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1.
Nat Commun ; 12(1): 4907, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389726

RESUMO

The intestinal mucosa constitutes an environment of closely regulated immune cells. Dendritic cells (DC) interact with the gut microbiome and antigens and are important in maintaining gut homeostasis. Here, we investigate DC transcriptome, phenotype and function in five anatomical locations of the gut lamina propria (LP) which constitute different antigenic environments. We show that DC from distinct gut LP compartments induce distinct T cell differentiation and cytokine secretion. We also find that PD-L1+ DC in the duodenal LP and XCR1+ DC in the colonic LP comprise distinct tolerogenic DC subsets that are crucial for gut homeostasis. Mice lacking PD-L1+ and XCR1+ DC have a proinflammatory gut milieu associated with an increase in Th1/Th17 cells and a decrease in Treg cells and have exacerbated disease in the models of 5-FU-induced mucositis and DSS-induced colitis. Our findings identify PD-L1+ and XCR1+ DC as region-specific physiologic regulators of intestinal homeostasis.


Assuntos
Antígeno B7-H1/imunologia , Células Dendríticas/imunologia , Homeostase/imunologia , Mucosa Intestinal/imunologia , Receptores de Quimiocinas/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Colite/genética , Colite/imunologia , Colite/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/imunologia , Homeostase/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia
2.
J Immunol ; 207(4): 1200-1210, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34321227

RESUMO

Esophagogastric adenocarcinomas (EAC) are obesity-associated malignancies underpinned by severe immune dysregulation and inflammation. Our previous work indicates that NK cells migrate to EAC omentum, where they undergo phenotypic and functional alterations and apoptosis. In this study, we investigate whether such erroneous chemotaxis to omentum is paralleled by compromised NK cell infiltration of EAC patient tumor and examine the role of the inflammatory chemokine fractalkine in shaping the NK cell-mediated response. Our data show diminished NK cell frequencies in EAC tumor compared with those in the circulation and reveal that intratumoral NK cell frequencies decline as visceral obesity increases in EAC patients. Our in vitro findings demonstrate that antagonism of fractalkine receptor CX3CR1 significantly reduces NK cell migration to EAC patient-derived, omental adipose tissue-conditioned media, but not toward tumor-conditioned media. These data suggest fractalkine is a key driver of NK cell chemotaxis to omentum but has a lesser role in NK cell homing to tumor in EAC. We propose that this may offer a novel therapeutic strategy to limit NK cell depletion in the omentum of obese EAC patients, and our data suggest the optimal timing for CX3CR1 antagonism is after neoadjuvant chemoradiotherapy. Our functional studies demonstrate that fractalkine induces the conversion from CX3CR1+CD27- to CX3CR1-CD27+ NK cells and increases their IFN-γ and TNF-α production, indicative of its role in shaping the dominant NK cell phenotype in EAC omentum. This study uncovers crucial and potentially druggable pathways underpinning NK cell dysfunction in obesity-associated cancer and provides compelling insights into fractalkine's diverse biological functions.


Assuntos
Quimiocina CX3CL1/imunologia , Quimiotaxia/imunologia , Células Matadoras Naturais/imunologia , Obesidade/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Adenocarcinoma/imunologia , Tecido Adiposo/imunologia , Movimento Celular/imunologia , Neoplasias Esofágicas/imunologia , Feminino , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptores de Quimiocinas/imunologia , Neoplasias Gástricas/imunologia
3.
Nat Commun ; 12(1): 4357, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272386

RESUMO

While various GPCRs, including US28, display constitutive, ligand-independent activity, it remains to be established whether ligand-dependent and -independent active conformations differ and can be selectively modulated. Previously, the agonist-bound conformation of US28 was stabilized and its structure was solved using the anti-US28 nanobody Nb7. Here we report the recognition of the constitutively active, apo-conformation of US28 by another nanobody VUN103. While the Nb7 intrabody selectively inhibits ligand-induced signaling, the VUN103 intrabody blocks constitutive signaling, indicating the existence of distinct US28 conformational states. By displacing Gαq protein, VUN103 prevents US28 signaling and reduces tumor spheroids growth. Overall, nanobodies specific for distinct GPCR conformational states, i.e. apo- and agonist-bound, can selectively target and discern functional consequences of ligand-dependent versus independent signaling.


Assuntos
Citomegalovirus/metabolismo , Receptores de Quimiocinas/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Anticorpos de Domínio Único/química , Esferoides Celulares/efeitos dos fármacos , Proteínas Virais/imunologia , Quimiocina CX3CL1/metabolismo , Cromatografia Líquida , Citomegalovirus/química , Células HEK293 , Humanos , Ligantes , Conformação Molecular , Ligação Proteica , Receptores Acoplados a Proteínas G/química , Espectrometria de Massas em Tandem , beta-Arrestinas/metabolismo
4.
Nat Med ; 27(6): 1043-1054, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34017133

RESUMO

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1+ cDC1 as an important driver of liver pathology.


Assuntos
Células Dendríticas/imunologia , Fígado Gorduroso/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Receptores de Quimiocinas/genética , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Reprogramação Celular/genética , Reprogramação Celular/imunologia , Células Dendríticas/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Humanos , Fígado/imunologia , Fígado/patologia , Linfonodos/imunologia , Linfonodos/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores de Quimiocinas/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
5.
Front Immunol ; 12: 641188, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33828552

RESUMO

Precisely controlled lymphocyte migration is critically required for immune surveillance and successful immune responses. Lymphocyte migration is strictly regulated by chemokines and chemokine receptors. Here we show that protein geranylgeranylation, a form of post-translational protein lipid modification, is required for chemokine receptor-proximal signaling. Mature thymocytes deficient for protein geranylgeranylation are impaired for thymus egress. Circulating mature T cells lacking protein geranylgeranylation fail to home to secondary lymphoid organs or to transmigrate in response to chemokines in vitro. Mechanistically, protein geranylgeranylation modifies the γ-subunits of the heterotrimeric small GTPases that are essential for chemokine receptor signaling. In addition, protein geranylgeranylation also promotes the differentiation of IL-17-producing T helper cells while inhibiting the differentiation of Foxp3+ regulatory T cells. Finally, mice with T cell lineage-specific deficiency of protein geranylgeranylation are resistant to experimental autoimmune encephalomyelitis induction. This study elucidated a critical role of protein geranylgeranylation in regulating T lymphocyte migration and function.


Assuntos
Quimiotaxia de Leucócito/imunologia , Encefalomielite Autoimune Experimental/imunologia , Prenilação de Proteína/imunologia , Receptores de Quimiocinas/imunologia , Células Th17/imunologia , Animais , Diferenciação Celular/imunologia , Camundongos , Esclerose Múltipla , Transdução de Sinais/imunologia
7.
Cells ; 10(1)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33466410

RESUMO

Although G protein-coupled receptor kinases (GRKs) have long been known to regulate G protein-coupled receptor (GPCR) desensitization, their more recently characterized functions as scaffolds and signalling adapters underscore that this small family of proteins governs a larger array of physiological functions than originally suspected. This review explores how GRKs contribute to the complex signalling networks involved in the migration of immune cells along chemokine gradients sensed by cell surface GPCRs. We outline emerging evidence indicating that the coordinated docking of several GRKs on an active chemokine receptor determines a specific receptor phosphorylation barcode that will translate into distinct signalling and migration outcomes. The guidance cues for neutrophil migration are emphasized based on several alterations affecting GRKs or GPCRs reported to be involved in pathological conditions.


Assuntos
Movimento Celular/imunologia , Quimiocinas/imunologia , Quinases de Receptores Acoplados a Proteína G/imunologia , Receptores de Quimiocinas/imunologia , Transdução de Sinais/imunologia , Animais , Humanos
8.
Am J Physiol Cell Physiol ; 319(5): C797-C806, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877204

RESUMO

Monocytes are critical mediators of the inflammatory response following myocardial infarction (MI) and ischemia-reperfusion injury. They are involved in both initiation and resolution of inflammation and play an integral role in cardiac repair. The antagonistic nature of their function is dependent on their subset heterogeneity and biphasic response following injury. New advancements in single-cell transcriptomics and mass cytometry have allowed us to identify smaller, transcriptionally distinct clusters that may have functional relevance in disease and homeostasis. Additionally, recent insights into the spatiotemporal dynamics of monocytes following ischemic injury and their subsequent interactions with the endothelium and other immune cells reveal a complex interplay between monocytes and the cardiac milieu. In this review, we highlight recent findings on monocyte functional heterogeneity, present new mechanistic insight into monocyte recruitment and fate specification following MI, and discuss promising therapeutic avenues targeting monocytes for the treatment of ischemic heart disease.


Assuntos
Linhagem da Célula/imunologia , Monócitos/imunologia , Infarto do Miocárdio/imunologia , Traumatismo por Reperfusão Miocárdica/imunologia , Transcriptoma/imunologia , Animais , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/genética , Quimiocinas/genética , Quimiocinas/imunologia , Modelos Animais de Doenças , Exossomos/transplante , Regulação da Expressão Gênica , Humanos , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucinas/genética , Interleucinas/imunologia , Isoflavonas/farmacologia , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/patologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/terapia , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos
9.
Front Immunol ; 11: 1076, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849489

RESUMO

In the past decade, mesenchymal stem cells (MSCs) tend to exhibit inherent tropism for refractory inflammatory diseases and engineered MSCs have appeared on the market as therapeutic agents. Recently, engineered MSCs target to cell surface molecules on immune cells has been a new strategy to improve MSC applications. In this review, we discuss the roles of multiple receptors (ICAM-1, Gal-9, PD-L1, TIGIT, CD200, and CXCR4) in the process of MSCs' immunosuppressive properties. Furthermore, we discuss the principles and strategies for developing receptor-regulated MSCs and their mechanisms of action and the challenges of using MSCs as immunosuppressive therapies.


Assuntos
Tolerância Imunológica , Células-Tronco Mesenquimais/imunologia , Receptores de Superfície Celular/imunologia , Animais , Antígeno B7-H1/imunologia , Moléculas de Adesão Celular/imunologia , Engenharia Celular/métodos , Galectinas/imunologia , Humanos , Imunossupressão/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Modelos Imunológicos , Receptores de Quimiocinas/imunologia , Receptores Imunológicos/imunologia
10.
J Hematol Oncol ; 13(1): 86, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616000

RESUMO

Chimeric antigen receptor T (CAR-T) cell therapy is regarded as an effective solution for relapsed or refractory tumors, particularly for hematological malignancies. Although the initially approved anti-CD19 CAR-T therapy has produced impressive outcomes, setbacks such as high relapse rates and resistance were experienced, driving the need to discover engineered CAR-T cells that are more effective for therapeutic use. Innovations in the structure and manufacturing of CAR-T cells have resulted in significant improvements in efficacy and persistence, particularly with the development of fourth-generation CAR-T cells. Paired with an immune modifier, the use of fourth-generation and next-generation CAR-T cells will not be limited because of cytotoxic effects and will be an efficient tool for overcoming the tumor microenvironment. In this review, we summarize the recent transformations in the ectodomain, transmembrane domain, and endodomain of the CAR structure, which, together with innovative manufacturing technology and improved cell sources, improve the prospects for the future development of CAR-T cell therapy.


Assuntos
Engenharia Celular/tendências , Imunoterapia Adotiva/tendências , Receptores de Antígenos Quiméricos/genética , Antígenos CD19/genética , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Antígenos CD28/química , Antígenos CD28/imunologia , Quimiotaxia de Leucócito , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Vetores Genéticos/genética , Humanos , Imunoterapia Adotiva/métodos , Lentivirus/genética , Linfoma Difuso de Grandes Células B/terapia , Neoplasias/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Ligação Proteica , Domínios Proteicos , Engenharia de Proteínas , Receptores de Quimiocinas/imunologia , Receptores de Antígenos Quiméricos/agonistas , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T/imunologia , Linfócitos T/transplante , Transdução Genética , Microambiente Tumoral
11.
J Exp Med ; 217(8)2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32525985

RESUMO

CD8+ tissue-resident memory T cells (TRM cells) are poised at the portals of infection and provide long-term protective immunity. Despite their critical roles, the precise mechanics governing TRM cell reactivation in situ are unknown. Using a TCR-transgenic Nur77-GFP reporter to distinguish "antigen-specific" from "bystander" reactivation, we demonstrate that lung CD8+ TRM cells are reactivated more quickly, yet less efficiently, than their counterparts in the draining LNs (TLN cells). Global profiling of reactivated memory T cells revealed tissue-defined and temporally regulated recall response programs. Unlike the reactivation of CD8+ TLN cells, which is strictly dependent on CD11c+XCR1+ APCs, numerous antigen-presenting partners, both hematopoietic and non-hematopoietic, were sufficient to reactivate lung CD8+ TRM cells, but the quality of TRM cell functional responses depended on the identity of the APCs. Together, this work uncovers fundamental differences in the activation kinetics, mechanics, and effector responses between CD8+ memory T cells in peripheral vs. lymphoid organs, revealing a novel tissue-specific paradigm for the reactivation of memory CD8+ T cells.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Pulmão/imunologia , Linfonodos/imunologia , Ativação Linfocitária , Animais , Antígenos CD11/genética , Antígenos CD11/imunologia , Camundongos , Camundongos Knockout , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologia
12.
J Immunol ; 205(3): 661-673, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32591401

RESUMO

Targeting Ag to surface receptors on conventional type 1 dendritic cells can enhance induction of Ab and T cell responses. However, it is unclear to what extent the targeted receptor influences the resulting responses. In this study, we target Ag to Xcr1, Clec9A, or DEC-205, surface receptors that are expressed on conventional type 1 dendritic cells, and compare immune responses in BALB/c and C57BL/6 mice in vitro and in vivo after intradermal DNA vaccination. Targeting hemagglutinin from influenza A to Clec9A induced Ab responses with higher avidity that more efficiently neutralized influenza virus compared with Xcr1 and DEC-205 targeting. In contrast, targeting Xcr1 resulted in higher IFN-γ+CD8+ T cell responses in spleen and lung and stronger cytotoxicity. Both Clec9A and Xcr1 targeting induced Th1-polarized Ab responses, although the Th1 polarization of CD4+ T cells was more pronounced after Xcr1 targeting. Targeting DEC-205 resulted in poor Ab responses in BALB/c mice and a more mixed Th response. In an influenza challenge model, targeting either Xcr1 or Clec9A induced full and long-term protection against influenza infection, whereas only partial short-term protection was obtained when targeting DEC-205. In summary, the choice of targeting receptor, even on the same dendritic cell subpopulation, may strongly influence the resulting immune response, suggesting that different targeting strategies should be considered depending on the pathogen.


Assuntos
Antígenos CD/imunologia , Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Lectinas Tipo C/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Receptores de Superfície Celular/imunologia , Receptores de Quimiocinas/imunologia , Receptores Imunológicos/imunologia , Células Th1/imunologia , Animais , Feminino , Células HEK293 , Humanos , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos BALB C
13.
JCI Insight ; 5(10)2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32434994

RESUMO

Success of DC vaccines relies on the quality of antigen presentation, costimulation, lymph node migration, and the release of IL-12, in case of Th1 priming. Here, we provide evidence for interaction between the injected vaccine DCs with endogenous lymph node-resident DCs for Th1 induction. While migration of the injected DCs was essential for antigen delivery to the lymph node, the injected DCs contributed only partially to Th0 priming and were unable to instruct Th1 generation. Instead, we provide evidence that the lymph node-resident XCR1+ DCs are activated by the injected DCs to present the cognate antigen and release IL-12 for Th1 polarization. The timing of interactions in the draining lymph nodes appeared step-wise as (a) injected DCs with cognate T cells, (b) injected DCs with bystander DCs, and (c) bystander DCs with T cells. The transcriptome of the bystander DCs showed a downregulation of Treg- and Th2/Th9-inducing genes and self-antigen presentation, as well as upregulation of MHC class II and genes required for Th1 instruction. Together, these data show that injected mature lymph node migratory DCs direct T cell priming and bystander DC activation, but not Th1 polarization, which is mediated by endogenous IL-12p70+XCR1+ resident bystander DCs. Our results are of importance for clinical DC-based vaccinations against tumors where endogenous DCs may be functionally impaired by chemotherapy.


Assuntos
Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Interleucina-12/imunologia , Células Th1/imunologia , Animais , Células Dendríticas/patologia , Camundongos , Receptores de Quimiocinas/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th1/patologia , Células Th2/imunologia , Células Th2/patologia
14.
Immunity ; 52(5): 856-871.e8, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32289253

RESUMO

Neutrophils are expanded and abundant in cancer-bearing hosts. Under the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.


Assuntos
Armadilhas Extracelulares/metabolismo , Neoplasias Experimentais/terapia , Receptores de Quimiocinas/agonistas , Receptores de Interleucina-8A/agonistas , Receptores de Interleucina-8B/agonistas , Animais , Linhagem Celular Tumoral , Citotoxicidade Imunológica/imunologia , Células HT29 , Humanos , Microscopia Intravital/métodos , Células Matadoras Naturais/imunologia , Ligantes , Camundongos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Receptores de Interleucina-8A/imunologia , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/imunologia , Receptores de Interleucina-8B/metabolismo , Linfócitos T Citotóxicos/imunologia
15.
Int Immunopharmacol ; 83: 106314, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32197226

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory disease that is characterized by leukocyte infiltration and subsequent axonal damage, demyelinating inflammation, and formation of sclerosing plaques in brain tissue. The results of various studies in patients indicate that autoimmunity and inflammation make an important impact on the pathogenesis of MS. Chemokines are key mediators of inflammation development and cell migration, mediating various immune cell responses, including chemotaxis and immune activation, and are important in immunity and inflammation, therefore we focus on chemokines and their receptors in multiple sclerosis. In this article, we summarize the study of the role of prominent chemokines and their receptors in MS patients and MS animal modelsand discuss their potential significance in inflammatory injury and repair of MS. We have also summarized the progress in the treatment of multiple sclerosis antagonists in recent years with chemokine receptors as targets.


Assuntos
Encéfalo/imunologia , Quimiocinas/imunologia , Inflamação/imunologia , Esclerose Múltipla/imunologia , Receptores de Quimiocinas/imunologia , Animais , Movimento Celular , Modelos Animais de Doenças , Humanos , Imunidade Celular
16.
Eur J Immunol ; 50(5): 666-675, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32114694

RESUMO

Analysis of chemokine receptor, and atypical chemokine receptor, expression is frequently hampered by the lack of availability of high-quality antibodies and the species specificity of those that are available. We have previously described methodology utilizing Alexa-Fluor-labeled chemokine ligands as versatile reagents to detect receptor expression. Previously this has been limited to hematopoietic cells and methodology for assessing expression of receptors on stromal cells has been lacking. Among chemokine receptors, the ones most frequently expressed on stromal cells belong to the atypical chemokine receptor subfamily. These receptors do not signal in the classic sense in response to ligand but scavenge their ligands and degrade them and thus sculpt in vivo chemokine gradients. Here, we demonstrate the ability to use either intratracheal or intravenous, Alexa-Fluor-labeled chemokine administration to detect stromal cell populations expressing the atypical chemokine receptor ACKR2. Using this methodology, we demonstrate, for the first time, expression of ACKR2 on blood endothelial cells. This observation sets the lung aside from other tissues in which ACKR2 is exclusively expressed on lymphatic endothelial cells and suggest unique roles for ACKR2 in the pulmonary environment.


Assuntos
Células Endoteliais/imunologia , Pulmão/imunologia , Receptores de Quimiocinas/imunologia , Células Estromais/imunologia , Animais , Carbocianinas/química , Células Endoteliais/citologia , Molécula de Adesão da Célula Epitelial/genética , Molécula de Adesão da Célula Epitelial/imunologia , Citometria de Fluxo , Corantes Fluorescentes/química , Expressão Gênica , Pulmão/irrigação sanguínea , Pulmão/citologia , Camundongos , Camundongos Knockout , Receptores de Quimiocinas/genética , Coloração e Rotulagem/métodos , Células Estromais/citologia
17.
Front Immunol ; 11: 325, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161595

RESUMO

Phagocytes are highly motile immune cells that ingest and clear microbial invaders, harmful substances, and dying cells. Their function is critically dependent on the expression of chemokine receptors, a class of G-protein-coupled receptors (GPCRs). Chemokine receptors coordinate the recruitment of phagocytes and other immune cells to sites of infection and damage, modulate inflammatory and wound healing responses, and direct cell differentiation, proliferation, and polarization. Besides, a structurally diverse group of atypical chemokine receptors (ACKRs) are unable to signal in G-protein-dependent fashion themselves but can shape chemokine gradients by fine-tuning the activity of conventional chemokine receptors. The optically transparent zebrafish embryos and larvae provide a powerful in vivo system to visualize phagocytes during development and study them as key elements of the immune response in real-time. In this review, we discuss how the zebrafish model has furthered our understanding of the role of two main classes of chemokine receptors, the CC and CXC subtypes, in phagocyte biology. We address the roles of the receptors in the migratory properties of phagocytes in zebrafish models for cancer, infectious disease, and inflammation. We illustrate how studies in zebrafish enable visualizing the contribution of chemokine receptors and ACKRs in shaping self-generated chemokine gradients of migrating cells. Taking the functional antagonism between two paralogs of the CXCR3 family as an example, we discuss how the duplication of chemokine receptor genes in zebrafish poses challenges, but also provides opportunities to study sub-functionalization or loss-of-function events. We emphasize how the zebrafish model has been instrumental to prove that the major determinant for the functional outcome of a chemokine receptor-ligand interaction is the cell-type expressing the receptor. Finally, we highlight relevant homologies and analogies between mammalian and zebrafish phagocyte function and discuss the potential of zebrafish models to further advance our understanding of chemokine receptors in innate immunity and disease.


Assuntos
Fagócitos/metabolismo , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Peixe-Zebra/imunologia , Animais , Humanos , Imunidade Inata , Inflamação/imunologia , Macrófagos/imunologia , Neoplasias/imunologia , Ferimentos e Lesões/imunologia
18.
Int J Med Microbiol ; 310(3): 151416, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32173267

RESUMO

Endothelium damage caused by Treponema pallidum is the key step in the systemic dissemination and pathophysiology of syphilis, particularly cardiovascular syphilis and neurosyphilis. However, the molecular mechanisms supporting endothelium damage of syphilis are undefined. The outer membrane proteins were thought to be involved. Tp92 was first identified as an outer membrane protein of T. pallidum. Homologous proteins to Tp92 play important roles in cell attachment, inflammation, and tissue destruction in other bacterial species. In this study, we investigated the effect of Tp92 on endothelial cells activation. The data showed that Tp92 induced chemerin production in activated endothelial cells. Endothelial cell-derived chemerin upregulated the expression of TNF-α and ICAM-1 in endothelial cells via CMKLR1. In addition, endothelial cell-derived chemerin promoted THP-1-derived macrophage migration towards endothelial cells. These findings suggest that Tp92 may play an important role in mediating endothelial cell activation by inducing the secretion of chemerin.


Assuntos
Antígenos de Superfície/imunologia , Proteínas de Bactérias/imunologia , Quimiocinas/imunologia , Células Endoteliais/imunologia , Receptores de Quimiocinas/imunologia , Transdução de Sinais , Antígenos de Superfície/genética , Proteínas de Bactérias/genética , Movimento Celular , Humanos , Molécula 1 de Adesão Intercelular/imunologia , Células THP-1 , Treponema pallidum , Fator de Necrose Tumoral alfa/imunologia
19.
Parasite Immunol ; 42(5): e12704, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32049381

RESUMO

Myeloid-derived suppressor cells (MDSCs) are heterogeneous population of monocyte and granulocyte progenitors that are highly suppressive against T cells. In BALB/c mice infected with a nematode Heligmosomoides polygyrus bakeri, we studied the dynamics of MDSCs, identified as CD11b+Gr-1+, induction in different tissues along with the development of parasite infection. We observed that MDSC-like cells are induced both by larvae and adult stages of H polygyrus bakeri. Gr-1+ cells of suppressive phenotype are recruited in the bone marrow, peripheral blood and peritoneal cavity during histotropic phase of infection and are present at that time in the intestine wall, where worms reside. Later, during intestinal phase, suppressive Gr-1+ cells increased in mesenteric lymph nodes and the spleen. l-arginine metabolism was important for the protective immunity, and parasite-induced Gr-1+ cells showed elevated arginase-1 and iNOS expression. Inhibition of arginase-1 and l-arginine administration caused reduced level of infection that coincided with weaker suppressive phenotype of Gr-1+ cells. We identified that l-arginine pathway activation and induction of MDSC-like cells characterize immunosuppressive state during H polygyrus bakeri infection in mice. Our findings confirm the role of MDSCs in parasitic infections and point l-arginine pathway as a potential target for immunomodulation during nematode infections.


Assuntos
Arginina/imunologia , Antígeno CD11b/imunologia , Monócitos/imunologia , Nematospiroides dubius/imunologia , Receptores de Quimiocinas/imunologia , Infecções por Strongylida/imunologia , Animais , Antígeno CD11b/genética , Feminino , Humanos , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/parasitologia , Nematospiroides dubius/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Receptores de Quimiocinas/genética , Baço/imunologia , Infecções por Strongylida/genética , Infecções por Strongylida/parasitologia
20.
Viruses ; 12(1)2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31963276

RESUMO

Herpes simplex viruses not only infect a variety of different cell types, including dendritic cells (DCs), but also modulate important cellular functions in benefit of the virus. Given the relevance of directed immune cell migration during the initiation of potent antiviral immune responses, interference with DC migration constitutes a sophisticated strategy to hamper antiviral immunity. Notably, recent reports revealed that HSV-1 significantly inhibits DC migration in vitro. Thus, we aimed to investigate whether HSV-2 also modulates distinct hallmarks of DC biology. Here, we demonstrate that HSV-2 negatively interferes with chemokine-dependent in vitro migration capacity of mature DCs (mDCs). Interestingly, rather than mediating the reduction of the cognate chemokine receptor expression early during infection, HSV-2 rapidly induces ß2 integrin (LFA-1)-mediated mDC adhesion and thereby blocks mDC migration. Mechanistically, HSV-2 triggers the proteasomal degradation of the negative regulator of ß2 integrin activity, CYTIP, which causes the constitutive activation of LFA-1 and thus mDC adhesion. In conclusion, our data extend and strengthen recent findings reporting the reduction of mDC migration in the context of a herpesviral infection. We thus hypothesize that hampering antigen delivery to secondary lymphoid organs by inhibition of mDC migration is an evolutionary conserved strategy among distinct members of Herpesviridae.


Assuntos
Movimento Celular , Células Dendríticas/patologia , Células Dendríticas/virologia , Herpesvirus Humano 2/patogenicidade , Adesão Celular , Células Cultivadas , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Herpesvirus Humano 2/imunologia , Humanos , Antígeno-1 Associado à Função Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Proteínas Virais/genética
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