RESUMO
Establishing a nonproductive, quiescent infection within monocytes is essential for the spread of human cytomegalovirus (HCMV). We investigated the mechanisms through which HCMV establishes a quiescent infection in monocytes. US28 is a virally encoded G protein-coupled receptor (GPCR) that is essential for silent infections within cells of the myeloid lineage. We found that preformed US28 was rapidly delivered to monocytes by HCMV viral particles, whereas the de novo synthesis of US28 was delayed for several days. A recombinant mutant virus lacking US28 (US28Δ) was unable to establish a quiescent infection, resulting in a fully productive lytic infection able to produce progeny virus. Infection with US28Δ HCMV resulted in the phosphorylation of the serine and threonine kinase Akt at Ser473 and Thr308, in contrast with the phosphorylation of Akt only at Ser473 after WT viral infection. Inhibiting the dual phosphorylation of Akt prevented the lytic replication of US28Δ, and ectopic expression of a constitutively phosphorylated Akt variant triggered lytic replication of wild-type HCMV. Mechanistically, we found that US28 was necessary and sufficient to attenuate epidermal growth factor receptor (EGFR) signaling induced during the entry of WT virus, which led to the site-specific phosphorylation of Akt at Ser473. Thus, particle-delivered US28 fine-tunes Akt activity by limiting HCMV-induced EGFR activation during viral entry, enabling quiescent infection in monocytes.
Assuntos
Citomegalovirus , Receptores ErbB , Monócitos , Proteínas Proto-Oncogênicas c-akt , Proteínas Virais , Replicação Viral , Citomegalovirus/fisiologia , Citomegalovirus/genética , Citomegalovirus/metabolismo , Humanos , Monócitos/virologia , Monócitos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Fosforilação , Proteínas Virais/metabolismo , Proteínas Virais/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Vírion/metabolismo , Vírion/genética , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/genética , Transdução de SinaisRESUMO
Converging evidence indicates that extra-embryonic yolk sac is the source of both macrophages and endothelial cells in adult mouse tissues. Prevailing views are that these embryonically derived cells are maintained after birth by proliferative self-renewal in their differentiated states. Here we identify clonogenic endothelial-macrophage (EndoMac) progenitor cells in the adventitia of embryonic and postnatal mouse aorta, that are independent of Flt3-mediated bone marrow hematopoiesis and derive from an early embryonic CX3CR1+ and CSF1R+ source. These bipotent progenitors are proliferative and vasculogenic, contributing to adventitial neovascularization and formation of perfused blood vessels after transfer into ischemic tissue. We establish a regulatory role for angiotensin II, which enhances their clonogenic and differentiation properties and rapidly stimulates their proliferative expansion in vivo. Our findings demonstrate that embryonically derived EndoMac progenitors participate in local vasculogenic responses in the aortic wall by contributing to the expansion of endothelial cells and macrophages postnatally.
Assuntos
Aorta , Macrófagos , Animais , Macrófagos/citologia , Macrófagos/metabolismo , Aorta/citologia , Camundongos , Receptor 1 de Quimiocina CX3C/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Diferenciação Celular , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Angiotensina II , Proliferação de Células , Células-Tronco/citologia , Células-Tronco/metabolismo , Camundongos Endogâmicos C57BL , Feminino , Neovascularização Fisiológica , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Masculino , Hematopoese/fisiologia , Tirosina Quinase 3 Semelhante a fmsRESUMO
Embryonic mortality is a significant problem in the commercial duck industry worldwide. Therefore, identification of new biomarkers for duck embryo development is necessary. In the chicken (order Galliformes), we previously showed that chemerin is a hormone locally produced by the reproductive tract in hens, particularly in the magnum area, leading to its accumulation in the egg white and within the embryo annexes during embryonic development. We therefore hypothesized that the chemerin concentration in egg white could be a biomarker of egg performance and reproductive parameters in Pekin ducks (order Anseriformes). Thus, we collected eggs from Pekin ducks over a 5-d period at three stages of the laying period (before the laying peak, after the laying peak, and at the end of the laying period) to measure the chemerin concentrations in egg white by enzyme-linked immunosorbent assay. The chemerin concentration in egg white decreased during the laying period and was not associated with reproductive parameters. We found negative correlations between the chemerin level in egg white and the albumen weight. Reverse-transcriptase quantitative polymerase chain reaction showed that chemerin and its three receptors CMKLR1, GPR1, and CCRL2 were expressed in the reproductive tract and within allantoic and amniotic annexes during embryo development. Chemerin concentrations strongly increased in amniotic fluid on embryonic day 16 (ED16) when the egg white was transferred into the amniotic sac. Finally, chemerin inhibition in egg white by in ovo injections of anti-chemerin antibodies (0.01, 0.1, and 1 µg) increased the embryo mortality rate. These data demonstrate the important role of the chemerin system during egg formation and embryo development in Pekin ducks, suggesting their potential use as biomarkers for determining the quality of poultry eggs and embryo development.
Assuntos
Proteínas Aviárias , Quimiocinas , Patos , Desenvolvimento Embrionário , Animais , Patos/embriologia , Patos/metabolismo , Patos/crescimento & desenvolvimento , Quimiocinas/metabolismo , Quimiocinas/genética , Feminino , Proteínas Aviárias/metabolismo , Proteínas Aviárias/genética , Clara de Ovo/química , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Biomarcadores/metabolismoRESUMO
Chemokine receptors are integral to the immune system and prime targets in drug discovery that have undergone extensive structural elucidation in recent years. We outline a timeline of these structural achievements, discuss the intracellular negative allosteric modulation of chemokine receptors, analyze the mechanisms of orthosteric receptor activation, and report on the emerging concept of biased signaling. Additionally, we highlight differences of G-protein binding among chemokine receptors. Intracellular allosteric modulators in chemokine receptors interact with a conserved motif within transmembrane helix 7 and helix 8 and exhibit a two-fold inactivation mechanism that can be harnessed for drug-discovery efforts. Chemokine recognition is a multi-step process traditionally explained by a two-site model within chemokine recognition site 1 (CRS1) and CRS2. Recent structural studies have extended our understanding of this complex mechanism with the identification of CRS1.5 and CRS3. CRS3 is implicated in determining ligand specificity and surrounds the chemokine by almost 180°. Within CRS3 we identified the extracellular loop 2 residue 45.51 as a key interaction mediator for chemokine binding. Y2917.43 on the other hand was shown in CCR1 to be a key determinant of signaling bias which, along with specific chemokine-dependent phosphorylation ensembles at the G-protein coupled receptors (GPCR's) C-terminus, seems to play a pivotal role in determining the direction of signal bias in GPCRs.
Assuntos
Receptores de Quimiocinas , Transdução de Sinais , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/química , Humanos , Quimiocinas/metabolismo , Quimiocinas/química , Ligação Proteica , Regulação Alostérica , Modelos Moleculares , Animais , Sítios de Ligação , Conformação Proteica , LigantesRESUMO
As a multifunctional adipokine, chemerin plays a crucial role in various pathophysiological processes through endocrine and paracrine manner. It can bind to three known receptors (ChemR23, GPR1 and CCRL2) and participate in energy metabolism, glucose and lipid metabolism, and inflammation, especially in metabolic diseases. Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases, which seriously affects the normal life of women of childbearing age. Patients with PCOS have significantly increased serum levels of chemerin and high expression of chemerin in their ovaries. More and more studies have shown that chemerin is involved in the occurrence and development of PCOS by affecting obesity, insulin resistance, hyperandrogenism, oxidative stress and inflammatory response. This article mainly reviews the production, subtypes, function and receptors of chemerin protein, summarizes and discusses the research status of chemerin protein in PCOS from the perspectives of metabolism, reproduction and inflammation, and provides theoretical basis and reference for the clinical diagnosis and treatment of PCOS.
Assuntos
Quimiocinas , Peptídeos e Proteínas de Sinalização Intercelular , Síndrome do Ovário Policístico , Síndrome do Ovário Policístico/metabolismo , Humanos , Quimiocinas/metabolismo , Feminino , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Receptores de Quimiocinas/metabolismo , Resistência à Insulina , Animais , Receptores Acoplados a Proteínas G/metabolismo , Fatores Quimiotáticos/metabolismoRESUMO
Age-related inflammation or inflammaging is a critical deciding factor of physiological homeostasis during aging. Cardiovascular diseases (CVDs) are exquisitely associated with aging and inflammation and are one of the leading causes of high mortality in the elderly population. Inflammaging comprises dysregulation of crosstalk between the vascular and cardiac tissues that deteriorates the vasculature network leading to development of atherosclerosis and atherosclerotic-associated CVDs in elderly populations. Leukocyte differentiation, migration and recruitment holds a crucial position in both inflammaging and atherosclerotic CVDs through relaying the activity of an intricate network of inflammation-associated protein-protein interactions. Among these interactions, small immunoproteins such as chemokines play a major role in the progression of inflammaging and atherosclerosis. Chemokines are actively involved in lymphocyte migration and severe inflammatory response at the site of injury. They relay their functions via chemokine-G protein-coupled receptors-glycosaminoglycan signaling axis and is a principal part for the detection of age-related atherosclerosis and related CVDs. This review focuses on highlighting the detailed intricacies of the effects of chemokine-receptor interaction and chemokine oligomerization on lymphocyte recruitment and its evident role in clinical manifestations of atherosclerosis and related CVDs. Further, the role of chemokine mediated signaling for formulating next-generation therapeutics against atherosclerosis has also been discussed.
Assuntos
Envelhecimento , Aterosclerose , Quimiocinas , Inflamação , Humanos , Aterosclerose/metabolismo , Aterosclerose/imunologia , Envelhecimento/metabolismo , Envelhecimento/imunologia , Inflamação/metabolismo , Inflamação/imunologia , Quimiocinas/metabolismo , Animais , Transdução de Sinais , Receptores de Quimiocinas/metabolismoRESUMO
Conventional type 1 dendritic cells (cDC1) are the essential antigen-presenting DC subset in antitumor immunity. Suppressing B-cell lymphoma 9 and B-cell lymphoma 9-like (BCL9/BCL9L) inhibits tumor growth and boosts immune responses against cancer. However, whether oncogenic BCL9/BCL9L impairs antigen presentation in tumors is still not completely understood. Here, we show that targeting BCL9/BCL9L enhanced antigen presentation by stimulating cDC1 activation and infiltration into tumor. Pharmacological inhibition of BCL9/BCL9L with a novel inhibitor hsBCL9z96 or Bcl9/Bcl9l knockout mice markedly delayed tumor growth and promoted antitumor CD8+ T cell responses. Mechanistically, targeting BCL9/BCL9L promoted antigen presentation in tumors. This is due to the increase of cDC1 activation and tumor infiltration by the XCL1-XCR1 axis. Importantly, using single-cell transcriptomics analysis, we found that Bcl9/Bcl9l deficient cDC1 were superior to wild-type (WT) cDC1 at activation and antigen presentation via NF-κB/IRF1 signaling. Together, we demonstrate that targeting BCL9/BCL9L plays a crucial role in cDC1-modulated antigen presentation of tumor-derived antigens, as well as CD8+ T cell activation and tumor infiltration. Targeting BCL9/BCL9L to regulate cDC1 function and directly orchestrate a positive feedback loop necessary for optimal antitumor immunity could serve as a potential strategy to counter immune suppression and enhance cancer immunotherapy.
Assuntos
Apresentação de Antígeno , Células Dendríticas , Animais , Humanos , Camundongos , Apresentação de Antígeno/imunologia , Apresentação de Antígeno/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/genética , Neoplasias/patologia , Receptores de Quimiocinas , Fatores de Transcrição/genética , Fatores de Transcrição/imunologiaRESUMO
AlphaFold and AlphaFold-Multimer have become two essential tools for the modeling of unknown structures of proteins and protein complexes. In this work, we extensively benchmarked the quality of chemokine-chemokine receptor structures generated by AlphaFold-Multimer against experimentally determined structures. Our analysis considered both the global quality of the model, as well as key structural features for chemokine recognition. To study the effects of template and multiple sequence alignment parameters on the results, a new prediction pipeline called LIT-AlphaFold (https://github.com/LIT-CCM-lab/LIT-AlphaFold) was developed, allowing extensive input customization. AlphaFold-Multimer correctly predicted differences in chemokine binding orientation and accurately reproduced the unique binding orientation of the CXCL12-ACKR3 complex. Further, the predictions of the full receptor N-terminus provided insights into a putative chemokine recognition site 0.5. The accuracy of chemokine N-terminus binding mode prediction varied between complexes, but the confidence score permitted the distinguishing of residues that were very likely well positioned. Finally, we generated a high-confidence model of the unsolved CXCL12-CXCR4 complex, which agreed with experimental mutagenesis and cross-linking data.
Assuntos
Benchmarking , Quimiocinas , Modelos Moleculares , Conformação Proteica , Quimiocinas/metabolismo , Quimiocinas/química , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/química , Ligação Proteica , Humanos , Sequência de AminoácidosRESUMO
BACKGROUND: The clinical significance and comprehensive characteristics of chemokines and chemokine receptors in colorectal cancer (CRC) have not been previously reported. Our study aims to investigate the expression profiles of chemokines and chemokine receptors, as well as establish subtypes in CRC. METHODS: 1009 CRC samples were enrolled in our study. Consensus unsupervised clustering analysis was conducted to establish subtypes, and a risk score model was developed using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analyses. 36 pairs of tissue specimens of CRC patients and two CRC cell lines were used to validate the subtypes and risk score in vitro. Quantitative real-time PCR and western blotting were employed to validate mRNA and protein expression levels, respectively. Flow cytometry was utilized for analyzing cell apoptosis, while cell viability assay and EdU assay were conducted to assess cell proliferation ability. RESULTS: The Cluster B group shares similarities with the low-risk group in terms of exhibiting a higher level of immune cell infiltration and belonging to hot tumor. Patients CRC in the Cluster B group demonstrate a more favorable prognosis and exhibit better response to immunotherapy and chemotherapy. On the other hand, the Cluster A group resembles the high-risk group as it displays lower levels of immune cell infiltration, indicating a cold tumor phenotype. CRC patients in the Cluster A group have poorer prognoses and show less therapeutic efficacy towards immunotherapy and chemotherapy. Furthermore, we utilized a total of 36 pairs of tissue samples obtained from patients with CRC, along with two CRC cell lines for validation in vitro. This comprehensive approach further enhances the scientific validity and reliability of the identified subtypes and risk score in their ability to predict prognosis, response to immunotherapy, and response to chemotherapy among CRC patients. CONCLUSION: We first established robust prognostic subtypes based on chemokines and chemokine receptors, which could potentially serve as a novel biomarker for guiding individualized treatment in patients with CRC undergoing immunotherapy and chemotherapy.
Assuntos
Quimiocinas , Neoplasias Colorretais , Imunoterapia , Receptores de Quimiocinas , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapia , Imunoterapia/métodos , Prognóstico , Feminino , Masculino , Quimiocinas/metabolismo , Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Idoso , Regulação Neoplásica da Expressão Gênica , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacosRESUMO
It is known that stress influences immune cell function. The underlying molecular mechanisms are unclear. We recently reported that many chemokine receptors (CRs) heteromerize with α1-adrenoceptors (α1-ARs) through which CRs are regulated. Here, we show that arginine vasopressin receptor 1A (AVPR1A) heteromerizes with all human CRs, except chemokine (C-X-C motif) receptor (CXCR)1, in recombinant systems and that such heteromers are detectable in THP-1 cells and human monocytes. We demonstrate that ligand-free AVPR1A differentially regulates the efficacy of CR partners to mediate chemotaxis and that AVPR1A ligands disrupt AVPR1A:CR heteromers, which enhances chemokine (C-C motif) receptor (CCR)1-mediated chemotaxis and inhibits CCR2-, CCR8-, and CXCR4-mediated chemotaxis. Using bioluminescence resonance energy transfer to monitor G protein activation and CRISPR/Cas9 gene-edited THP-1 cells lacking AVPR1A or α1B-AR, we show that CRs that share the propensity to heteromerize with α1B/D-ARs and AVPR1A exist and function within interdependent hetero-oligomeric complexes through which the efficacy of CRs to mediate chemotaxis is controlled. Our findings suggest that hetero-oligomers composed of CRs, α1B/D-ARs, and AVPR1A may enable stress hormones to regulate immune cell trafficking.
Assuntos
Quimiotaxia , Monócitos , Receptores de Quimiocinas , Receptores de Vasopressinas , Humanos , Monócitos/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Receptores de Vasopressinas/metabolismo , Receptores de Vasopressinas/genética , Células THP-1 , Multimerização Proteica , Células HEK293 , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Sistemas CRISPR-Cas , Transdução de Sinais , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 1/genética , LigantesRESUMO
Chemokine receptors are important components of cellular signaling and play a critical role in directing leukocytes during inflammatory reactions. Their importance extends to numerous pathological processes, including tumor differentiation, angiogenesis, metastasis, and associations with multiple inflammatory disorders. The necessity to monitor the in vivo interactions of cellular chemokine receptors has been driven the recent development of novel positron emission tomography (PET) imaging agents. This imaging modality provides non-invasive localization and quantitation of these receptors that cannot be provided through blood or tissue-based assays. Herein, we provide a review of PET imaging of the chemokine receptors that have been imaged to date, namely CXCR3, CXCR4, CCR2, CCR5, and CMKLR1. The quantification of these receptors can aid in understanding various diseases, including cancer, atherosclerosis, idiopathic pulmonary fibrosis, and acute respiratory distress syndrome. The development of specific radiotracers targeting these receptors will be discussed, including promising results for disease diagnosis and management. However, challenges persist in fully translating these imaging advancements into practical therapeutic applications. Given the success of CXCR4 PET imaging to date, future research should focus on clinical translation of these approaches to understand their role in the management of a wide variety of diseases.
Assuntos
Tomografia por Emissão de Pósitrons , Receptores de Quimiocinas , Humanos , Tomografia por Emissão de Pósitrons/métodos , Animais , Receptores de Quimiocinas/metabolismoRESUMO
Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as α4ß7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-α, interferon (IFN)-α, IFN-ß, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-ß receptor pathway, and nuclear factor-κB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS.
Assuntos
Quimiocinas , Síndrome de Sjogren , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Humanos , Quimiocinas/metabolismo , Quimiocinas/imunologia , Transdução de Sinais , Animais , Receptores de Retorno de Linfócitos/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/imunologiaRESUMO
Chemokine receptors are relevant targets for a multitude of immunological diseases, but drug attrition for these receptors is remarkably high. While many drug discovery programs have been pursued, most prospective drugs failed in the follow-up studies due to clinical inefficacy, and hence there is a clear need for alternative approaches. Allosteric modulators of receptor function represent an excellent opportunity for novel drugs, as they modulate receptor activation in a controlled manner and display increased selectivity, and their pharmacological profile can be insurmountable. Here, we discuss allosteric ligands and their pharmacological characterization for modulation of chemokine receptors. Ligands are included if (1) they show clear signs of allosteric modulation in vitro and (2) display evidence of binding in a topologically distinct manner compared to endogenous chemokines. We discuss how allosteric ligands affect binding of orthosteric (endogenous) ligands in terms of affinity as well as binding kinetics in radioligand binding assays. Moreover, their effects on signaling events in functional assays and how their binding site can be elucidated are specified. We substantiate this with examples of published allosteric ligands targeting chemokine receptors and hypothetical graphs of pharmacological behavior. This review should serve as an effective starting point for setting up assays for characterizing allosteric ligands to develop safer and more efficacious drugs for chemokine receptors and, ultimately, other G protein-coupled receptors.
Assuntos
Receptores de Quimiocinas , Humanos , Receptores de Quimiocinas/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , LigantesRESUMO
Adult neurogenesis continues throughout life but declines dramatically with age and in neurodegenerative disorders such as Alzheimer's disease. In parallel, microglia become activated resulting in chronic inflammation in the aged brain. A unique type of microglia, suggested to support neurogenesis, exists in the subventricular zone (SVZ), but little is known how they are affected by aging. We analyzed the transcriptome of aging microglia and identified a unique neuroprotective activation profile in aged SVZ microglia, which is partly shared with disease-associated microglia (DAM). CX3C motif chemokine receptor 1 (CX3CR1) is characteristically expressed by brain microglia where it directs migration to targets for phagocytosis. We show that Cx3cr1 expression, as in DAM, is downregulated in old SVZ microglia and that heterozygous Cx3cr1 mice have increased proliferation and neuroblast number in the aged SVZ but not in the dentate gyrus, identifying CX3CR1 signaling as a novel age and brain region-specific regulator of neurogenesis.
Assuntos
Envelhecimento , Receptor 1 de Quimiocina CX3C , Microglia , Neurogênese , Animais , Camundongos , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Encéfalo/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Neurogênese/fisiologia , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Ativação Transcricional/fisiologia , HumanosRESUMO
Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, is largely incurable in the metastatic setting. ccRCC is characterized by excessive lipid accumulation that protects cells from stress and promotes tumor growth, suggesting that the underlying regulators of lipid storage could represent potential therapeutic targets. Here, we evaluated the regulatory roles of GPR1 and CMKLR1, two G protein-coupled receptors of the protumorigenic adipokine chemerin that is involved in ccRCC lipid metabolism. Both genetic and pharmacologic suppression of either receptor suppressed lipid formation and induced multiple forms of cell death, including apoptosis, ferroptosis, and autophagy, thereby significantly impeding ccRCC growth in cell lines and patient-derived xenograft models. Comprehensive lipidomic and transcriptomic profiling of receptor competent and depleted cells revealed overlapping and unique signaling of the receptors granting control over triglyceride synthesis, ceramide production, and fatty acid saturation and class production. Mechanistically, both receptors enforced suppression of adipose triglyceride lipase, but each receptor also demonstrated distinct functions, such as the unique ability of CMKLR1 to control lipid uptake through regulation of sterol regulatory element-binding protein 1c and the CD36 scavenger receptor. Treating patient-derived xenograft models with the CMKLR1-targeting small molecule 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) led to a dramatic reduction in tumor growth, lipid storage, and clear-cell morphology. Together, these findings provide mechanistic insights into lipid regulation in ccRCC and identify a targetable axis at the core of the histologic definition of this tumor that could be exploited therapeutically. Significance: Extracellular control of lipid accumulation via G protein receptor-mediated cell signaling is a metabolic vulnerability in clear cell renal cell carcinoma, which depends on lipid storage to avoid oxidative toxicity.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Metabolismo dos Lipídeos , Receptores de Quimiocinas , Receptores Acoplados a Proteínas G , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/genética , Animais , Camundongos , Receptores de Quimiocinas/metabolismo , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Apoptose , Proliferação de Células , Transdução de SinaisRESUMO
Esophageal carcinoma (ESCA) is an aggressive solid tumor. The 5-year survival rate for patients with ESCA is estimated to be less than 20%, mainly due to tumor invasion and metastasis. Therefore, it is urgent to improve early diagnostic tools and effective treatments for ESCA patients. Tumor microenvironment (TME) enhances the ability of tumor cells to proliferate, migrate, and escape from the immune system, thus promoting the occurrence and development of tumor. TME contains chemokines. Chemokines consist of four major families, which are mainly composed of CC and CXC families. The main purpose of this review is to understand the CC and CXC chemokines and their receptors in ESCA, to improve the understanding of tumorigenesis of ESCA and determine new biomarkers for the diagnosis and prognosis of ESCA. We reviewed the literature on CC and CXC chemokines and their receptors in ESCA identified by PubMed database. This article introduces the general structures and functions of CC, CXC chemokines and their receptors in TME, as well as their roles in the progress of ESCA. Chemokines are involved in the development of ESCA, such as cancer cell invasion, metastasis, angiogenesis, and radioresistance, and are key determinants of disease progression, which have a great impact on patient prognosis and treatment response. In addition, a full understanding of their mechanism of action is essential to further verify that these chemokines and their receptors may serve as biomarkers or therapeutic targets of ESCA.
Assuntos
Quimiocinas , Neoplasias Esofágicas , Microambiente Tumoral , Humanos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/imunologia , Quimiocinas/metabolismo , Receptores de Quimiocinas/metabolismo , Biomarcadores Tumorais/metabolismo , PrognósticoRESUMO
The adipokines, visfatin, chemerin, and its receptor are expressed in the testis. It has also been shown that heat-stress alters the secretion and expression of other adipokines. Testicular heat-stress is now well known to cause the impairment in the testis. It has also been documented that heat-stress changes the expression of genes and proteins in the testis. To the best of our knowledge, the expression and localization of visfatin chemerin and its receptor have not been investigated in the heat-stressed testis. Therefore, the present study has investigated the expression and localization of these proteins in the heat-stressed testis. The expression of visfatin and chemerin and receptor exhibits a differential repossess against the heat stress. Visfatin expression was up-regulated while chemerin and chemerin receptor was down-regulated in the heat-stressed testis as shown by western blot analysis. The immunolocalization of visfatin and chemerin showed increased abundance in the seminiferous tubules of heat-stressed mice testis. Furthermore, abundance of visfatin, chemerin, and its receptor showed a decrease in abundance in the Leydig cells of heat-stressed testis. The decreased abundance of these proteins in the Leydig cells coincides with decreased 3ß-HSD immunostaining along with decreased testosterone levels. These results suggest that heat-stress might decrease testosterone secretion by modulating visfatin and chemerin in the Leydig cells. The increased abundance of visfatin and chemerin in the primary spermatocytes, round spermatid, and multinucleated germ cells also coincides with increased immunostaining of active caspase-3. Moreover, expression of Bcl-2 was down-regulated, and expression of active caspase-3 and HSP70 were up-regulated along with increased oxidative stress in the heat-stressed testis, suggesting stimulated apoptosis. In conclusion, our results showed that visfatin, chemerin, and its receptor are differentially expressed in the testis under heat-stress and within the testis also it might differentially regulate testosterone biosynthesis in the Leydig cells and apoptosis in the seminiferous tubules.
Assuntos
Quimiocinas , Resposta ao Choque Térmico , Nicotinamida Fosforribosiltransferase , Receptores de Quimiocinas , Testículo , Masculino , Animais , Camundongos , Quimiocinas/metabolismo , Testículo/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Células Intersticiais do Testículo/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Caspase 3/metabolismoRESUMO
Enterococci are common commensal bacteria that colonize the gastrointestinal tracts of most mammals, including humans. Importantly, these bacteria are one of the leading causes of nosocomial infections. This study examined the role of colonic macrophages in facilitating Enterococcus faecalis infections in mice. We determined that depletion of colonic phagocytes resulted in the reduction of E. faecalis dissemination to the gut-draining mesenteric lymph nodes. Furthermore, we established that trafficking of monocyte-derived CX3CR1-expressing macrophages contributed to E. faecalis dissemination in a manner that was not reliant on CCR7, the conventional receptor involved in lymphatic migration. Finally, we showed that E. faecalis mutants with impaired intracellular survival exhibited reduced dissemination, suggesting that E. faecalis can exploit host immune cell migration to disseminate systemically and cause disease. Our findings indicate that modulation of macrophage trafficking in the context of antibiotic therapy could serve as a novel approach for preventing or treating opportunistic infections by disseminating enteric pathobionts like E. faecalis.
Assuntos
Receptor 1 de Quimiocina CX3C , Colo , Enterococcus faecalis , Macrófagos , Receptores CCR2 , Receptores de Quimiocinas , Animais , Receptor 1 de Quimiocina CX3C/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Macrófagos/microbiologia , Macrófagos/imunologia , Camundongos , Colo/microbiologia , Colo/imunologia , Receptores CCR2/metabolismo , Receptores CCR2/genética , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Infecções por Bactérias Gram-Positivas/imunologia , Infecções por Bactérias Gram-Positivas/microbiologia , Camundongos Endogâmicos C57BL , Linfonodos/microbiologia , Linfonodos/imunologia , Receptores CCR7/metabolismo , Receptores CCR7/genéticaRESUMO
OBJECTIVE: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by significant difficulties in social interaction, communication, and repeated stereotypic behaviour. Aflatoxin B1 (AFB1) is the most potent and well-known mycotoxin in various food sources. Despite its propensity to generate significant biochemical and structural changes in human and animal tissues, the influence of AFB1 on ASD has yet to be thoroughly studied. Mounting evidence indicates that chemokine receptors play a crucial function in the central nervous system and are implicated in developing several neuroinflammatory disorders. Chemokine receptors in individuals with ASD were elevated in the anterior cingulate gyrus astrocytes, cerebellum, and brain. METHODS: The BTBR T+Itpr3tf/J (BTBR) mice are inbred strains that exhibit strong and consistently observed deficits in social interactions, characterized by excessive self-grooming and limited vocalization in social contexts. We examined the impact of AFB1 on CCR3-, CCR7-, CCR9-, CXCR3-, CXCR4-, and CXCR6-expressing I-A/I-E+ cells in the spleen of the BTBR mouse model of autism. We evaluated the mRNA levels of CCR3, CCR7, CCR9, CXCR3, CXCR4, and CXCR6 chemokine receptors in the brain. RESULTS: The exposure to AFB1 in BTBR mice resulted in a significant rise in the number of I-A/I-E+CCR3+, I-A/I-E+CCR7+, I-A/I-E+CCR9+, I-A/I-E+CXCR3+, I-A/I-E+CXCR4+, and I-A/I-E+CXCR6+ cells. Furthermore, exposure to AFB1 increased mRNA expression levels of CCR3, CCR7, CCR9, CXCR3, CXCR4, and CXCR6 in the brain. CONCLUSIONS: These findings highlight that AFB1 exposure increases the expression of chemokine receptors in BTBR mice, indicating the necessity for further research into AFB1's role in the development of ASD.
Assuntos
Aflatoxina B1 , Transtorno do Espectro Autista , Encéfalo , Modelos Animais de Doenças , Baço , Animais , Transtorno do Espectro Autista/induzido quimicamente , Aflatoxina B1/toxicidade , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/metabolismo , Masculino , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Camundongos , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismoRESUMO
Over the past few decades, significant strides have been made in understanding the pivotal roles that chemokine networks play in tumor biology. These networks, comprising chemokines and their receptors, wield substantial influence over cancer immune regulation and therapeutic outcomes. As a result, targeting these chemokine systems has emerged as a promising avenue for cancer immunotherapy. However, therapies targeting chemokines face significant challenges in solid tumor treatment, due to the complex and fragile of the chemokine networks. A nuanced comprehension of the complicacy and functions of chemokine networks, and their impact on the tumor microenvironment, is essential for optimizing their therapeutic utility in oncology. This review elucidates the ways in which chemokine networks interact with cancer immunity and tumorigenesis. We particularly elaborate on recent innovations in manipulating these networks for cancer treatment. The review also highlights future challenges and explores potential biomaterial strategies for clinical applications.