thus, type I IFN and CXCR3 were critical for properly positioning NK cells to constrain antiviral T cell responses. Development of strategies to curtail migration of NK cells between lymphoid compartments may enhance vaccine-elicited immune responses.


Assuntos
Células Matadoras Naturais/imunologia , Tecido Linfoide/imunologia , Receptores CXCR3/metabolismo , Animais , Movimento Celular/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Tolerância Imunológica , Imunidade Inata , Ativação Linfocitária , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/imunologia
6.
Sci Rep ; 11(1): 13912, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230534

RESUMO

Anti-PD-L1 antibodies benefit many cancer patients, even those with "non-inflamed tumor". Determining which patients will benefit remains an important clinical goal. In a non-inflamed tumor mouse model, we found that PD-L1 was highly expressed on antigen-presenting cells (APCs) especially on CD103+ CD11c+ dendritic cells in tumor-draining lymph nodes (dLNs), suppressing T-cell priming by APCs. In this model, anti-PD-L1 antibodies enhanced T-cell priming and increased CXCR3+ activated T-cells in dLNs, which was followed by the trafficking of T-cells to tumors in response to CXCR3 ligands. As predictive biomarker, each APCs-related gene expression (AP score) alone or T-cells trafficking-related chemokine gene expression (T score) alone were still less than perfect among the 17 mouse models examined. However a combining score of AP score and T score (AP/T score) precisely identified anti-PD-L1-sensitive tumors. In the phase 3 trial of atezolizumab vs docetaxel in advanced NSCLC patients (OAK), the AP/T score could identify atezolizumab-treated NSCLC patients who achieved significant improvement in overall survival. This biomarker concept would be a clinically valuable for prediction of anti-PD-L1 antibody efficacy.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Movimento Celular , Apresentação Cruzada/imunologia , Linfonodos/imunologia , Receptores CXCR3/metabolismo , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Apresentação Cruzada/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ligantes , Linfonodos/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Modelos Biológicos , Linfócitos T/efeitos dos fármacos
7.
Front Immunol ; 12: 680944, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248964

RESUMO

Obesity in the United States and worldwide reached epidemic proportions within the last 20 years. Obesity is a very powerful health determinant or indicator that facilitates the development and progression of several metabolic diseases, insulin resistance, and low-grade chronic inflammation. Low-grade chronic inflammation in adipose tissue (AT) is marked by the accumulation of T cells, macrophages, and other immune cells and increased production of proinflammatory cytokines. During the onset of obesity but before the influx of macrophages, the AT is infiltrated by T cells that are strongly implicated in the initiation of obesity-associated inflammation. In comparing mice fed a high-fat diet (HFD) with those fed a normal diet (ND), we observed in HFD epididymal AT induction and infiltration of activated T cells, an accumulation and polarization of macrophages, and an increase in populations of activated CD4+ T cells and CD8+ T cells that express CXCR3 or killer cell lectin-like receptor subfamily G member 1 (KLRG1). Levels of inflammatory cytokines and leptin and the results of in vitro co-culture experiments revealed interactions among HFD- and ND-induced CD8+ T cells, macrophages, and adipocytes. Our findings suggest that obese tissues activate and induce both CD4+ and CD8+ CD69+ T cells and augment the expression of CXCR3 receptors, which promotes the recruitment and numbers of pro-inflammatory M1 macrophages to maintain low-grade chronic inflammation. The results support the hypothesis that CXCR3-expressing CD8+T cells play an essential role in the initiation and maintenance of adipose tissue inflammation.


Assuntos
Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Dieta Hiperlipídica , Macrófagos/imunologia , Macrófagos/metabolismo , Animais , Biomarcadores , Peso Corporal , Células Cultivadas , Doença Crônica , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Metabolismo Energético , Expressão Gênica , Imunofenotipagem , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Contagem de Linfócitos , Masculino , Camundongos , Receptores CXCR3/genética , Receptores CXCR3/metabolismo
8.
Mol Med Rep ; 24(1)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34080653

RESUMO

Increasing evidence has demonstrated that regulatory T cells (Tregs) suppress innate immunity, as well as protect the kidneys from ischemia­reperfusion injury (IRI) and offer a potentially effective strategy to prevent or alleviate renal IRI. The present study explored whether C­X­C motif chemokine receptor 3 (CXCR3) alleviated renal IRI by increasing Tregs. Male C57BL/6J mice were divided into sham­surgery, IRI, CXCR3 overexpression (OE­CXCR3)+IRI, PC61+IRI and OE­CXCR3+PC61+IRI groups. Histopathological examination of the kidney was carried out using hematoxylin­eosin and Masson staining. The levels of serum creatinine (Scr) and blood urea nitrogen (BUN) were measured. Blood and kidney levels of IL­6, TNF­α, C­C motif chemokine ligand (CCL)­2 and IL­10 were detected by ELISA and western blotting. The levels of superoxide dismutase (SOD), glutathione peroxidase (GSH­Px) and malondialdehyde (MDA) in kidney tissues were also measured to assess oxidative stress. The population of Tregs in the kidney was assessed using flow cytometry. The results demonstrated that administration of OE­CXCR3 to IRI mice significantly decreased the levels of Scr, BUN, IL­6, TNF­α, CCL­2 and MDA, increased the levels of IL­10, SOD and GSH­Px, and mitigated the morphologic injury and fibrosis induced by IR compared with the IRI group. In addition, administration of OE­CXCR3 induced significant reductions in the expression levels of fibrosis­related markers, including fibronectin and type IV collagen, and increased the number of Tregs. These roles of OE­CXCR3 were significantly neutralized following deletion of Tregs with PC61 (anti­CD25 antibody). Together, the present study demonstrated that injection of OE­CXCR3 lentiviral vectors into animal models can alleviate renal IRI by increasing the number of Tregs. The results may be a promising approach for the treatment of renal IRI.


Assuntos
Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Modelos Animais de Doenças , Fibrose , Imunidade Inata , Inflamação , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras , Traumatismo por Reperfusão/patologia , Linfócitos T Reguladores/imunologia , Transcriptoma , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
9.
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
10.
Commun Biol ; 4(1): 569, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980979

RESUMO

Following the FDA-approval of the hematopoietic stem cell (HSC) mobilizer plerixafor, orally available and potent CXCR4 antagonists were pursued. One such proposition was AMD11070, which was orally active and had superior antagonism in vitro; however, it did not appear as effective for HSC mobilization in vivo. Here we show that while AMD11070 acts as a full antagonist, plerixafor acts biased by stimulating ß-arrestin recruitment while fully antagonizing G protein. Consequently, while AMD11070 prevents the constitutive receptor internalization, plerixafor allows it and thereby decreases receptor expression. These findings are confirmed by the successful transfer of both ligands' binding sites and action to the related CXCR3 receptor. In vivo, plerixafor exhibits superior HSC mobilization associated with a dramatic reversal of the CXCL12 gradient across the bone marrow endothelium, which is not seen for AMD11070. We propose that the biased action of plerixafor is central for its superior therapeutic effect in HSC mobilization.


Assuntos
Benzilaminas/farmacologia , Ciclamos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Receptores CXCR4/metabolismo , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacologia , Animais , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Benzilaminas/metabolismo , Butilaminas/metabolismo , Butilaminas/farmacologia , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Ciclamos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Feminino , Fator Estimulador de Colônias de Granulócitos , Células HEK293 , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Preparações Farmacêuticas/metabolismo , Receptores CXCR3/efeitos dos fármacos , Receptores CXCR3/metabolismo , Receptores CXCR4/efeitos dos fármacos , beta-Arrestinas/efeitos dos fármacos , beta-Arrestinas/metabolismo
11.
Front Immunol ; 12: 622537, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841403

RESUMO

Introduction: B cells are important regulators of both adaptive and innate immunity. The normal liver contains significant numbers of B cells, and their numbers increase dramatically in immune-mediated liver diseases. Our previous observations suggest a hepatoprotective effect of the antidepressant mirtazapine in human and experimental immune-mediated liver disease. Therefore, we performed a series of experiments to determine the impact of mirtazapine treatment on hepatic B cell homeostasis, as reflected by B cell number, trafficking and phenotype using flow cytometry (FCM) and intravital microscopy (IVM) analysis. Mirtazapine treatment rapidly induced a significant reduction in total hepatic B cell numbers, paralleled by a compositional shift in the predominant hepatic B cell subtype from B2 to B1. This shift in hepatic B cells induced by mirtazapine treatment was associated with a striking increase in total hepatic levels of the chemokine CXCL10, and increased production of CXCL10 by hepatic macrophages and dendritic cells. Furthermore, mirtazapine treatment led to an upregulation of CXCR3, the cognate chemokine receptor for CXCL10, on hepatic B cells that remained in the liver post-mirtazapine. A significant role for CXCR3 in the hepatic retention of B cells post-mirtazapine was confirmed using CXCR3 receptor blockade. In addition, B cells remaining in the liver post-mirtazapine produced lower amounts of the proinflammatory Th1-like cytokines IFNγ, TNFα, and IL-6, and increased amounts of the Th2-like cytokine IL-4, after stimulation in vitro. Conclusion: Mirtazapine treatment rapidly alters hepatic B cell populations, enhancing hepatic retention of CXCR3-expressing innate-like B cells that generate a more anti-inflammatory cytokine profile. Mirtazapine-induced hepatic B cell shifts could potentially represent a novel therapeutic approach to immune-mediated liver diseases characterized by B cell driven pathology.


Assuntos
Antidepressivos/uso terapêutico , Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Hepatopatias/imunologia , Fígado/imunologia , Mirtazapina/uso terapêutico , Animais , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Humanos , Imunidade Inata , Hepatopatias/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores CXCR3/metabolismo , Células Th1/imunologia , Células Th2/imunologia
12.
PLoS One ; 16(3): e0249205, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33770137

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is associated with development of generalized osteoporosis. Bone-degrading osteoclasts are derived from circulating precursor cells of monocytic lineage, and the intermediate monocyte population is important as osteoclast precursors in inflammatory conditions. T cells of various subsets are critical in the pathogenesis of both RA and associated osteoporosis, but so far, no studies have examined associations between circulating intermediate monocytes, T cell subsets and bone characteristics in patients with RA. The aim of this study was to investigate the frequency of intermediate monocytes in patients with untreated early rheumatoid arthritis (ueRA) compared to healthy controls (HC), and to explore the correlation between intermediate monocytes and a comprehensive panel of T helper cell subsets, bone density and bone microarchitecture in ueRA patients. METHODS: 78 patients with ueRA fulfilling the ACR/EULAR 2010 criteria were included and compared to 29 age- and sex-matched HC. Peripheral blood samples were obtained before start of treatment and proportions of monocyte subsets and CD4+ helper and regulatory T cell subsets were analyzed by flow cytometry. Bone densitometry was performed on 46 of the ueRA patients at inclusion using DXA and HR-pQCT. RESULTS: Flow cytometric analyses showed that the majority of ueRA patients had frequencies of intermediate monocytes comparable to HC. The intermediate monocyte population correlated positively with CXCR3+ Th17 cells in ueRA patients but not in HC. However, neither the proportions of intermediate monocytes nor CXCR3+ Th17 cells were associated with bone density or bone microarchitecture measurements. CONCLUSIONS: Our findings suggest that in early RA, the intermediate monocytes do not correlate with bone characteristics, despite positive correlation with circulating CXCR3+ Th17 cells. Future longitudinal studies in patients with longer disease duration are required to fully explore the potential of intermediate monocytes to drive bone loss in RA.


Assuntos
Artrite Reumatoide/imunologia , Monócitos/metabolismo , Receptores CXCR3/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Artrite Reumatoide/metabolismo , Humanos
13.
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
14.
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
15.
Mol Cell ; 81(10): 2148-2165.e9, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-33743195

RESUMO

Developing strategies to activate tumor-cell-intrinsic immune response is critical for improving tumor immunotherapy by exploiting tumor vulnerability. KDM4A, as a histone H3 lysine 9 trimethylation (H3K9me3) demethylase, has been found to play a critical role in squamous cell carcinoma (SCC) growth and metastasis. Here we report that KDM4A inhibition promoted heterochromatin compaction and induced DNA replication stress, which elicited antitumor immunity in SCC. Mechanistically, KDM4A inhibition promoted the formation of liquid-like HP1γ puncta on heterochromatin and stall DNA replication, which activated tumor-cell-intrinsic cGAS-STING signaling through replication-stress-induced cytosolic DNA accumulation. Moreover, KDM4A inhibition collaborated with PD1 blockade to inhibit SCC growth and metastasis by recruiting and activating CD8+ T cells. In vivo lineage tracing demonstrated that KDM4A inhibition plus PD1 blockade efficiently eliminated cancer stem cells. Altogether, our results demonstrate that targeting KDM4A can activate anti-tumor immunity and enable PD1 blockade immunotherapy by aggravating replication stress in SCC cells.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Replicação do DNA/genética , Epigênese Genética , Histona Desmetilases/metabolismo , Imunidade/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Estresse Fisiológico/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Dano ao DNA/genética , Células Epiteliais/metabolismo , Deleção de Genes , Humanos , Metástase Linfática , Camundongos Transgênicos , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR3/metabolismo , Células Th1/imunologia
16.
J Exp Med ; 218(5)2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33630019

RESUMO

Congenital human cytomegalovirus (cHCMV) infection of the brain is associated with a wide range of neurocognitive sequelae. Using infection of newborn mice with mouse cytomegalovirus (MCMV) as a reliable model that recapitulates many aspects of cHCMV infection, including disseminated infection, CNS infection, altered neurodevelopment, and sensorineural hearing loss, we have previously shown that mitigation of inflammation prevented alterations in cerebellar development, suggesting that host inflammatory factors are key drivers of neurodevelopmental defects. Here, we show that MCMV infection causes a dramatic increase in the expression of the microglia-derived chemokines CXCL9/CXCL10, which recruit NK and ILC1 cells into the brain in a CXCR3-dependent manner. Surprisingly, brain-infiltrating innate immune cells not only were unable to control virus infection in the brain but also orchestrated pathological inflammatory responses, which lead to delays in cerebellar morphogenesis. Our results identify NK and ILC1 cells as the major mediators of immunopathology in response to virus infection in the developing CNS, which can be prevented by anti-IFN-γ antibodies.


Assuntos
Encéfalo/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Linfócitos/imunologia , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Encéfalo/virologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Quimiocina CXCL9/metabolismo , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/virologia , Regulação da Expressão Gênica/imunologia , Humanos , Imunidade Inata/imunologia , Inflamação/genética , Inflamação/virologia , Células Matadoras Naturais/metabolismo , Linfócitos/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/imunologia , Microglia/metabolismo , Microglia/virologia , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Receptores CXCR3/metabolismo
17.
PLoS Pathog ; 17(2): e1009367, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33617602

RESUMO

Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears to be immune-mediated. Therefore, we investigated the role of CD8 T cells in the outcome of the infection in immunocompetent elderly subjects. We enrolled twenty two HEV-3-infected patients displaying similar viral determinants and fifteen healthy donors. Among the infected group, sixteen patients experienced clinical symptoms related to liver disease while six remained asymptomatic. Here we report that symptomatic infection is characterized by an expansion of highly activated effector memory CD8 T (EM) cells, regardless of antigen specificity. This robust activation is associated with key features of early T cell exhaustion including a loss in polyfunctional type-1 cytokine production and partial commitment to type-2 cells. In addition, we show that bystander activation of EM cells seems to be dependent on the inflammatory cytokines IL-15 and IL-18, and is supported by an upregulation of the activating receptor NKG2D and an exuberant expression of T-Bet and T-Bet-regulated genes including granzyme B and CXCR3. We also show that the inflammatory chemokines CXCL9-10 are increased in symptomatic patients thereby fostering the recruitment of highly cytotoxic EM cells into the liver in a CXCR3-dependent manner. Finally, we find that the EM-biased immune response returns to homeostasis following viral clearance and disease resolution, further linking the EM cells response to viral burden. Conversely, asymptomatic patients are endowed with low-to-moderate EM cell response. In summary, our findings define immune correlates that contribute to HEV-3 pathogenesis and emphasize the central role of EM cells in governing the outcome of the infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vírus da Hepatite E/classificação , Hepatite E/patologia , Memória Imunológica/imunologia , Receptores CXCR3/metabolismo , Idoso , Estudos de Casos e Controles , Citocinas/metabolismo , Feminino , Genótipo , Hepatite E/imunologia , Hepatite E/virologia , Vírus da Hepatite E/genética , Vírus da Hepatite E/imunologia , Humanos , Masculino , Pessoa de Meia-Idade
18.
J Immunol ; 206(6): 1151-1160, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33558376

RESUMO

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS. We have previously demonstrated that CNS-specific CD8 T cells possess a disease-suppressive function in MS and variations of its animal model, experimental autoimmune encephalomyelitis (EAE), including the highly clinically relevant relapsing-remitting EAE disease course. Regulatory CD8 T cell subsets have been identified in EAE and other autoimmune diseases, but studies vary in defining phenotypic properties of these cells. In relapsing-remitting EAE, PLP178-191 CD8 T cells suppress disease, whereas PLP139-151 CD8 T cells lack this function. In this study, we used this model to delineate the unique phenotypic properties of CNS-specific regulatory PLP178-191 CD8 T cells versus nonregulatory PLP139-151 or OVA323-339 CD8 T cells. Using multiparametric flow cytometric analyses of phenotypic marker expression, we identified a CXCR3+ subpopulation among activated regulatory CD8 T cells, relative to nonregulatory counterparts. This subset exhibited increased degranulation and IFN-γ and IL-10 coproduction. A similar subset was also identified in C57BL/6 mice within autoregulatory PLP178-191 CD8 T cells but not within nonregulatory OVA323-339 CD8 T cells. This disease-suppressing CD8 T cell subpopulation provides better insights into functional regulatory mechanisms, and targeted enhancement of this subset could represent a novel immunotherapeutic approach for MS.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla/imunologia , Bainha de Mielina/patologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Separação Celular , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Feminino , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Camundongos , Esclerose Múltipla/patologia , Bainha de Mielina/imunologia , Receptores CXCR3/metabolismo , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/transplante
19.
Int J Mol Sci ; 22(4)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33557113

RESUMO

Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1ß, Tnf-α, Il-6, Arg1, Igf-1, Tgf-ß and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the "two-hit" hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led to the appearance of schizophrenia-like disturbances in adult offspring. Our results revealed the deficits manifested as a diminished number of aggressive interactions, presence of depressive-like episodes, and increase of exploratory activity, as well as a dichotomy in the sensorimotor gating in the prepulse inhibition (PPI) test expressed as two behavioural phenotypes (MIAPPI-low and MIAPPI-high). Furthermore, in the offspring rats subjected to a prenatal challenge (i.e., MIA) we noticed the lack of modulation of behavioural changes after the additional acute immune stimulus (Poly I:C) in adulthood. The important finding reported in this article is that MIA affects the expression and levels of the neuron-microglia proteins in the frontal cortex and hippocampus of adult offspring. We found that the changes in the CX3CL1-CX3CR1 axis could affect microglial trajectory, including decreased hippocampal mRNA level of MhcII and elevated cortical expression of Igf-1 in the MIAPPI-high animals and/or could cause the up-regulation of an inflammatory response (Il-6, Tnf-α, iNos) after the "second hit" in both examined brain regions and, at least in part, might differentiate behavioural disturbances in adult offspring. Consequently, the future effort to identify the biological background of these interactions in the Poly I:C-induced MIA model in Sprague-Dawley rats is desirable to unequivocally clarify this issue.


Assuntos
Imunomodulação/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microglia/imunologia , Poli I-C/farmacologia , Esquizofrenia/etiologia , Animais , Comportamento Animal , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Hipocampo/metabolismo , Masculino , Microglia/metabolismo , Microglia/patologia , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/metabolismo , Fotoperíodo , RNA Mensageiro/genética , Ratos , Receptores CXCR3/metabolismo , Esquizofrenia/metabolismo , Comportamento Social
20.
Sci Rep ; 11(1): 2613, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510341

RESUMO

Apical periodontitis (AP) is an acute or chronic inflammatory disease caused by complex interactions between infected root canal and host immune system. It results in the induction of inflammatory mediators such as chemokines and cytokines leading to periapical tissue destruction. To understand the molecular pathogenesis of AP, we have investigated inflammatory-related genes that regulate AP development. We found here that macrophage-derived CXCL9, which acts through CXCR3, is recruited by progressed AP. The inhibition of CXCL9 by a CXCR3 antagonist reduced the lesion size in a mouse AP model with decreasing IL-1ß, IL-6 and TNFα expression. The treatment of peritoneal macrophages with CXCL9 and LPS induced the transmigration and upregulation of osteoclastogenic cytokines such as IL-1ß, IL-6 and matrix metalloprotease 2, a marker of activated macrophages. This suggests that the CXCL9-CXCR3 axis plays a crucial role in the development of AP, mediated by the migration and activation of macrophages for periapical tissue destruction. Our data thus show that CXCL9 regulates the functions of macrophages which contribute to AP pathogenesis, and that blocking CXCL9 suppresses AP progression. Knowledge of the principal factors involved in the progression of AP, and the identification of related inflammatory markers, may help to establish new therapeutic strategies.


Assuntos
Quimiocina CXCL9/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Periodontite Periapical/imunologia , Receptores CXCR3/metabolismo , Animais , Linhagem Celular Tumoral , Ensaios de Migração de Macrófagos , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno/imunologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Periodontite Periapical/metabolismo , Periodontite Periapical/patologia , Receptores CXCR3/antagonistas & inibidores , Raiz Dentária/patologia
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