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1.
Adv Exp Med Biol ; 1231: 33-43, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32060844

RESUMO

The tumor microenvironment is the primary location in which tumor cells and the host immune system interact. There are many physiological, biochemical, cellular mechanisms in the neighbor of tumor which is composed of various cell types. Interactions of chemokines and chemokine receptors can recruit immune cell subsets into the tumor microenvironment. These interactions can modulate tumor progression and metastasis. In this chapter, we will focus on chemokine (C-C motif) ligand 7 (CCL7) that is highly expressed in the tumor microenvironment of various cancers, including colorectal cancer, breast cancer, oral cancer, renal cancer, and gastric cancer. We reviewed how CCL7 can affect cancer immunity and tumorigenesis by describing its regulation and roles in immune cell recruitment and stromal cell biology.


Assuntos
Quimiocina CCL7/imunologia , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia , Animais , Carcinogênese/imunologia , Humanos , Receptores de Quimiocinas/metabolismo
2.
Expert Opin Drug Metab Toxicol ; 16(1): 11-30, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31903790

RESUMO

Introduction: Chemokine receptors are important therapeutic targets for the treatment of many human diseases. This study will provide an overview of approved chemokine receptor antagonists and promising candidates in advanced clinical trials.Areas covered: We will describe clinical aspects of chemokine receptor antagonists regarding their clinical efficacy, mechanisms of action, and re-purposed applications.Expert opinion: Three chemokine antagonists have been approved: (i) plerixafor is a small-molecule CXCR4 antagonist that mobilizes hematopoietic stem cells; (ii) maraviroc is a small-molecule CCR5 antagonist for anti-HIV treatment; and (iii) mogamulizumab is a monoclonal-antibody CCR4 antagonist for the treatment of mycosis fungoides or Sézary syndrome. Moreover, phase 3 trials are ongoing to evaluate many potent candidates, including CCR5 antagonists (e.g. leronlimab), dual CCR2/CCR5 antagonists (e.g. cenicriviroc), and CXCR4 antagonists (e.g. balixafortide, mavorixafor, motixafortide). The success of chemokine receptor antagonists depends on the selective blockage of disease-relevant chemokine receptors which are indispensable for disease progression. Although clinical translation has been slow, antagonists targeting chemokine receptors with multifaced functions offer the potential to treat a broad spectrum of human diseases.


Assuntos
Desenvolvimento de Medicamentos , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Humanos , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Receptores CCR4/antagonistas & inibidores , Receptores CCR4/metabolismo , Receptores CCR5/efeitos dos fármacos , Receptores CCR5/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/metabolismo , Receptores de Quimiocinas/metabolismo
3.
Life Sci ; 231: 116688, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31348950

RESUMO

The extended infection with Helicobacter pylori (H. pylori), one of the most frequent infectious agents in humans, may cause gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. During H. pylori infection, different kinds of inflammatory cells such as dendritic cells, macrophages, neutrophils, mast cells, eosinophils, T cells and B cells are accumulated into the stomach. The interactions between chemokines and their respective receptors recruit particular types of the leukocytes that ultimately determine the nature of immune response and therefore, have a main influence on the consequence of infection. The suitable production of chemokines especially in the early stages of H. pylori infection shapes appropriate immune responses that contribute to the H. pylori elimination. The unbalanced expression of the chemokines can contribute in the induction of inappropriate responses that result in the tissue damage or malignancy. Thus, chemokines and their receptors may be promising potential targets for designing the therapeutic strategies against various types H. pylori-related gastrointestinal disorders. In this review, a comprehensive explanation regarding the roles played by chemokines in H. pylori-mediated peptic ulcer, gastritis and gastric malignancies was provided while presenting the potential utilization of these chemoattractants as therapeutic elements.


Assuntos
Quimiocinas/metabolismo , Quimiocinas/farmacologia , Infecções por Helicobacter/terapia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Quimiocinas CXC/imunologia , Quimiocinas CXC/metabolismo , Mucosa Gástrica/metabolismo , Gastrite , Infecções por Helicobacter/complicações , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Helicobacter pylori/metabolismo , Helicobacter pylori/patogenicidade , Humanos , Receptores CXCR/imunologia , Receptores CXCR/metabolismo , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Estômago/patologia , Neoplasias Gástricas/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
4.
Immunology ; 157(3): 232-247, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31087644

RESUMO

Regulatory T (Treg) cells play a crucial role in maintaining self-tolerance and resolution of immune responses by employing multifaceted immunoregulatory mechanisms. However, Treg cells readily infiltrate into the tumor microenvironment (TME) and dampen anti-tumor immune responses, thereby becoming a barrier to effective cancer immunotherapy. There has been a substantial expansion in the development of novel immunotherapies targeting various inhibitory receptors (IRs), such as CTLA4, PD1 and LAG3, but these approaches have mechanistically focused on the elicitation of anti-tumor responses. However, enhanced inflammation in the TME could also play a detrimental role by facilitating the recruitment, stability and function of Treg cells by up-regulating chemokines that promote Treg cell migration, and/or increasing inhibitory cytokine production. Furthermore, IR blockade may enhance Treg cell function and survival, thereby serving as a resistance mechanism against effective immunotherapy. Given that Treg cells are comprised of functionally and phenotypically heterogeneous sub-populations that may alter their characteristics in a context-dependent manner, it is critical to identify unique molecular pathways that are preferentially used by intratumoral Treg cells. In this review, we discuss markers that serve to identify certain Treg cell subsets, distinguished by chemokine receptors, IRs and cytokines that facilitate their migration, stability and function in the TME. We also discuss how these Treg cell subsets correlate with the clinical outcome of patients with various types of cancer and how they may serve as potential TME-specific targets for novel cancer immunotherapies.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Evasão Tumoral , Animais , Quimiocinas/imunologia , Quimiocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Fenótipo , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Microambiente Tumoral
5.
Gen Comp Endocrinol ; 280: 194-199, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075272

RESUMO

Although chemokines mainly function to activate leukocytes and to direct their migration, novel evidence indicates non-immune functions for chemokines within the nervous and endocrine systems. These include development of the nervous system, neuromodulation, neuroendocrine regulation and direct neurotransmitter-like actions. In order to clarify a potential role for chemokines and their receptors in the stress response of fish, we studied changes in the expression patterns of CXC ligands and their receptors in the stress axis organs of carp, during a restraint stress procedure. We showed that stress down-regulated the gene expression of CXCL9-11 (CXCb1 and CXCb2) in stress axis organs and up-regulated expression of CXCR4 chemokine receptor in NPO and pituitary. Moreover, upon stress, reduced gene expression of CXCL12a and CXCL14 was observed in the head kidney. Our results imply that in teleost fish, CXC chemokines and their receptors are involved in neuroendocrine regulation. The active regulation of their expression in stress axis organs during periods of restraint indicates a significant role in the stress response.


Assuntos
Carpas/metabolismo , Quimiocinas CXC/metabolismo , Receptores de Quimiocinas/metabolismo , Estresse Fisiológico , Animais , Carpas/genética , Quimiocinas CXC/genética , Regulação da Expressão Gênica , Receptores de Quimiocinas/genética
6.
Int J Mol Sci ; 20(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075818

RESUMO

Major depressive disorder (MDD) is a debilitating condition, whose high prevalence and multisymptomatic nature set its standing as a leading contributor to global disability. To better understand this psychiatric disease, various pathophysiological mechanisms have been proposed, including changes in monoaminergic neurotransmission, imbalance of excitatory and inhibitory signaling in the brain, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, and abnormalities in normal neurogenesis. While previous findings led to a deeper understanding of the disease, the pathogenesis of MDD has not yet been elucidated. Accumulating evidence has confirmed the association between chronic inflammation and MDD, which is manifested by increased levels of the C-reactive protein, as well as pro-inflammatory cytokines, such as Interleukin 1 beta, Interleukin 6, and the Tumor necrosis factor alpha. Furthermore, recent findings have implicated a related family of cytokines with chemotactic properties, known collectively as chemokines, in many neuroimmune processes relevant to psychiatric disorders. Chemokines are small (8-12 kDa) chemotactic cytokines, which are known to play roles in direct chemotaxis induction, leukocyte and macrophage migration, and inflammatory response propagation. The inflammatory chemokines possess the ability to induce migration of immune cells to the infection site, whereas their homeostatic chemokine counterparts are responsible for recruiting cells for their repair and maintenance. To further support the role of chemokines as central elements to healthy bodily function, recent studies suggest that these proteins demonstrate novel, brain-specific mechanisms including the modulation of neuroendocrine functions, chemotaxis, cell adhesion, and neuroinflammation. Elevated levels of chemokines in patient-derived serum have been detected in individuals diagnosed with major depressive disorder, bipolar disorder, and schizophrenia. Furthermore, despite the considerable heterogeneity of experimental samples and methodologies, existing biomarker studies have clearly demonstrated the important role of chemokines in the pathophysiology of psychiatric disorders. The purpose of this review is to summarize the data from contemporary experimental and clinical studies, and to evaluate available evidence for the role of chemokines in the central nervous system (CNS) under physiological and pathophysiological conditions. In light of recent results, chemokines could be considered as possible peripheral markers of psychiatric disorders, and/or targets for treating depressive disorders.


Assuntos
Quimiocinas/metabolismo , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Humanos , Neurogênese , Plasticidade Neuronal , Receptores de Quimiocinas/metabolismo , Transmissão Sináptica
7.
PLoS Biol ; 17(5): e3000287, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31141500

RESUMO

Atypical chemokine receptor 2 (ACKR2) is a chemokine-scavenging receptor. ACKR2-/-embryos display a reduction in size of a novel, to our knowledge, embryonic skin macrophage population referred to as 'intermediate' cells. CC chemokine receptor 2 (CCR2)-/-embryos display an identical phenotype, indicating that these cells require CCR2 to enable them to populate embryonic skin. Further analysis revealed that ACKR2-/-embryos have higher circulating concentrations of the CCR2 ligand, CC ligand 2 (CCL2); thus, ACKR2 regulates intraembryonic CCL2 levels. We show that ACKR2 is strongly expressed by trophoblasts and that it blocks movement of inflammatory chemokines, such as CCL2, from the maternal decidua into the embryonic circulation. We propose that trophoblastic ACKR2 is responsible for ensuring chemokine compartmentalisation on the maternal decidua, without which chemokines enter the embryonic circulation, disrupting gradients essential for directed intraembryonic cell migration. Overall, therefore, we describe a novel, to our knowledge, molecular mechanism whereby maternal decidual chemokines can function in a compartmentalised fashion without interfering with intraembryonic leukocyte migration. These data suggest similar functions for other atypical chemokine receptors in the placenta and indicate that defects in such receptors may have unanticipated developmental consequences.


Assuntos
Quimiocinas/metabolismo , Mamíferos/metabolismo , Placenta/metabolismo , Animais , Movimento Celular , Decídua/metabolismo , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Feminino , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Gravidez , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/metabolismo , Pele/embriologia , Pele/metabolismo , Transcrição Genética , Saco Vitelino/metabolismo
8.
Dev Comp Immunol ; 98: 80-88, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31026469

RESUMO

The chemokine ligand XCL1 plays critical roles in immune responses with diverse physiological and pathological implications through interactions with a cognate G protein-coupled receptor XCR1. To shed insight into their versatile nature, we analyzed genetic variations of XCL1 and XCR1 in murine rodents, including commonly-used model organisms Mus musculus (house mouse) and Rattus norvegicus (Norway rat). Our results showed that adaptive selection has contributed to the genetic diversification of these proteins in murine lineage. Moreover, in both M. musculus and R. norvegicus, the chemokine and its receptor exhibit similar signs of selective sweeps resulting from positive selection. In light of currently available structural and interaction information for chemokines and their receptors, the similarity of XCL1/XCR1 evolutionary patterns among murine species and the parallels of their evolutionary footprints within individual species suggest that interplay could exist between the adaptively selected changes, or between the domains on which the identified changes are located, and consequently preserve the physiological interaction of XCL1 and XCR1.


Assuntos
Adaptação Fisiológica/genética , Quimiocinas C/genética , Evolução Molecular , Variação Genética , Receptores de Quimiocinas/genética , Seleção Genética , Animais , Quimiocinas C/metabolismo , Camundongos Endogâmicos C57BL , Ligação Proteica , Ratos Sprague-Dawley , Receptores de Quimiocinas/metabolismo , Roedores , Especificidade da Espécie
9.
Cell ; 177(3): 556-571.e16, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30955881

RESUMO

Differentiation of proinflammatory CD4+ conventional T cells (Tconv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to Treg predicts protective ICOS+ PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ Tconv abundance and controls tumor growth.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Animais , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Toxina Diftérica/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Quimiocinas/metabolismo , Linfócitos T Reguladores/imunologia , Microambiente Tumoral
10.
Immunol Rev ; 289(1): 9-30, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30977202

RESUMO

Chemotaxis is fundamental for leukocyte migration in immunity and inflammation and contributes to the pathogenesis of many human diseases. Although chemokines and various other chemoattractants were initially appreciated as important mediators of acute inflammation, in the past years they have emerged as critical mediators of cell migration during immune surveillance, organ development, and cancer progression. Such advances in our knowledge in chemokine biology have paved the way for the development of specific pharmacological targets with great therapeutic potential. Chemoattractants may belong to different classes, including a complex chemokine system of approximately 50 endogenous molecules that bind to G protein-coupled receptors, which are expressed by a wide variety of cell types. Also, an unknown number of other chemoattractants may be generated by pathogens and damaged/dead cells. Therefore, blocking chemotaxis without causing side effects is an extremely challenging task. In this review, we focus on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the whole organ level in homeostasis, inflammation, and infection.


Assuntos
Quimiocinas/metabolismo , Fatores Quimiotáticos/metabolismo , Inflamação/imunologia , Leucócitos/imunologia , Animais , Movimento Celular , Homeostase , Humanos , Receptores de Quimiocinas/metabolismo
12.
Acta Neuropsychiatr ; 31(5): 246-251, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30867081

RESUMO

OBJECTIVE: Although accumulating evidence supports the hypothesis that immune/inflammatory mechanisms are associated with the pathophysiology of bipolar disorder (BD), data about the profile of chemokines (chemotactic cytokines) and chemokine receptors are still scarce. The current study was designed to evaluate the expression of chemokine receptors on lymphocytes of patients with BD in comparison with controls. METHODS: Thirty-three patients with type I BD (N = 21 in euthymia; N = 6 in mania/hypomania; N = 6 in depression) and 22 age- and sex-matched controls were subjected to clinical evaluation and peripheral blood draw. The expression of chemokine receptors CCR3, CCR5, CXCR4, and CXCR3 on CD4+ and CD8+ lymphocytes was assessed by flow cytometry. RESULTS: Patients with BD had decreased percentage of CD4+CXCR3+ (p = 0.024), CD4+CCR3+ (p = 0.042), and CD4+CCR5+ (0.013) lymphocytes in comparison with controls. The percentage of both CD4+ and CD8+ lymphocytes expressing the chemokine receptor CXCR4 was similar in patients with BD and controls. Likewise, the percentages of CD8+CXCR3+, CD8+CCR3+, and CD8+CCR5+ lymphocytes were similar in patients with BD and controls. CONCLUSION: Our findings reinforce the hypothesis that immune pathways, especially involving CD4+ lymphocytes, are involved in the physiopathology of BD.


Assuntos
Transtorno Bipolar/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Receptores de Quimiocinas/metabolismo , Adulto , Idoso , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade
13.
Future Oncol ; 15(12): 1385-1395, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30880459

RESUMO

Despite the progress made in molecular and clinical research, patients with diffuse large B-cell lymphoma (DLBCL) still have a bad prognosis. Recently, chemokines/chemokine receptors have become the subject of interest in relation to DLBCL. Studies have demonstrated the important role of chemokines/chemokine receptors in the communication between DLBCL cells and tumor microenvironment. Studies have also reported the ability of chemokines/chemokine receptors in promoting the proliferation and invasion of DLBCL cells. Here, we summarize the data on mechanisms of DLBCL supporting the involvement of chemokine/chemokine receptor changes. We focus on the available evidence regarding chemokines/chemokine receptors as biomarkers and therapeutic targets for DLBCL.


Assuntos
Biomarcadores Tumorais/metabolismo , Quimiocinas/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Receptores de Quimiocinas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biópsia , Quimiocinas/antagonistas & inibidores , Progressão da Doença , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Terapia de Alvo Molecular/métodos , Invasividade Neoplásica/patologia , Prognóstico , Intervalo Livre de Progressão , Receptores de Quimiocinas/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
14.
Hum Genomics ; 13(1): 15, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894217

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is the most common, progressive, and polygenic cause of irreversible visual impairment in the world. The molecular pathogenesis of the primary events of AMD is poorly understood. We have investigated a transcriptome-wide analysis of differential gene expression, single-nucleotide polymorphisms (SNPs), indels, and simple sequence repeats (SSRs) in datasets of the human peripheral retina and RPE-choroid-sclera control and AMD. METHODS AND RESULTS: Adaptors and unbiased components were removed and checked to ensure the quality of the data sets. Molecular function, biological process, cellular component, and pathway analyses were performed on differentially expressed genes. Analysis of the gene expression datasets identified 5011 upregulated genes, 11,800 downregulated genes, 42,016 SNPs, 1141 indels, and 6668 SRRs between healthy controls and AMD donor material. Enrichment categories for gene ontology included chemokine activity, cytokine activity, cytokine receptor binding, immune system process, and signal transduction respectively. A functional pathways analysis identified that chemokine receptors bind chemokines, complement cascade genes, and create cytokine signaling in immune system pathway genes (p value < 0.001). Finally, allele-specific expression was found to be significant for Chemokine (C-C motif) ligand (CCL) 2, 3, 4, 13, 19, 21; C-C chemokine receptor (CCR) 1, 5; chemokine (C-X-C motif) ligand (CXCL) 9, 10, 16; C-X-C chemokine receptor type (CXCR) 6; as well as atypical chemokine receptor (ACKR) 3,4 and pro-platelet basic protein (PPBP). CONCLUSIONS: Our results improve our overall understanding of the chemokine receptors' signaling pathway in AMD conditions, which may lead to potential new diagnostic and therapeutic targets.


Assuntos
Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Receptores de Quimiocinas/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Quimiocinas/genética , Quimiocinas/metabolismo , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Humanos , Masculino , Repetições de Microssatélites , Receptores de Quimiocinas/metabolismo , Transdução de Sinais/genética , Transcriptoma
15.
Cell Mol Life Sci ; 76(16): 3249-3261, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30830241

RESUMO

In addition to their modulation through de novo expression and degradation, surface levels of chemokine receptors are tuned by their ligand-dependent recycling to the plasma membrane, which ensures that engaged receptors become rapidly available for further rounds of signaling. Dysregulation of this process contributes to the pathogenesis of chronic lymphocytic leukemia (CLL) by enhancing surface expression of chemokine receptors, thereby favoring leukemic cell accumulation in the protective niche of lymphoid organs. In this review, we summarize our current understanding of the process of chemokine receptor recycling, focusing on the impact of its dysregulation in CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Receptores de Quimiocinas/metabolismo , Arrestinas/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfonodos/metabolismo , Fosforilação , Transdução de Sinais
16.
Theriogenology ; 129: 121-129, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30844653

RESUMO

Atypical chemokine receptor (ACKR) 1, ACKR2, ACKR3, and ACKR4, chemokine decoy receptors that lack G-protein-mediated signaling pathways, internalize and degrade chemokines to control their availability and function. Chemokines play important roles in the endometrium during the estrous cycle and pregnancy, but the expression and regulation of ACKRs have not been determined in pigs. Therefore, we examined the expression of ACKRs in the endometrium throughout the estrous cycle and pregnancy and in conceptus tissues in pigs. ACKR1, ACKR2, ACKR3, and ACKR4 mRNA was expressed in the endometrium, with higher levels of ACKR3 on day 12 of the estrous cycle than in pregnancy and higher levels of ACKR4 on day 15 of pregnancy than in the estrous cycle. ACKR1, ACKR2, and ACKR3, but not ACKR4, mRNA was detected in conceptus and chorioallantoic tissues during pregnancy. ACKR2 and ACKR3 mRNA and ACKR4 protein were mainly localized to luminal epithelial cells and weakly to glandular epithelial cells in the endometrium. Increasing doses of progesterone increased the expression of ACKR2 and ACKR4 and decreased the expression of ACKR3 in endometrial tissues. On day 12 of pregnancy, the expression of ACKR4 mRNA was lower in the endometria of gilts with somatic cell nucleus transfer-derived conceptuses than in the endometria of gilts carrying conceptuses derived from natural mating. These results indicate that the expression of ACKRs is dynamically regulated at the maternal-conceptus interface, suggesting that ACKR proteins might play critical roles in regulating endometrial chemokines to support the establishment and maintenance of pregnancy in pigs.


Assuntos
Endométrio/metabolismo , Ciclo Estral/metabolismo , Prenhez/metabolismo , Receptores de Quimiocinas/metabolismo , Suínos/metabolismo , Animais , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Imuno-Histoquímica , Técnicas de Transferência Nuclear/veterinária , Gravidez , Receptores de Quimiocinas/genética , Suínos/genética
17.
Immunobiology ; 224(3): 440-448, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30795859

RESUMO

Mycobacterial antigen-specific CD4+ Th1 cells have pivotal role in protective immunity against mycobacterial infections including pulmonary tuberculosis. In the course of the infection, Th1 cells differentiate in the lung-draining lymph nodes and migrate into the infected lung. Chemokine receptors on T cells are involved in T cell migration into the intestine and skin. However, role of chemokine receptors in the migration of CD4+ T cells into the lung is not yet established. To address the issue, the role of chemokine receptors in T cell migration into the mycobacteria-infected lung was analyzed using mycobacterial Ag85B peptide 25-specific T cell receptor-transgenic (P25) CD4+ T cells. The P25 T cells in the Mycobacterium bovis BCG-infected lung and lung-draining mediastinal lymph node expressed chemokine receptors CCR5, CCR6, CXCR3 and CXCR5 which bind chemokines expressed by the BCG-infected lung. To further analyze the role of the chemokine receptors in the migration of the BCG-primed P25 T cells into the lung or mediastinal lymph node, the P25 T cells were adoptively transferred into the BCG-infected wild type mice, and their migration into the lung was monitored. Unexpectedly, blocking of chemokine receptor function with pertussis toxin, a G-protein inhibitor, failed to suppress migration of the T cells into the infected lung although the treatment completely blocked migration of the mediastinal lymph node P25 T cells into the recipient lymph node. The results suggest that interaction of chemokine receptors on mycobacterial antigen-specific Th1 cells with chemokines is dispensable in their migration into the mycobacteria-infected lung.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Pulmão/imunologia , Infecções por Mycobacterium/imunologia , Mycobacterium bovis/fisiologia , Receptores de Quimiocinas/metabolismo , Animais , Movimento Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Pulmão/microbiologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética
18.
Reprod Biol Endocrinol ; 17(1): 25, 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30777067

RESUMO

BACKGROUND: In dairy cows, the energy cost of milk yield results in a negative energy balance (EB) and body fat mobilization that impairs reproductive efficiency. Emerging evidence suggests that the novel adipokines, Retinoic acid receptor responder protein 2 (RARRES2), and its main receptor, Chemokine-like receptor 1 (CMKLR1) are involved in the regulation of metabolic and ovarian functions. So, we investigated in a first experiment the plasma RARRES2, and RARRES2 and CMKLR1 mRNA expression levels in subcutaneous adipose tissue (SAT) and granulosa cells (GC) at different times of body fat mobilization in dairy cows (4, 8, 20 and 44 weeks postpartum, wk. pp. for SAT and 8, 20 and 44 wk. pp. for GC). Then, in a second experiment we examined the effect of high (HE) and low energy (LE) diets on the RARRES2 system and its links with metabolic and reproductive parameters. METHODS: The first experiment included 9 animals fed with HE diet from 4 to 44 wk. pp. and the second one included animals fed either a HE diet (n = 8) or a LE diet (n = 8) from - 4 to 16 wk. peripartum. In both experiments, various metabolic and reproductive parameters were determined and associated with plasma RARRES2 as measured by bovine ELISA. RARRES2 and CMKLR1 mRNA expression levels were analyzed by RT-qPCR in SAT after biopsy and GC after aspiration of follicles. RESULTS: Plasma RARRES2 levels were higher at 4 wk. pp. as compared to 20 and 44 wk. pp. and they were positively correlated with body fat mobilization and milk yield. RARRES2 and CMKLR1 mRNA expression levels increased from 4 to 8 wk. pp. (fat mobilization, EB < 0) and remained unchanged at 20 and 44 wk. pp. (fat reconstitution, EB > 0) as compared to 4 wk. pp. in SAT. RARRES2 and CMKLR1 mRNA levels decreased from 8 to 44 wk. pp. in GC from small follicles. In the second experiment, plasma RARRES2 increased from - 4 to 8 wk. peripartum similarly in both LE and HE cows. In addition, the area under of plasma RARRES2 curve was highly negatively associated with the number of small follicles obtained in HE animals during the cycle before the first artificial insemination. In SAT of HE cows, RARRES2 mRNA expression decreased at 1 wk. pp. compared to - 4 and 16 wk. peripartum whereas opposite expression patterns were obtained for CMKLR1. Similar results were observed for CMKLR1 mRNA expression in LE cows while there was no variation in RARRES2 mRNA expression. Moreover, RARRES2 mRNA was higher expressed in LE than in HE cows at 1 wk. pp. CONCLUSIONS: The lactation-induced fat and energy mobilization influenced plasma RARRES2 profile and mRNA expression pattern of RARRES2 and CMKLR1 similarly in both SAT and GC. In addition, the energy content of the diet did not affect plasma RARRES2 but it altered RARRES2 mRNA expression in SAT and the area under the curve of plasma RARRES2 that was negatively associated to the number of small follicles in HE animals. Thus, RARRES2 could be a metabolic or ovarian signal involved in the interactions between metabolic and reproductive functions in dairy cows.


Assuntos
Quimiocinas/genética , Metabolismo Energético/genética , Perfilação da Expressão Gênica/métodos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Receptores de Quimiocinas/genética , Reprodução/genética , Tecido Adiposo/metabolismo , Animais , Bovinos , Quimiocinas/sangue , Quimiocinas/metabolismo , Dieta/veterinária , Feminino , Células da Granulosa/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Leite/metabolismo , Período Pós-Parto , Receptores de Quimiocinas/metabolismo , Gordura Subcutânea/metabolismo
19.
J Gen Virol ; 100(4): 545-553, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30730289

RESUMO

Cytomegaloviruses (CMVs) are large, complex pathogens that persistently and systemically colonize most mammals. Human cytomegalovirus (HCMV) causes congenital harm, and has proved hard to control. One problem is that key vaccine targets - virus entry and spread in naive hosts - remain ill-defined. As CMVs predate human speciation, those of other mammals can provide new insight. Murine CMV (MCMV) enters new hosts via olfactory neurons. Like HCMV it binds to heparan, which is lacking from most differentiated apical epithelia but is displayed on olfactory neuronal cilia. It then spreads via infected dendritic cells (DCs), which migrate to draining lymph nodes (LNs), rejoin the circulation by entering high endothelial venules (HEVs), and extravasate into other tissues. This migration depends quantitatively on M33, a constitutively active viral G protein-coupled receptor (GPCR). The homologous US28 GPCR of HCMV can substitute for M33 in allowing MCMV-infected DCs to leave LNs via HEVs, so HCMV could potentially use the same route. The capacity of DCs to seed MCMV to tissues, and for other DCs to collect it for redistribution, suggest that DC recirculation chronically maintains and links diverse CMV reservoirs through lytic exchange.


Assuntos
Infecções por Citomegalovirus/virologia , Citomegalovirus/fisiologia , Internalização do Vírus , Animais , Citomegalovirus/genética , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Humanos , Linfonodos/metabolismo , Linfonodos/virologia , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo
20.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1126-1137, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30738810

RESUMO

In experimental obesity, the hypothalamus is affected by an inflammatory response activated by dietary saturated fats. This inflammation is triggered as early as one day after exposure to a high-fat diet, and during its progression, there is recruitment of inflammatory cells from the systemic circulation. The objective of the present study was identifying chemokines potentially involved in the development of hypothalamic diet-induced inflammation. In order to identify chemokines potentially involved in this process, we performed a real-time PCR array that determined Ackr2 as one of the transcripts undergoing differential regulation in obese-prone as compared to obese-resistant mice fed a high-fat diet for three days. ACKR2 is a decoy receptor that acts as an inhibitor of the signals generated by several CC inflammatory chemokines. Our results show that Ackr2 expression is rapidly induced after exposure to dietary fats both in obese-prone and obese-resistant mice. In immunofluorescence studies, ACKR2 was detected in hypothalamic neurons expressing POMC and NPY and also in microglia and astrocytes. The lentiviral overexpression of ACKR2 in the hypothalamus reduced diet-induced hypothalamic inflammation; however, there was no change in spontaneous caloric intake and body mass. Nevertheless, the overexpression of ACKR2 resulted in improvement of glucose tolerance, which was accompanied by reduced insulin secretion and increased whole body insulin sensitivity. Thus, ACKR2 is a decoy chemokine receptor expressed in most hypothalamic cells that is modulated by dietary intervention and acts to reduce diet-induced inflammation, leading to improved glucose tolerance due to improved insulin action.


Assuntos
Perfilação da Expressão Gênica , Glucose/metabolismo , Hipotálamo/metabolismo , Inflamação/genética , Obesidade/genética , Receptores de Quimiocinas/genética , Animais , Astrócitos/metabolismo , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Teste de Tolerância a Glucose , Hipotálamo/citologia , Inflamação/etiologia , Inflamação/metabolismo , Resistência à Insulina/genética , Masculino , Camundongos , Neurônios/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Receptores de Quimiocinas/metabolismo
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