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1.
Nature ; 579(7798): 284-290, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32103175

RESUMO

Cancer recurrence after surgery remains an unresolved clinical problem1-3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4-6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.


Assuntos
Epigênese Genética , Terapia Genética , Células Supressoras Mieloides/fisiologia , Neoplasias/terapia , Microambiente Tumoral , Animais , Azacitidina/farmacologia , Benzamidas/farmacologia , Diferenciação Celular , Movimento Celular/efeitos dos fármacos , Quimioterapia Adjuvante , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Camundongos , Células Supressoras Mieloides/citologia , Metástase Neoplásica/terapia , Neoplasias/cirurgia , Piridinas/farmacologia , Receptores CCR2/genética , Receptores de Interleucina-8B/genética , Microambiente Tumoral/efeitos dos fármacos
2.
Cell Mol Life Sci ; 76(24): 4869-4886, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31377844

RESUMO

The chemokine system mediates acute inflammation by driving leukocyte migration to damaged or infected tissues. However, elevated expression of chemokines and their receptors can contribute to chronic inflammation and malignancy. Thus, great effort has been taken to target these molecules. The first hint of the druggability of the chemokine system was derived from the role of chemokine receptors in HIV infection. CCR5 and CXCR4 function as essential co-receptors for HIV entry, with the former accounting for most new HIV infections worldwide. Not by chance, an anti-CCR5 compound, maraviroc, was the first FDA-approved chemokine receptor-targeting drug. CCR5, by directing leukocytes to sites of inflammation and regulating their activation, also represents an important player in the inflammatory response. This function is shared with CCR2 and its selective ligand CCL2, which constitute the primary chemokine axis driving the recruitment of monocytes/macrophages to inflammatory sites. Both receptors are indeed involved in the pathogenesis of several immune-mediated diseases, and dual CCR5/CCR2 targeting is emerging as a more efficacious strategy than targeting either receptor alone in the treatment of complex human disorders. In this review, we focus on the distinctive and complementary contributions of CCR5 and CCR2/CCL2 in HIV infection, multiple sclerosis, liver fibrosis and associated hepatocellular carcinoma. The emerging therapeutic approaches based on the inhibition of these chemokine axes are highlighted.


Assuntos
Quimiocina CCL2/genética , Inflamação/genética , Receptores CCR2/genética , Receptores CCR5/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Marcação de Genes , HIV/genética , HIV/patogenicidade , Infecções por HIV/genética , Infecções por HIV/terapia , Infecções por HIV/virologia , Humanos , Inflamação/terapia , Cirrose Hepática/genética , Cirrose Hepática/terapia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Esclerose Múltipla/genética , Esclerose Múltipla/terapia
3.
Immunohorizons ; 3(8): 412-421, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455692

RESUMO

Infection with the intestinal parasite Giardia duodenalis is one of the most common causes of diarrheal disease in the world. Previous work has demonstrated that the cells and mechanisms of the adaptive immune system are critical for clearance of this parasite. However, the innate system has not been as well studied in the context of Giardia infection. We have previously demonstrated that Giardia infection leads to the accumulation of a population of CD11b+, F4/80+, ARG1+, and NOS2+ macrophages in the small intestinal lamina propria. In this report, we sought to identify the accumulation mechanism of duodenal macrophages during Giardia infection and to determine if these cells were essential to the induction of protective Giardia immunity. We show that F4/80+, CD11b+, CD11cint, CX3CR1+, MHC class II+, Ly6C-, ARG1+, and NOS2+ macrophages accumulate in the small intestine during infections in mice. Consistent with this resident macrophage phenotype, macrophage accumulation does not require CCR2, and the macrophages incorporate EdU, indicating in situ proliferation rather than the recruitment of monocytes. Depletion of macrophages using anti-CSF1R did not impact parasite clearance nor development of regulatory T cell or Th17 cellular responses, suggesting that these macrophages are dispensable for protective Giardia immunity.


Assuntos
Giardia lamblia/imunologia , Giardíase/imunologia , Macrófagos/imunologia , Animais , Proliferação de Células/efeitos dos fármacos , Citocinas/genética , Nucleotídeos de Desoxiuracil/administração & dosagem , Nucleotídeos de Desoxiuracil/farmacologia , Duodeno/imunologia , Duodeno/parasitologia , Técnicas de Inativação de Genes , Giardíase/parasitologia , Intestino Delgado/imunologia , Macrófagos/classificação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membrana Mucosa/imunologia , Fenótipo , Receptores CCR2/genética , Receptores CCR2/metabolismo , Células Th17/imunologia
4.
Nat Commun ; 10(1): 3229, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324779

RESUMO

Bone marrow-derived circulating monocytes contribute to the replenishment and maintenance of the intestinal macrophage population. Intestinal monocytes undergo context-dependent phenotypic and functional adaptations to either maintain local immune balance or support intestinal inflammation. Here we use monocyte adoptive transfer to dissect the dynamics of monocyte-to-macrophage differentiation in normal and inflamed small intestine. We find that during homeostasis CCR2 and ß7-integrin mediate constitutive homing of monocytes to the gut. By contrast, intestinal inflammation increases monocyte recruitment via CCR2, but not ß7-integrin. In the non-inflamed intestine, monocytes gradually differentiate to express genes typically associated with tolerogenic macrophage functions. Conversely, immediately upon entry into the inflamed intestine, monocytes adapt a different expression pattern in a partly Trem-1-dependent manner. Our observations suggest that inflammation fundamentally changes the kinetics and modalities of monocyte differentiation in tissues.


Assuntos
Diferenciação Celular/imunologia , Inflamação/imunologia , Intestino Delgado/imunologia , Monócitos/imunologia , Transferência Adotiva , Animais , Diferenciação Celular/genética , Células Cultivadas , Inflamação/genética , Inflamação/metabolismo , Cadeias beta de Integrinas/genética , Cadeias beta de Integrinas/imunologia , Cadeias beta de Integrinas/metabolismo , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Monócitos/citologia , Monócitos/metabolismo , Receptores CCR2/genética , Receptores CCR2/imunologia , Receptores CCR2/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Receptor Gatilho 1 Expresso em Células Mieloides/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo
5.
PLoS Pathog ; 15(7): e1007847, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31306468

RESUMO

Salmonella exploit host-derived nitrate for growth in the lumen of the inflamed intestine. The generation of host-derived nitrate is dependent on Nos2, which encodes inducible nitric oxide synthase (iNOS), an enzyme that catalyzes nitric oxide (NO) production. However, the cellular sources of iNOS and, therefore, NO-derived nitrate used by Salmonella for growth in the lumen of the inflamed intestine remain unidentified. Here, we show that iNOS-producing inflammatory monocytes infiltrate ceca of mice infected with Salmonella. In addition, we show that inactivation of type-three secretion system (T3SS)-1 and T3SS-2 renders Salmonella unable to induce CC- chemokine receptor-2- and CC-chemokine ligand-2-dependent inflammatory monocyte recruitment. Furthermore, we show that the severity of the pathology of Salmonella- induced colitis as well as the nitrate-dependent growth of Salmonella in the lumen of the inflamed intestine are reduced in mice that lack Ccr2 and, therefore, inflammatory monocytes in the tissues. Thus, inflammatory monocytes provide a niche for Salmonella expansion in the lumen of the inflamed intestine.


Assuntos
Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Monócitos/metabolismo , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidade , Animais , Quimiocina CCL2/deficiência , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Feminino , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Monócitos/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores CCR2/deficiência , Receptores CCR2/genética , Receptores CCR2/metabolismo , Salmonelose Animal/metabolismo , Salmonelose Animal/microbiologia , Salmonelose Animal/patologia , Salmonella typhimurium/genética , Sistemas de Secreção Tipo III/metabolismo
6.
Virol Sin ; 34(5): 538-548, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31215000

RESUMO

Japanese encephalitis (JE) is a viral encephalitis disease caused by Japanese encephalitis virus (JEV) infection. Uncontrolled inflammatory responses in the central nervous system (CNS) are a hallmark of severe JE. Although the CCR2-CCL2 axis is important for monocytes trafficking during JEV infection, little is known about its role in CNS trafficking of CD8+ T cells. Here, we characterized a mouse model of JEV infection, induced via intravenous injection (i.v.) and delineated the chemokines and infiltrating peripheral immune cells in the brains of infected mice. The CNS expression of chemokines, Ccl2, Ccl3, and Ccl5, and their receptors, Ccr2 or Ccr5, was significantly up-regulated after JEV infection and was associated with the degree of JE pathogenesis. Moreover, JEV infection resulted in the migration of a large number of CD8+ T cells into the CNS. In the brains of JEV-infected mice, infiltrating CD8+ T cells expressed CCR2 and CCR5 and were found to comprise mainly effector T cells (CD44+CD62L-). JEV infection dramatically enhanced the expression of programmed death 1 (PD-1) on infiltrating CD8+ T cells in the brain, as compared to that on peripheral CD8+ T cells in the spleen. This effect was more pronounced on infiltrating CCR2+CD8+ T cells than on CCR2-CD8+ T cells. In conclusion, we identified a new subset of CD8+ T cells (PD1+CCR2+CD8+ T cells) present in the CNS of mice during acute JEV infection. These CD8+ T cells might play a role in JE pathogenesis.


Assuntos
Encéfalo/imunologia , Linfócitos T CD8-Positivos/imunologia , Movimento Celular , Encefalite Japonesa/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptores CCR2/imunologia , Doença Aguda , Animais , Encéfalo/patologia , Encéfalo/virologia , Modelos Animais de Doenças , Vírus da Encefalite Japonesa (Espécie) , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/genética , Receptores CCR2/genética , Subpopulações de Linfócitos T/imunologia , Regulação para Cima
7.
Glia ; 67(8): 1434-1448, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31179602

RESUMO

Microglial activation has been recognized as a major contributor to inflammation of the epileptic brain. Seizures are commonly accompanied by remarkable microgliosis and loss of neurons. In this study, we utilize the CX3CR1GFP/+ CCR2RFP/+ genetic mouse model, in which CX3CR1+ resident microglia and CCR2+ monocytes are labeled with GFP and RFP, respectively. Using a combination of time-lapse two-photon imaging and whole-cell patch clamp recording, we determined the distinct morphological, dynamic, and electrophysiological characteristics of infiltrated monocytes and resident microglia, and the evolution of their behavior at different time points following kainic acid-induced seizures. Seizure activated microglia presented enlarged somas with less ramified processes, whereas, infiltrated monocytes were smaller, highly motile cells that lacked processes. Moreover, resident microglia, but not infiltrated monocytes, proliferate locally in the hippocampus after seizure. Microglial proliferation was dependent on the colony-stimulating factor 1 receptor (CSF-1R) pathway. Pharmacological inhibition of CSF-1R reduced seizure-induced microglial proliferation, which correlated with attenuation of neuronal death without altering acute seizure behaviors. Taken together, we demonstrated that proliferation of activated resident microglia contributes to neuronal death in the hippocampus via CSF-1R after status epilepticus, providing potential therapeutic targets for neuroprotection in epilepsy.


Assuntos
Proliferação de Células , Gliose/fisiopatologia , Microglia/fisiologia , Monócitos/fisiologia , Estado Epiléptico/fisiopatologia , Animais , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Morte Celular , Modelos Animais de Doenças , Gliose/etiologia , Hipocampo/fisiopatologia , Ácido Caínico , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Neurônios/fisiologia , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptores CCR2/genética , Receptores CCR2/metabolismo , Estado Epiléptico/complicações , Técnicas de Cultura de Tecidos
8.
Nat Commun ; 10(1): 2410, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160587

RESUMO

Medulloblastoma, which is the most common malignant paediatric brain tumour, has a 70% survival rate, but standard treatments often lead to devastating life-long side effects and recurrence is fatal. One of the emerging strategies in the search for treatments is to determine the roles of tumour microenvironment cells in the growth and maintenance of tumours. The most attractive target is tumour-associated macrophages (TAMs), which are abundantly present in the Sonic Hedgehog (SHH) subgroup of medulloblastoma. Here, we report an unexpected beneficial role of TAMs in SHH medulloblastoma. In human patients, decreased macrophage number is correlated with significantly poorer outcome. We confirm macrophage anti-tumoural behaviour in both ex vivo and in vivo murine models of SHH medulloblastoma. Taken together, our findings suggest that macrophages play a positive role by impairing tumour growth in medulloblastoma, in contrast to the pro-tumoural role played by TAMs in glioblastoma, another common brain tumour.


Assuntos
Neoplasias Cerebelares/imunologia , Macrófagos/imunologia , Meduloblastoma/imunologia , Microambiente Tumoral/imunologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Proteínas de Ligação ao Cálcio , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Quimiocina CCL2/imunologia , Quimiocina CCL2/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Proteínas Hedgehog/metabolismo , Humanos , Macrófagos/metabolismo , Meduloblastoma/genética , Meduloblastoma/metabolismo , Camundongos , Proteínas dos Microfilamentos , Microglia/imunologia , Células Mieloides/imunologia , Receptores CCR2/genética , Regulação para Cima
9.
Nat Microbiol ; 4(8): 1389-1400, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31110361

RESUMO

Host defence against influenza A virus (IAV) infection depends not only on host resistance to eliminate the virus, but also disease tolerance to limit lung tissue damage and maintain pulmonary function. Fatal IAV infections are frequently the result of a maladaptive immune response that compromises disease tolerance rather than host resistance to infection. Here, we show that the leukotriene B4 (LTB4)-type I interferon (IFN) axis promotes a distinct mechanism of disease tolerance to pulmonary IAV infection. We demonstrate that mice genetically deficient in LTB4 signalling (Blt1R-/-) are more susceptible to IAV infection compared to control mice, despite similar pulmonary viral loads. The increased susceptibility of Blt1R-/- mice is associated with an accumulation of inflammatory monocyte-derived macrophages (IMMs) causing increased lung immunopathology. We mechanistically define that LTB4 signalling via the BLT1 receptor enhances the activation of the type I IFN-α/ß receptor (IFNAR)/ and signal transducer and activator of transcription 1 (STAT1), which leads to IFN-α production by interstitial macrophages to suppresse in situ IMM proliferation. Importantly, the delivery of a single dose of LTB4 at the peak viral load reduces IMM proliferation, controls tissue damage and increases survival without affecting host resistance to IAV. These results reveal an unexpected anti-inflammatory role of LTB4 in disease tolerance to IAV infection.


Assuntos
Tolerância Imunológica , Imunidade Inata/imunologia , Influenza Humana/imunologia , Interferon Tipo I/metabolismo , Leucotrieno B4/metabolismo , Macrófagos/metabolismo , Animais , Morte Celular , Linhagem Celular , Proliferação de Células , Humanos , Vírus da Influenza A/imunologia , Influenza Humana/patologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/imunologia , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores CCR2/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais
10.
Food Funct ; 10(6): 3303-3311, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31094410

RESUMO

The present study aimed to test the mechanisms by which GPETAFLR, released from the enzymatic hydrolysis of lupine protein, may modulate the inflammatory response and plasticity in human primary monocytes. Human circulating monocytes and mature macrophages were used to analyze the effects of GPETAFLR on plasticity and inflammatory response using biochemical, flow cytometry, quantitative real-time PCR, and ELISA assays. GPETAFLR skewed the monocyte plasticity towards the anti-inflammatory non-classical CD14+CD16++ monocyte subset and reduced the inflammatory competence of LPS-treated human monocytes diminishing IL-1ß, IL-6, and TNF-α and increasing IL-10 production and gene expression. Results showed that GPETAFLR decreased the frequency of the LPS-induced activated monocyte population (CD14++CD16-), diminished monocyte activation involved down-regulation of CCR2 mRNA expression and protein expression, and decreased gene expression of the LPS-induced chemoattractant mediator CCL2. Our findings imply a new understanding of the mechanisms by which GPETAFLR favor a continuous and gradual plasticity process in the human monocyte/macrophage system and offer novel benefits derived from the consumption of Lupinus angustifolius L. in the prevention of inflammatory-related diseases.


Assuntos
Lupinus/química , Monócitos/efeitos dos fármacos , Peptídeos/farmacologia , Proteínas de Plantas/química , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Monócitos/imunologia , Peptídeos/química , Peptídeos/isolamento & purificação , Hidrolisados de Proteína/química , Receptores CCR2/genética , Receptores CCR2/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
11.
Life Sci ; 228: 72-84, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31034839

RESUMO

AIMS: Calcific aortic valve disease (CAVD) emerges as a challenging clinical issue, which is associated with high cardiovascular mortality. It has been demonstrated that osteoblastic transformation of AVICs is a key mechanism of CAVD and C-C motif chemokine receptors (CCRs) may favor this process. Thus, we aimed to investigate whether CCRs were involved in osteoblastic transformation of AVICs during the development CAVD. MAIN METHODS: We first analyzed microarray data (GSE51472 and GSE12644) to identify differentially expressed genes between CAVD aortic valve tissue and normal samples, followed by verification of immunohistochemistry, qPCR and western blotting. Primary aortic valvular interstitial cells (AVICs) were incubated with specific inhibitors and/or siRNA of CCR2 and CCL2 under pro-calcifying medium. The levels of CCL2 in the medium were measured by ELISA. In addition, we used recombinant CCL2 to activate CCR2 in calcifying AVICs. Alizarin red S staining and calcium deposition were used to evaluate the degree of calcification. Western blotting was used to determine osteoblastic transformation of AVIC and total Akt and phosphorylated Akt expression. KEY FINDING: CCR2 levels were remarkably up-regulated in calcified aortic valve and calcifying AVICs. Silencing CCR2 inhibited the osteoblastic transformation and calcification of AVICs. In addition, recombinant CCL2 activated CCR2 and accelerated AVICs calcification through PI3K/Akt pathway. SIGNIFICANCE: We characterize abnormal activation of CCL2/CCR2 axis as a promoter of AVICs osteoblastic transformation and calcification. Our findings implicate the CCL2/CCR2-PI3K/Akt pathway as a potential target for treatment of CAVD.


Assuntos
Estenose da Valva Aórtica/patologia , Valva Aórtica/patologia , Calcinose/patologia , Osteoblastos/patologia , Receptores CCR2/metabolismo , Adulto , Idoso , Animais , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Calcinose/genética , Calcinose/metabolismo , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoblastos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Ratos Sprague-Dawley , Receptores CCR2/análise , Receptores CCR2/genética , Transdução de Sinais , Transcriptoma , Regulação para Cima
12.
J Ethnopharmacol ; 238: 111878, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30986521

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Dahuang Zhechong Pill (DZP) is a classical formula from "Synopsis of Prescriptions of the Golden Chamber". It has been used for treatment of abdominal masses (including tumorous diseases) for thousands of years. AIM OF THE STUDY: Our previous work showed that DZP suppresses CCl-4 induced hepatic fibrosis by downregulating the expression of interleukin-13. We aimed to test if DZP suppresses the metastasis of colorectal cancer (CRC) by ameliorating the fibrosis status of the future metastatic organ. MATERIALS AND METHODS: Liver metastasis was observed by injection of MC38-EGFP cells with stably expressing enhanced green fuorescence protein beneath the splenic capsule of C57BL/6J mice. MC38-EGFP-derived exosomes were analyzed by Label-free comparative proteomics. mRNA expression was determined by Quantitative PCR. Protein expression was determined by immunohistochemistry, immunofuorescence and Western blot. Collagen deposition was determined by Masson staining. All data were statistically analyzed using SPSS. RESULTS: DZP drastically reduced the metastatic tumor number and fluorescence intensity in a splenic liver metastasis model. It also lowered the expression of mature TGF-ß1 and decreased the fibronectin contents & collagen deposition. Exosome proteomics showed that the upregualted CC chemokine ligand-2 (CCL2) was repressed by DZP treatment. Importantly, DZP markedly lowered the expression of CCL2 and its receptor CCR2 in the liver. Exosomal CCL2 activated macrophage recruitment and shifted the M1/M2 paradigm to a M2 phenotype. DZP reduced the macrophage infiltration and attenuated the M2 polarizaion in tumor-bearing mice liver. It decreased the F4/80 positive areas and specifically reduced the ratio of CCR2+ positive macrophage. Anti-fibrosis and inhibition of CCR2 suppress the growth and metastasis of CRC. CONCLUSIONS: DZP inhibits the liver metastasis of CRC by suppressing CCL2 mediated M2-skewing paradigm and ameliorating the pro-fibrotic microenvironment.


Assuntos
Quimiocina CCL2/metabolismo , Neoplasias Colorretais/patologia , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Hepáticas/secundário , Metástase Neoplásica/prevenção & controle , Antineoplásicos Fitogênicos , Neoplasias Colorretais/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Cirrose Hepática/prevenção & controle , Macrófagos , Neoplasias Experimentais/tratamento farmacológico , Piridonas/farmacologia , Pirrolidinonas/farmacologia , Receptores CCR2/genética , Receptores CCR2/metabolismo
13.
PLoS One ; 14(3): e0214421, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30921390

RESUMO

OBJECTIVE: We investigated the association of genetic polymorphisms in chemokine and chemokine receptor genes with poor immunological recovery in HIV patients starting combined antiretroviral therapy (cART) with low CD4 T-cell counts. METHODS: A case-control study was conducted in 412 HIV-infected patients starting cART with CD4 T-cell count <200 cells/µL and successful viral control for two years. CD4 count increase below 200 cells/µL after two years on cART was used to define INR (immunological non-responder) patients. Polymorphisms in CXCL12, CCL5 and CCR2 genes were genotyped using sequenom's MassARRAY platform. RESULTS: Thirty two percent (134/412) of patients were classified as INR. After adjusting by age, route of HIV infection, length of infection before cART and viral hepatitis coinfection, CCR2 rs1799864-AG genotype was significantly associated with INR status (OR [95% CI]: 1.80 [1.04-3.11]; p = 0.04), and CXCL12 rs1801157-TT genotype showed a trend (OR [95% CI]: 2.47 [0.96-6.35]; p = 0.06). CONCLUSIONS: CCR2 rs1799864-AG or CXCL12 rs1801157-TT genotypes influence on the probability of poor CD4 recovery in the population of HIV patients starting cART with low CD4 counts. Genotyping of these polymorphisms could be used to estimate the risk of poor CD4 restoration, mainly in patients who are diagnosed late in the course of infection.


Assuntos
Terapia Antirretroviral de Alta Atividade , Quimiocina CXCL12/genética , Tolerância Imunológica/genética , Polimorfismo Genético , Receptores CCR2/genética , Adulto , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/imunologia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Replicação Viral/efeitos dos fármacos
14.
Oncol Rep ; 41(4): 2491-2501, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816510

RESUMO

Benign prostatic hyperplasia (BPH) is a common chronic disease in older males. The pathogenesis of BPH remains elusive but may be associated with chronic inflammation. Chemokines and chemokine receptors have been implicated as critical mediators in the immune response and inflammatory processes. In the present study, the aim was to evaluate the association of three polymorphisms in chemokine genes, namely C­C motif chemokine ligand (CCL)2 rs1024611, CC chemokine receptor 2 (CCR2) rs1799864 and CCL5 rs2107538, with BPH risk. These polymorphisms were genotyped in 109 patients with BPH and 160 control subjects, using the polymerase chain reaction and multiple ligase detection reaction method. The CCL5 rs2107538 polymorphism was identified to be associated with a significantly lower risk of BPH [A/G vs. G/G: odds ratio (OR)=0.37, 95% confidence interval (CI)=0.17­0.78; A/A + A/G vs. G/G: OR=0.39, 95% CI=0.19­0.79; A vs. G: OR=0.58, 95% CI=0.35­0.96). However, this polymorphism was also associated with the development of larger prostate volumes in patients with BPH (A/G vs. G/G: OR=3.02, 95% CI=1.28­7.11; AA + AG vs. GG: OR=2.83, 95% CI=1.28­6.26; A vs. G: OR=1.94, 95% CI=1.08­3.49). The CCR2 rs1799864 polymorphism was associated with lower International Prostate Symptom Score values (A/A + A/G vs. G/G: OR=0.39, 95% CI=0.17­0.91; A vs. G: OR=0.43, 95% CI=0.20­0.90) and low Qmax (A/G vs. G/G: OR=0.38, 95% CI=0.16­0.92; AA + AG vs. GG: OR=0.39, 95% CI=0.17­0.91) in the patients. No association was observed between the CCL2 rs1024611 polymorphism and BPH. These results suggest that the CCR2 and CCL5 genes may contribute to the occurrence and progression of BPH.


Assuntos
Quimiocina CCL2/genética , Quimiocina CCL5/genética , Predisposição Genética para Doença , Hiperplasia Prostática/genética , Receptores CCR2/genética , Idoso , Estudos de Casos e Controles , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Polimorfismo de Nucleotídeo Único , Próstata/patologia , Hiperplasia Prostática/patologia , Fatores de Risco
15.
PLoS Pathog ; 15(3): e1007627, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30897162

RESUMO

Cryptococcus neoformans is a leading cause of invasive fungal infections among immunocompromised patients. However, the cellular constituents of the innate immune response that promote clearance versus progression of infection upon respiratory acquisition of C. neoformans remain poorly defined. In this study, we found that during acute C. neoformans infection, CCR2+ Ly6Chi inflammatory monocytes (IM) rapidly infiltrate the lungs and mediate fungal trafficking to lung-draining lymph nodes. Interestingly, this influx of IM is detrimental to the host, since ablating IM or impairing their recruitment to the lungs improves murine survival and reduces fungal proliferation and dissemination. Using a novel conditional gene deletion strategy, we determined that MHC class II expression by IM did not mediate their deleterious impact on the host. Furthermore, although ablation of IM reduced the number of lymphocytes, innate lymphoid cells, and eosinophils in the lungs, the effects of IM were not dependent on these cells. We ascertained that IM in the lungs upregulated transcripts associated with alternatively activated (M2) macrophages in response to C. neoformans, consistent with the model that IM assume a cellular phenotype that is permissive for fungal growth. We also determined that conditional knockout of the prototypical M2 marker arginase 1 in IM and deletion of the M2-associated transcription factor STAT6 were not sufficient to reverse the harmful effects of IM. Overall, our findings indicate that C. neoformans can subvert the fungicidal potential of IM to enable the progression of infection through a mechanism that is not dependent on lymphocyte priming, eosinophil recruitment, or downstream M2 macrophage polarization pathways. These results give us new insight into the plasticity of IM function during fungal infections and the level of control that C. neoformans can exert on host immune responses.


Assuntos
Criptococose/imunologia , Monócitos/fisiologia , Receptores CCR2/metabolismo , Animais , Criptococose/patologia , Cryptococcus neoformans/metabolismo , Cryptococcus neoformans/patogenicidade , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/imunologia , Imunidade Inata/fisiologia , Inflamação/imunologia , Inflamação/microbiologia , Pulmão/patologia , Pneumopatias Fúngicas/fisiopatologia , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Monócitos/microbiologia , Receptores CCR2/genética
16.
Int J Mol Sci ; 20(3)2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30764543

RESUMO

Colorectal cancer is the source of one of the most common cancer-related deaths worldwide, where the main cause of patient mortality remains metastasis. The aim of this study was to determine the role of CCL7 (chemokine (C-C motif) ligand 7) in tumor progression and finding whether it could predict survival of colorectal cancer patients. Initially, our study focused on the crosstalk between mesenchymal stem cells (MSCs) and CT26 colon carcinoma cells and resulted in identifying CCL7 as a chemokine upregulated in CT26 colon cancer cells cocultured with MSCs, compared with CT26 in monoculture in vitro. Moreover, we showed that MSCs enhance CT26 tumor cell proliferation and migration. We analyzed the effect of CCL7 overexpression on tumor progression in a murine CT26 model, where cells overexpressing CCL7 accelerated the early phase of tumor growth and caused higher lung metastasis rates compared with control mice. Microarray analysis revealed that tumors overexpressing CCL7 had lower expression of immunoglobulins produced by B lymphocytes. Additionally, using Jh mutant mice, we confirmed that in the CT26 model, CCL7 has an immunoglobulin-, and thereby, B-cell-dependent effect on metastasis formation. Finally, higher expression of CCL7 receptor CCR2 (C-C chemokine receptor type 2) was associated with shorter overall survival of colorectal cancer patients. Altogether, we showed that CCL7 is essentially involved in the progression of colorectal cancer in a CT26 mouse model and that the expression of its receptor CCR2 could be related to a different outcome pattern of patients with colorectal carcinoma.


Assuntos
Quimiocina CCL7/genética , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Receptores CCR2/genética , Regulação para Cima , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocina CCL7/análise , Neoplasias do Colo/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Receptores CCR2/análise
17.
PLoS Negl Trop Dis ; 13(1): e0007033, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30650073

RESUMO

Several studies have proposed different genetic markers of susceptibility to develop chronic Chagas cardiomyopathy (CCC). Many genes may be involved, each one making a small contribution. For this reason, an appropriate approach for this problematic is to study a large number of single nucleotide polymorphisms (SNPs) in individuals sharing a genetic background. Our aim was to analyze two CCR2 and seven CCR5 SNPs and their association to CCC in Argentina. A case-control study was carried out in 480 T. cruzi seropositive adults from Argentinean Gran Chaco endemic region (Wichi and Creole) and patients from Buenos Aires health centres. They were classified according to the Consensus on Chagas-Mazza Disease as non-demonstrated (non-DC group) or demonstrated (DC group) cardiomyopathy, i.e. asymptomatic or with CCC patients, respectively. Since, after allelic analysis, 2 out of 9 studied SNPs did not fit Hardy-Weinberg equilibrium in the unaffected non-DC group from Wichi patients, we analyzed them as a separate population. Only rs1800024T and rs41469351T in CCR5 gene showed significant differences within non-Wichi population (Creole + patients from Buenos Aires centres), being the former associated to protection, and the latter to risk of CCC. No evidence of association was observed between any of the analyzed CCR2-CCR5 gene polymorphisms and the development of CCC; however, the HHE haplotype was associated with protection in Wichi population. Our findings support the hypothesis that CCR2-CCR5 genes and their haplotypes are associated with CCC; however, depending on the population studied, different associations can be found. Therefore, the evolutionary context, in which the genes or haplotypes are associated with diseases, acquires special relevance.


Assuntos
Cardiomiopatia Chagásica/genética , Predisposição Genética para Doença , Receptores CCR2/genética , Receptores CCR5/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Argentina , Estudos de Casos e Controles , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
18.
J Pediatr (Rio J) ; 95(3): 350-357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29733805

RESUMO

OBJECTIVE: The prevalence of non-alcoholic fatty liver disease in children has risen significantly, owing to the worldwide childhood obesity epidemic in the last two decades. Non-alcoholic fatty liver disease is closely linked to sedentary lifestyle, increased body mass index, and visceral adiposity. In addition, individual genetic variations also have a role in the development and progression of non-alcoholic fatty liver disease. The aim of this study was to investigate the gene polymorphisms of MCP-1 (-2518 A/G) (rs1024611), CCR-2 (190 G/A) (rs1799864), ABCA1 (883 G/A) (rs4149313), and IL-17A (-197 G/A) (rs2275913) in obese Turkish children with non-alcoholic fatty liver disease. METHODS: The study recruited 186 obese children aged 10-17 years, including 101 children with non-alcoholic fatty liver disease and 85 children without non-alcoholic fatty liver disease. Anthropometric measurements, insulin resistance, a liver panel, a lipid profile, liver ultrasound examination, and genotyping of the four variants were performed. RESULTS: No difference was found between the groups in respect to age and gender, body mass index, waist/hip ratio, or body fat ratio. In addition to the elevated ALT levels, AST and GGT levels were found significantly higher in the non-alcoholic fatty liver disease group compared to the non non-alcoholic fatty liver disease group (p<0.05). The A-allele of IL-17A (-197 G/A) (rs2275913) was associated with non-alcoholic fatty liver disease (odds ratio [OR] 2.05, 95% confidence interval: 1.12-3.77, p=0.02). CONCLUSIONS: The findings of this study suggest that there may be an association between IL-17A (-197 G/A) (rs2275913) polymorphism and non-alcoholic fatty liver disease development in obese Turkish children.


Assuntos
Hepatopatia Gordurosa não Alcoólica/genética , Obesidade Pediátrica/complicações , Polimorfismo Genético/genética , Transportador 1 de Cassete de Ligação de ATP/genética , Adolescente , Índice de Massa Corporal , Quimiocina CCL2/genética , Criança , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Interleucina-17/genética , Masculino , Hepatopatia Gordurosa não Alcoólica/complicações , Receptores CCR2/genética
19.
Br J Biomed Sci ; 76(1): 11-16, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30175654

RESUMO

BACKGROUND: Polymorphisms of certain genes may have an effect on either persistence of infection or spontaneous clearance of hepatitis C virus (HCV). We hypothesized that one or more variants of chemokines (CCL2 and CCL5) and chemokine receptors (CC chemokine receptor type 2 [CCR2]) genes are associated with the susceptibility to HCV infection. METHODS: We recruited 1460 patients with chronic HCV (CHC), 108 subjects with spontaneous virus clearance (SVC) and 1446 individuals as a healthy control group. All were genotyped for single nucleotide polymorphisms: rs13900 C/T of CCL2, rs3817655 T/A of CCL5 and rs743660 G/A and rs1799864 G/A of CCR2 using allelic discrimination real-time PCR technique. RESULTS: The carriage of the A allele of CCR2 rs743660 was significantly higher in CHC compared to SVC (odds ratio [OR] 4.03) and to controls (1.42) and in controls compared to SVC (2.85) (all P < 0.01). Similarly, the A allele of CCR2 rs1799864 was significantly higher in the CHC group when compared with both SVC (1.97) and controls (2.13) (both P < 0.01), but the OR between controls and SVC was not significant (1.08, P = 0.723). Carriage of C allele of CCL2 rs13900 and the T allele of CCL5 rs3817655 were significantly higher in SVC group when compared with both CHC (OR = 0.19 and OR = 0.24, respectively) and control groups (OR = 0.65 and OR = 0.45, respectively [all P < 0.01]). CONCLUSIONS: Susceptibility to HCV infection is associated with A alleles of both (rs743660 and rs1799864 G/A) of CCR2 while spontaneous clearance of HCV is associated with the C allele of rs13900 of CCL2 and T allele of rs3817655 of CCL5.


Assuntos
Quimiocina CCL2/genética , Quimiocina CCL5/genética , Predisposição Genética para Doença , Hepacivirus/imunologia , Hepatite C Crônica/genética , Polimorfismo de Nucleotídeo Único , Receptores CCR2/genética , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Quimiocina CCL2/imunologia , Quimiocina CCL5/imunologia , Criança , Feminino , Expressão Gênica , Frequência do Gene , Hepacivirus/crescimento & desenvolvimento , Hepacivirus/patogenicidade , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Receptores CCR2/imunologia , Remissão Espontânea
20.
Mol Cancer Res ; 17(2): 604-617, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30446625

RESUMO

Basal-like breast cancers are an aggressive breast cancer subtype, which often lack estrogen receptor, progesterone receptor, and Her2 expression, and are resistant to antihormonal and targeted therapy, resulting in few treatment options. Understanding the underlying mechanisms that regulate progression of basal-like breast cancers would lead to new therapeutic targets and improved treatment strategies. Breast cancer progression is characterized by inflammatory responses, regulated in part by chemokines. The CCL2/CCR2 chemokine pathway is best known for regulating breast cancer progression through macrophage-dependent mechanisms. Here, we demonstrated important biological roles for CCL2/CCR2 signaling in breast cancer cells. Using the MCF10CA1d xenograft model of basal-like breast cancer, primary tumor growth was significantly increased with cotransplantation of patient-derived fibroblasts expressing high levels of CCL2, and was inhibited with CRISP/R gene ablation of stromal CCL2. CRISP/R gene ablation of CCR2 in MCF10CA1d breast cancer cells inhibited breast tumor growth and M2 macrophage recruitment and validated through CCR2 shRNA knockdown in the 4T1 model. Reverse phase protein array analysis revealed that cell-cycle protein expression was associated with CCR2 expression in basal-like breast cancer cells. CCL2 treatment of basal-like breast cancer cell lines increased proliferation and cell-cycle progression associated with SRC and PKC activation. Through pharmacologic approaches, we demonstrated that SRC and PKC negatively regulated expression of the cell-cycle inhibitor protein p27KIP1, and are necessary for CCL2-induced breast cancer cell proliferation. IMPLICATIONS: This report sheds novel light on CCL2/CCR2 chemokine signaling as a mitogenic pathway and cell-cycle regulator in breast cancer cells.


Assuntos
Neoplasias da Mama/metabolismo , Proteína Quinase C/metabolismo , Receptores CCR2/metabolismo , Quinases da Família src/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ciclo Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Quimiocina CCL2/metabolismo , Progressão da Doença , Ativação Enzimática , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Receptores CCR2/genética , Transdução de Sinais
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