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1.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370263

RESUMO

Chemerin is a multifunctional adipokine with established roles in inflammation, adipogenesis and glucose homeostasis. Increasing evidence suggest an important function of chemerin in cancer. Chemerin's main cellular receptors, chemokine-like receptor 1 (CMKLR1), G-protein coupled receptor 1 (GPR1) and C-C chemokine receptor-like 2 (CCRL2) are expressed in most normal and tumor tissues. Chemerin's role in cancer is considered controversial, since it is able to exert both anti-tumoral and tumor-promoting effects, which are mediated by different mechanisms like recruiting innate immune defenses or activation of endothelial angiogenesis. For this review article, original research articles on the role of chemerin and its receptors in cancer were considered, which are listed in the PubMed database. Additionally, we included meta-analyses of publicly accessible DNA microarray data to elucidate the association of expression of chemerin and its receptors in tumor tissues with patients' survival.


Assuntos
Quimiocinas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Neovascularização Patológica/genética , Receptores de Quimiocinas/genética , Receptores Acoplados a Proteínas-G/genética , Animais , Quimiocinas/imunologia , Bases de Dados Genéticas , Modelos Animais de Doenças , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Imunidade Inata , Inflamação , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias/patologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/mortalidade , Neovascularização Patológica/patologia , Receptores CCR/genética , Receptores CCR/imunologia , Receptores de Quimiocinas/imunologia , Receptores Acoplados a Proteínas-G/imunologia , Transdução de Sinais , Análise de Sobrevida
2.
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
3.
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
4.
Cancer Res ; 79(8): 2009-2020, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30737232

RESUMO

Enhancer of zeste homolog (EZH2) is a key epigenetic regulator of gene expression and is frequently overexpressed in various cancer types, suggesting a role in oncogenesis. The therapeutic potential of EZH2 inhibitors is currently being explored, but their effect on antitumor immunity is largely unknown. Here we report that suppressing EZH2 activity using EZH2 inhibitor GSK126 resulted in increased numbers of myeloid-derived suppressor cells (MDSC) and fewer CD4+ and IFNγ+CD8+ T cells, which are involved in antitumor immunity. Addition of a neutralizing antibody against the myeloid differentiation antigen GR-1 or gemcitabine/5-fluorouracil-depleted MDSCs alleviated MDSC-mediated immunosuppression and increased CD4+ and CD8+ T-cell tumor infiltration and GSK126 therapeutic efficacy. Mechanistically, we identified a novel pathway of MDSC production in cancer in which EZH2 inhibition directs myeloid differentiation from primitive hematopoietic progenitor cells. These findings suggest that modulating the tumor immune microenvironment may improve the efficacy of EZH2 inhibitors. SIGNIFICANCE: This study uncovers a potential mechanism behind disappointing results of a phase I clinical trial of EZH2 inhibitor GSK126 and identifies a translatable combinational strategy to overcome it.


Assuntos
Carcinoma Pulmonar de Lewis/imunologia , Neoplasias do Colo/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Indóis/farmacologia , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Piridonas/farmacologia , Animais , Anticorpos Neutralizantes , Apoptose , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Células Supressoras Mieloides/metabolismo , Receptores de Quimiocinas/imunologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Front Immunol ; 10: 147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30800123

RESUMO

Tumor-associated vascular endothelium comprises a specialized and diverse group of endothelial cells that, although not cancer themselves, are integral to cancer progression. Targeting the tumor vasculature can have significant efficacy in reducing tumor burden, although loss of efficacy due to acquisition of resistance mechanisms is common. Here we review mechanisms by which tumor endothelial cells (TEC) utilize chemokine receptors to support tumor progression. We illustrate how chemokine receptors support and may serve as functional markers of the diverse TEC population. We focus on ACKR1 (DARC), ACKR3 (CXCR7), CXCR4, and CCR2, as these are the best studied chemokine receptors in TEC; and suggest that targeting these receptors on the tumor vasculature may prove efficacious in slowing or reversing tumor growth. We also mention CXCR2 and CXCR3 as important mediators or tumor angiogenesis, given their distinct roles with angiogenic and angiostatic chemokines, respectively.


Assuntos
Células Endoteliais/imunologia , Neoplasias/imunologia , Receptores de Quimiocinas/imunologia , Animais , Quimiocinas/imunologia , Humanos
6.
Fish Shellfish Immunol ; 88: 217-224, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30807858

RESUMO

Chemokine receptors are a superfamily of seven-transmembrane domain G-coupled receptors and have important roles in immune surveillance, inflammation, and development. In previous studies, a series of CXCRs in grouper (Epinephelus coioides) was identified; however, the function of CXCR in viral infection has not been studied. To better understand the effect of the CXCR family on the fish immune response, full-length CXCR1a was cloned, and its immune response to Singapore grouper iridovirus (SGIV) was investigated. Grouper CXCR1a shared a seven-transmembrane (7-TM) region and a G protein-coupled receptor (GPCR) family 1 that contained a triaa stretch (DRY motif). Phylogenetic analysis indicated that CXCR1a showed the nearest relationship to Takifugu rubripes, followed by other fish, bird and mammal species. Fluorescence microscopy revealed that CXCR1a was expressed predominantly in the cytoplasm. Overexpression of CXCR1a in grouper cells significantly inhibited the replication of SGIV, demonstrating that CXCR1a delayed the occurrence of cytopathic effects (CPE) induced by SGIV infection and inhibited viral gene transcription. Furthermore, our results also showed that CXCR1a overexpression significantly increased the expression of interferon-related cytokines and activated ISRE and IFN promoter activities. Taken together, the results demonstrated that CXCR1a might have an antiviral function against SGIV infection.


Assuntos
Bass/genética , Bass/imunologia , Infecções por Vírus de DNA/veterinária , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologia , Animais , Citocinas/metabolismo , Infecções por Vírus de DNA/imunologia , Infecções por Vírus de DNA/virologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/virologia , Microscopia de Fluorescência , Filogenia , Ranavirus/fisiologia , Replicação Viral/imunologia
7.
Nutr Neurosci ; 22(10): 725-737, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29447086

RESUMO

Objectives: A spectrum of immunomodulatory properties was attributed to vitamin D (VD). Here, the VD effects on expression of some Th17 cell- related cytokines, chemokines and chemokine receptors were investigated in experimental autoimmune encephalomyelitis (EAE). Methods: One group of C57BL/6 mice, considered as healthy group, was treated with phosphate buffered saline (PBS). EAE was induced in other three groups and treated from day +3 to +30 with PBS, olive oil (VD vehicle) or 200 ng of VD. At day 31, the expression of interleukin-17 (IL-17), IL-23, chemokine (C-C motif) ligand 20 (CCL20), CCL22, CC chemokine receptor 4 (CCR4) and CCR6 in spinal cord and serum IL-17 and IL-23 levels were measured by real-time PCR and ELISA, respectively. Results: The expression of IL-17, IL-23 P19, IL-23 P40, CCL20, CCL22 and CCR4 in spinal cord and serum IL-17 and IL-23 levels in PBS-administrated EAE mice were significantly increased compared with healthy group. In EAE mice treated with VD, the expression of aforementioned parameters was significantly reduced in comparison with PBS-administrated EAE mice. Conclusion: VD down-regulates the expression of some inflammatory cytokines, chemokines and chemokine receptors in EAE mice. The possible therapeutic potential of VD in multiple sclerosis can be considered in future investigation.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Mediadores da Inflamação/imunologia , Vitamina D/administração & dosagem , Animais , Quimiocinas/imunologia , Citocinas/imunologia , Regulação para Baixo , Feminino , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-23/imunologia , Camundongos Endogâmicos C57BL , Receptores de Quimiocinas/imunologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
9.
Front Biosci (Landmark Ed) ; 24: 18-34, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30468645

RESUMO

G protein-coupled receptors (GPCRs) form a most diverse family of integral membrane proteins that mediate homeostatic and pathological processes, most notably by orchestrating cell distribution throughout the body, their infiltration, and time of presence in inflamed tissues. Here we discuss loss-of-orientation-effects in GPCR-mediated cell trafficking and migration and their impact on the phenotype of autoimmune diseases. In this context, we provide a systemic and integrative view of the contribution of abnormal GPCR expression as well as the levels of natural ligands and functional autoantibodies to the phenotype of autoimmune diseases. Currently, several studies propose that functional autoantibodies (including those targeting GPCRs) constitute an exclusively pathogenic or pathognomonic phenomenon. Here we reinforce the need of revising this point of view, and suggest that functional autoantibodies primary play a role in normal human physiology, while dysregulation of their functions causes autoimmune disease. Because patients with autoimmune diseases still suffer from severe morbidity and mortality rates, we consider expanding our knowledge on (patho)physiological roles of GPCR as a prerequisite for the development of novel specific therapeutic modalities.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Movimento Celular/imunologia , Receptores Acoplados a Proteínas-G/imunologia , Animais , Autoanticorpos/metabolismo , Doenças Autoimunes/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Modelos Imunológicos , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
10.
Immunology ; 156(2): 147-163, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30315653

RESUMO

Although dengue can progress to severe stages, the exact causes of this phenomenon are unknown; however, the possibility of monocyte participation is acknowledged. It has been suggested that monocyte subsets (classical, intermediate and non-classical) play differential roles in dengue immunopathology. Therefore, we determined the count of monocyte subsets and obtained the clinical information of patients with dengue. We noted a significant decrease in the count of non-classical monocytes in patients compared with controls. With this finding, we focused on studying the phenotype of non-classical monocytes in the present study. An increase in activation and differentiation markers, such as CD64, CD86, the percentage of tumor necrosis factor-α+ cells and exposure of phosphatidylserine, were recorded in the non-classical monocytes of patients compared with controls. Moreover, a significant decrease in the expression of CX3CR1 with a corresponding increase in the expressions of CCR2, CCR5, CD11b and CD54 was detected in the non-classical monocytes of patients in comparison with that of the controls. Significant increases in the frequency of microparticles from endothelium and in the concentrations of interleukin-6 (IL-6), IL-8 and IL-10 were noted in the plasma of patients. These findings demonstrate that in patients with dengue, non-classical monocytes are activated, exhibiting a phenotype associated with more differentiation, produces tumor necrosis factor-α and has a profile of less endothelial surveillance closer to the cellular migration. These changes were associated with hepatic compromise, endothelial alteration and high concentration of circulating cytokines. Hence, alterations of non-classical monocytes seem to be associated with the immunopathology of dengue infection.


Assuntos
Dengue/imunologia , Endotélio Vascular/imunologia , Fígado/imunologia , Monócitos/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Adolescente , Adulto , Idoso , Antígenos CD/imunologia , Citocinas/imunologia , Dengue/patologia , Endotélio Vascular/patologia , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Receptores de Quimiocinas/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia
11.
Front Immunol ; 9: 2772, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555465

RESUMO

Chemerin [RARRES2 [retinoic acid receptor responder 2], TIG2 [tazarotene induced gene 2 (TIG2)]] is a multifunctional cytokine initially described in skin cultures upon exposure to the synthetic retinoid tazarotene. Its secreted pro-form, prochemerin, is widely expressed, found systemically, and is readily converted into active chemerin by various proteases. Subsequent studies elucidated major roles of chemerin as both a leukocyte chemoattractant as well as an adipokine. Chemerin's main chemotactic receptor, the G-protein coupled receptor CMKLR1, is expressed on macrophages, dendritic, and NK cells. With respect to its role in immunology, chemerin mediates trafficking of these cells to sites of inflammation along its concentration gradient, and likely helps coordinate early responses, as it has been shown to have antimicrobial and angiogenic properties, as well. Recently, there has been mounting evidence that chemerin is an important factor in various cancers. As with its role in immune responses-where it can act as both a pro- and anti-inflammatory mediator-the potential functions or correlations chemerin has in or with cancer appears to be context dependent. Most studies, however, suggest a downregulation or loss of chemerin/RARRES2 in malignancies compared to the normal tissue counterparts. Here, we perform a comprehensive review of the literature to date and summarize relevant findings in order to better define the roles of chemerin in the setting of the tumor microenvironment and tumor immune responses, with an ultimate focus on the potential for therapeutic intervention.


Assuntos
Quimiocinas/imunologia , Regulação para Baixo/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Animais , Células Dendríticas/imunologia , Células Dendríticas/patologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Macrófagos/imunologia , Macrófagos/patologia , Neoplasias/patologia , Receptores de Quimiocinas/imunologia
12.
Front Immunol ; 9: 2629, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30483271

RESUMO

Solid tumors are initiated by genetic mutations in non-hematopoietic cells and progress into invasive malignant tumors. This tumor progression often culminates in metastatic disease that is largely refractory to current therapeutic modalities and thus dramatically reduces survival of tumor patients. As solid tumors account for more than 80% of cancer-related deaths, it is necessary to develop novel therapeutic strategies to treat the diseases. An attractive strategy is to target macrophages in both primary tumors [known as tumor-associated macrophages (TAMs)] and metastatic tumors [called metastasis-associated macrophages (MAMs)]. TAMs and MAMs are abundant in most solid tumors and can promote tumor metastasis. Several studies in various models of solid tumors suggest that the accumulation of TAMs, MAMs, and their progenitor cells is regulated by chemokine ligands released by tumor and stromal cells. Consequently, these macrophage-recruiting chemokines could be potential therapeutic targets to prevent malignant tumor development through disruption of the accumulation of pro-metastatic macrophages. This review will discuss the role of chemokine ligands and their receptors in TAM and MAM accumulation in primary and secondary tumor sites, and finally discuss the therapeutic potential of inhibitors against these macrophage-recruiting chemokines.


Assuntos
Quimiocinas/imunologia , Macrófagos/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Quimiocinas/imunologia , Animais , Quimiocinas/antagonistas & inibidores , Humanos , Macrófagos/patologia , Metástase Neoplásica , Neoplasias/patologia , Células Estromais/imunologia , Células Estromais/patologia
13.
Semin Immunol ; 38: 63-71, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30337241

RESUMO

As main drivers of leukocyte recruitment during inflammatory reactions, chemokines act as mediatrs of alarmins in priming host defense responses after tissue exposure to toxic or infectious agents, immunomediated damage, and in inflammation-driven tumors. Chemokines can therefore be considered alarm signals generated by tissues in a broad number of conditions, and mechanisms controlling chemokines biological activities are therefore key to regulate tissue reactions induced by alarmins. By transporting, presenting or scavenging different sets of chemokines, atypical chemokine receptors represent an emerign subfamily of chemokine receptors which operates in tissues as chemokine gatekeepers in order to establish and shape their gradients and coordinate leukocyte recruitment.


Assuntos
Alarminas/imunologia , Quimiocinas/imunologia , Inflamação/imunologia , Neoplasias/imunologia , Alarminas/metabolismo , Animais , Quimiocinas/metabolismo , Humanos , Inflamação/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Modelos Imunológicos , Neoplasias/metabolismo , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Transdução de Sinais/imunologia
14.
Curr Pharm Biotechnol ; 19(9): 715-727, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30332947

RESUMO

BACKGROUND: Vascular remodeling is an alteration in the structure of vessels in response to injury or hemodynamic changes. Disturbance of the structural and functional integrity of the endothelial cell layer can be observed in vascular remodeling associated with inflammation. Chemokines have been implicated in a wide range of diseases with prominent inflammatory components, and also in vascular remodeling. Among them, CC-chemokines are of great interest. They act through conventional CC-chemokine receptors (CCRs), widely expressed by leucocytes which are attracted to sites of chronic inflammation. However, many experimental data show that CCRs are expressed by vascular cells, suggesting a direct, leukocyte-independent effect on vascular remodeling. OBJECTIVE: Here, we discuss the role of CC-chemokines in atherosclerosis, angiogenesis, restenosis and renal dysfunction through direct activation of endothelial cells, endothelial progenitors, vascular smooth muscle cells, platelets, erythrocytes, mesangial cells and fibroblasts. RESULTS: The pathophysiological role of CC-chemokines has become more interesting since the discovery of the atypical chemokine receptor (ACKR) subfamily, that does not couple with G proteins and fails to transmit conventional intracellular signals. It has been demonstrated to be a chemokine scavenger or decoy receptor with a role in the regulation of acute inflammatory responses. CONCLUSION: At the vascular level, ACKRs are expressed by endothelial cells and endothelial lymphatic cells that seem to regulate angio- and lymph-angiogenesis. Pleiotropic effects of CC-chemokines on vascular wall cells and leukocytes increase their importance in vascular remodeling and suggest new drugs to counteract vascular dysfunction.


Assuntos
Quimiocinas CC/imunologia , Receptores de Quimiocinas/imunologia , Doenças Vasculares/imunologia , Remodelação Vascular/imunologia , Animais , Quimiocinas CC/antagonistas & inibidores , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Humanos , Inflamação , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/imunologia , Receptores de Quimiocinas/antagonistas & inibidores , Doenças Vasculares/tratamento farmacológico , Remodelação Vascular/efeitos dos fármacos
15.
J Crohns Colitis ; 12(suppl_2): S641-S652, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30137309

RESUMO

The principal targets for anti-chemokine therapy in inflammatory bowel disease (IBD) have been the receptors CCR9 and CXCR3 and their respective ligands CCL25 and CXCL10. More recently CCR6 and its ligand CCL20 have also received attention, the expression of the latter in enterocytes being manipulated through Smad7 signalling. These pathways, selected based on their fundamental role in regulating mucosal immunity, have led to the development of several therapeutic candidates that have been tested in early phase clinical trials with variable clinical efficacy. In this article, we appraise the status of chemokine-directed therapy in IBD, review recent developments, and nominate future areas for therapeutic focus.


Assuntos
Quimiocinas , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Receptores de Quimiocinas , Animais , Anticorpos Monoclonais/uso terapêutico , Quimiocina CCL20/imunologia , Quimiocina CCL20/metabolismo , Quimiocina CXCL10/antagonistas & inibidores , Quimiocina CXCL10/imunologia , Quimiocinas/antagonistas & inibidores , Quimiocinas/imunologia , Quimiocinas/metabolismo , Quimiocinas CC/imunologia , Humanos , Terapia de Alvo Molecular , Oligonucleotídeos/uso terapêutico , Receptores CCR/antagonistas & inibidores , Receptores CCR/imunologia , Receptores CCR6/imunologia , Receptores CXCR3/imunologia , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/imunologia , Proteína Smad7/antagonistas & inibidores , Sulfonamidas/uso terapêutico
16.
Nat Commun ; 9(1): 2611, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973593

RESUMO

Tumor-derived soluble factors promote the production of Gr-1+CD11b+ immature myeloid cells, and TGFß signaling is critical in their immune suppressive function. Here, we report that miR-130a and miR-145 directly target TGFß receptor II (TßRII) and are down-regulated in these myeloid cells, leading to increased TßRII. Ectopic expression of miR-130a and miR-145 in the myeloid cells decreased tumor metastasis. This is mediated through a downregulation of type 2 cytokines in myeloid cells and an increase in IFNγ-producing cytotoxic CD8 T lymphocytes. miR-130a- and miR-145-targeted molecular networks including TGFß and IGF1R pathways were correlated with higher tumor stages in cancer patients. Lastly, miR-130a and miR-145 mimics, as well as IGF1R inhibitor NT157 improved anti-tumor immunity and inhibited metastasis in preclinical mouse models. These results demonstrated that miR-130a and miR-145 can reprogram tumor-associated myeloid cells by altering the cytokine milieu and metastatic microenvironment, thus enhancing host antitumor immunity.


Assuntos
Regulação Neoplásica da Expressão Gênica , Imunidade Inata/efeitos dos fármacos , Neoplasias Pulmonares/genética , Neoplasias Mamárias Experimentais/genética , MicroRNAs/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Animais , Antineoplásicos/farmacologia , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Injeções Intravenosas , Interferon gama/genética , Interferon gama/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Transgênicos , MicroRNAs/imunologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Mieloides/patologia , Oligorribonucleotídeos/administração & dosagem , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Pirogalol/análogos & derivados , Pirogalol/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo II/imunologia , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologia , Transdução de Sinais , Sulfonamidas/farmacologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia
17.
J Innate Immun ; 10(4): 328-338, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30021216

RESUMO

In this study, we analyzed interferon (IFN)-γ-producing cells and M1/M2 macrophage polarization in Legionella pneumophila pneumonia following anti-Gr-1 antibody treatment. Anti-Gr-1 treatment induced an M1-to-M2 shift of macrophage subtypes in the lungs and weakly in the peripheral blood, which was associated with increased mortality in legionella-infected mice. CD8+ T lymphocytes and natural killer cells were the dominant sources of IFN-γ in the acute phase, and anti-Gr-1 treatment reduced the number of IFN-γ-producing CD8+ T lymphocytes. In the CD3-gated population, most Gr-1-positive cells were CD8+ T lymphocytes in the lungs and lymph nodes (LNs) of infected mice. Additionally, the number of IFN-γ-producing Gr-1+ CD8+ T lymphocytes in the lungs and LNs increased 2 and 4 days after L. pneumophila infection, with anti-Gr-1 treatment attenuating these populations. Antibody staining revealed that Gr-1+ CD8+ T lymphocytes were Ly6C-positive cells rather than Ly6G, a phenotype regarded as memory type cells. Furthermore, the adoptive transfer of Gr-1+ CD8+ T lymphocytes induced increases in IFN-γ, M1 shifting and reduced bacterial number in the Legionella pneumonia model. These data identified Ly6C+ CD8+ T lymphocytes as a source of IFN-γ in innate immunity and partially associated with reduced IFN-γ production, M2 polarization, and high mortality in anti-Gr-1 antibody-treated mice with L. pneumophila pneumonia.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Legionella pneumophila/fisiologia , Doença dos Legionários/imunologia , Macrófagos/imunologia , Pneumonia/imunologia , Doença Aguda , Animais , Anticorpos Bloqueadores/administração & dosagem , Diferenciação Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Memória Imunológica , Interferon gama/metabolismo , Camundongos , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Células Th1/imunologia , Equilíbrio Th1-Th2 , Células Th2/imunologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-29868513

RESUMO

Coxsackievirus B3 (CVB3) is the primary cause of viral myocarditis. An early and abundant neutrophil accumulation in the myocardium is a hallmark of early CVB3 infection. Yet the relative contribution of neutrophils to host susceptibility to CVB3 myocarditis remains largely unknown. Herein, peripheral neutrophil depletion was implemented in a BALB/c mouse model of acute CVB3 myocarditis using the specific 1A-8 (anti-Ly6G) or a RB6-8C5 (anti-Gr-1) mAb covering a wide range. Anti-Ly6G treatment led to systemic neutropenia throughout the disease, but did not alter virus replication, disease susceptibility and histopathological changes in the heart and pancreas of mice. In contrast, depletion of both neutrophils and monocytes/macrophages by anti-Gr-1 mAb prior to and after infection significantly promoted susceptibility of mice to CVB3 infection which was associated with exacerbated cardiac and pancreatic viral load. However, depletion of Gr1+ cells significantly suppressed acute myocarditis and pancreatic acini destruction at day 7 post infection via reducing Ly6Chigh monocyte population in the circulation. Additionally, cardiac interstitial fibrosis was not affected by neutrophil depletion, whereas Gr-1+ cells other than neutrophils increased cardiac fibrosis at day 21 p.i. by increasing cardiac expression of profibrotic cytokine TNF-α and TGF-ß. Thus, Neutrophil function is most likely not essential for CVB3 control and peripheral neutrophils play dispensable role in the pathogenesis of acute myocarditis and pancreatitis during CVB3 infection. Whereas Gr-1+ cells other than neutrophils play a major role in limiting viral replication while promoting myocardial and pancreatic inflammatory injury and fibrosis.


Assuntos
Antígenos Ly/imunologia , Infecções por Coxsackievirus/imunologia , Fibrose/induzido quimicamente , Miocardite/induzido quimicamente , Neutrófilos/imunologia , Receptores de Quimiocinas/imunologia , Replicação Viral/efeitos dos fármacos , Animais , Antígenos Ly/farmacologia , Infecções por Coxsackievirus/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrose/patologia , Coração/virologia , Inflamação , Leucócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/patologia , Neutropenia , Pâncreas/patologia , Pâncreas/virologia , Receptores de Quimiocinas/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Carga Viral
19.
Dermatitis ; 29(4): 179-186, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29939854

RESUMO

Allergic contact dermatitis (ACD) is a common skin disease that results in significant cost and morbidity. Despite its high prevalence, therapeutic options are limited. Allergic contact dermatitis is regulated primarily by T cells within the adaptive immune system, but also by natural killer and innate lymphoid cells within the innate immune system. The chemokine receptor system, consisting of chemokine peptides and chemokine G protein-coupled receptors, is a critical regulator of inflammatory processes such as ACD. Specific chemokine signaling pathways are selectively up-regulated in ACD, most prominently CXCR3 and its endogenous chemokines CXCL9, CXCL10, and CXCL11. Recent research demonstrates that these 3 chemokines are not redundant and indeed activate distinct intracellular signaling profiles such as those activated by heterotrimeric G proteins and ß-arrestin adapter proteins. Such differential signaling provides an attractive therapeutic target for novel therapies for ACD and other inflammatory diseases.


Assuntos
Quimiocinas/imunologia , Dermatite Alérgica de Contato/imunologia , Receptores de Quimiocinas/imunologia , Imunidade Adaptativa/imunologia , Dermatite Alérgica de Contato/tratamento farmacológico , Haptenos/imunologia , Humanos , Terapia de Alvo Molecular , Receptores CCR/imunologia , Receptores CCR4/imunologia , Receptores CXCR3/imunologia , Linfócitos T/imunologia
20.
Front Immunol ; 9: 873, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29740452

RESUMO

Interleukin-27 (IL-27) and its subunit P28 (also known as IL-30) have been shown to inhibit autoimmunity and have been suggested as potential immunotherapeutic for autoimmune diseases such as multiple sclerosis (MS). However, the potential of IL-27 and IL-30 as immunotherapeutic, and their mechanisms of action have not been fully understood. In this study, we evaluated the efficacy of adeno-associated viral vector (AAV)-delivered IL-27 (AAV-IL-27) and IL-30 (AAV-IL-30) in a murine model of MS. We found that one single administration of AAV-IL-27, but not AAV-IL-30 completely blocked the development of experimental autoimmune encephalomyelitis (EAE). AAV-IL-27 administration reduced the frequencies of Th17, Treg, and GM-CSF-producing CD4+ T cells and induced T cell expression of IFN-γ, IL-10, and PD-L1. However, experiments involving IL-10-deficient mice and PD-1 blockade revealed that AAV-IL-27-induced IL-10 and PD-L1 expression were not required for the prevention of EAE development. Surprisingly, neither AAV-IL-27 nor AAV-IL-30 treatment inhibited EAE development and Th17 responses when given at disease onset. We found that mice with established EAE had significant expansion of CD11b+Gr-1+ cells, and AAV-IL-27 treatment further expanded these cells and induced their expression of Th17-promoting cytokines such as IL-6. Adoptive transfer of AAV-IL-27-expanded CD11b+Gr-1+ cells enhanced EAE development. Thus, expansion of CD11b+Gr-1+ cells provides an explanation for the resistance to IL-27 therapy in mice with established disease.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Terapia Genética/métodos , Interleucina-27/imunologia , Esclerose Múltipla/imunologia , Células Mieloides/imunologia , Animais , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , Dependovirus/genética , Encefalomielite Autoimune Experimental/terapia , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-27/administração & dosagem , Interleucina-27/genética , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/terapia , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Resultado do Tratamento
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