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1.
Scand J Immunol ; 90(6): e12832, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31544253

RESUMO

We aimed to analyse the relative abundance of miR-505 in age-related macular degeneration (AMD) and elucidate its underlying mechanisms. Relative expression of miR-505 was analysed by real-time polymerase chain reaction (PCR). Macrophage polarization was characterized by measurement of molecular markers including Ym-1, Arg-1, TNF-α and iNOS via both real-time PCR and Western blot. Vascular endothelial growth factor (VEGF) content was determined by enzyme-linked immunosorbent assay. Choroidal neovascularization (CNV) formation was evaluated by choroidal flat mount technique. The regulatory action of miR-505-5p on 3'UTR of Transmembrane Protein 229B (TMEM229B) was interrogated by luciferase reporter assay. miR-505 was aberrantly upregulated in both AMD and laser-induced choroidal neovascularization mouse model. Administration with miR-505 specific inhibitor suppressed M2 polarization in CNV mice as indicated by decreasing both Ym-1 and Arg-1. Meanwhile, VEGF expression and CNV formation were greatly suppressed by miR-505 inhibition as well. The similar phenotype was consolidated in Prostaglandin E2 (PGE2)-stimulated bone marrow-derived macrophages. At the molecular level, miR-505-5p directly targeted and negatively regulated TMEM229B expression, while forced ectopic expression of TMEM229B significantly rescued miR-505-imposed M2 polarization. Our data have uncovered the critical contribution of miR-505 in AMD, which is predominantly mediated by downregulation of TMEM229B.


Assuntos
Neovascularização de Coroide/etiologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Proteínas de Membrana/genética , MicroRNAs/genética , Animais , Neovascularização de Coroide/patologia , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Modelos Animais de Doenças , Expressão Gênica , Regulação da Expressão Gênica , Genes Reporter , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Interferência de RNA , Fator A de Crescimento do Endotélio Vascular/genética
2.
Nat Commun ; 10(1): 3978, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484936

RESUMO

The pH in atherosclerotic lesions varies between individuals. IgE activates macrophage Na+-H+ exchanger (Nhe1) and induces extracellular acidification and cell apoptosis. Here, we show that the pH-sensitive pHrodo probe localizes the acidic regions in atherosclerotic lesions to macrophages, IgE, and cell apoptosis. In Apoe-/- mice, Nhe1-deficiency or anti-IgE antibody reduces atherosclerosis and blocks lesion acidification. Reduced atherosclerosis in Apoe-/- mice receiving bone marrow from Nhe1- or IgE receptor FcεR1-deficient mice, blunted foam cell formation and signaling in IgE-activated macrophages from Nhe1-deficient mice, immunocomplex formation of Nhe1 and FcεR1 in IgE-activated macrophages, and Nhe1-FcεR1 colocalization in atherosclerotic lesion macrophages support a role of IgE-mediated macrophage Nhe1 activation in atherosclerosis. Intravenous administration of a near-infrared fluorescent pH-sensitive probe LS662, followed by coregistered fluorescent molecular tomography-computed tomography imaging, identifies acidic regions in atherosclerotic lesions in live mice, ushering a non-invasive and radiation-free imaging approach to monitor atherosclerotic lesions in live subjects.


Assuntos
Aterosclerose/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Trocador 1 de Sódio-Hidrogênio/metabolismo , Ácidos/química , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apoptose/genética , Aterosclerose/genética , Humanos , Concentração de Íons de Hidrogênio , Ativação de Macrófagos/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/genética , Transdução de Sinais/genética , Trocador 1 de Sódio-Hidrogênio/genética
3.
Technol Cancer Res Treat ; 18: 1533033819868225, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31401938

RESUMO

OBJECTIVE: Tumor-treating fields are currently used to successfully treat various cancers; however, the specific pathways associated with its efficacy remain unknown in the immune responses. Here, we evaluated tumor-treating fields-mediated initiation of the macrophage-specific immune response. MATERIALS AND METHODS: We subjected RAW 264.7 mouse macrophages to clinically relevant levels of tumor-treating fields (0.9 V/cm, 150 kHz) and evaluated alterations in cytokine expression and release, as well as cell viability. Additionally, we investigated the status of immunomodulatory pathways to determine their roles in tumor-treating fields-mediated immune activation. RESULTS AND DISCUSSION: Our results indicated that tumor-treating fields treatment at 0.9 V/cm decreased cell viability and increased cytokine messenger RNA/protein levels, as well as levels of nitric oxide and reactive oxygen species, relative to controls. The levels of tumor necrosis factor α, interleukin 1ß, and interleukin 6 were markedly increased in tumor-treating fields-treated RAW 264.7 cells cocultured with 4T1 murine mammary carcinoma cells compared with those in 4T1 or RAW 264.7 cells with or without tumor-treating fields treatment. Moreover, the viability of 4T1 cells treated with the conditioned medium of tumor-treating fields-stimulated RAW 264.7 cells decreased, indicating that macrophage activation by tumor-treating fields effectively killed the tumor cells. Moreover, tumor-treating fields treatment activated the nuclear factor κB and mitogen-activated protein kinase pathways involved in immunomodulatory signaling. CONCLUSION: These results provide critical insights into the mechanisms through which tumor-treating fields affect macrophage-specific immune responses and the efficacy of this method for cancer treatment.


Assuntos
Antígenos de Histocompatibilidade Classe II/imunologia , Ativação de Macrófagos/imunologia , Terapia de Campo Magnético , Neoplasias/radioterapia , Animais , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/efeitos da radiação , Humanos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Ativação de Macrófagos/genética , Ativação de Macrófagos/efeitos da radiação , Macrófagos/imunologia , Macrófagos/efeitos da radiação , Camundongos , NF-kappa B/genética , Neoplasias/imunologia , Neoplasias/patologia , Células RAW 264.7 , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos da radiação
4.
Int J Mol Sci ; 20(15)2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31382688

RESUMO

We recently reported that neonatal ischemia induces microglia/macrophage activation three days post-ischemia. We also found that female mice sustained smaller infarcts than males three months post-ischemia. The objective of our current study was to examine whether differential acute neuroinflammatory response and infiltrated immune cells occurs between male and females after three days post-ischemia. Permanent middle cerebral artery occlusion was induced in male and female postnatal 9-day-old (P9) mice, and mice were sacrificed three days after ischemia. Brains were analyzed for mRNA transcription after microglia magnetic cell sorting to evaluate M1 and M2 markers. FACS analysis was performed to assess myeloid infiltration and microglial expression of CX3 chemokine receptor 1 (CX3CR1). Inflammatory cytokine expression and microglia/macrophage activation were analyzed via in situ hybridization combined with immunofluorescence techniques. Lesion volume and cell death were measured. An increase in microglia/macrophages occurred in male versus female mice. The cells exhibited amoeboid morphology, and TNFα and ptgs2 (Cox-2) genes were more expressed in males. More myeloid cell infiltration was found in male versus female brains. However, we did not observe sex-dependent differences in the injured volume or cell death density. Our data show that sex differences in the acute microglial and immune responses to neonatal ischemia are likely both gene- and region-specific.


Assuntos
Isquemia Encefálica/imunologia , Imunidade Inata/genética , Inflamação/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Animais Recém-Nascidos/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Feminino , Infarto da Artéria Cerebral Média , Inflamação/genética , Inflamação/patologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Caracteres Sexuais , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia
5.
Genomics ; 111(4): 986-996, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31307632

RESUMO

The underlying mechanisms of macrophage polarization have been detected by genome-wide transcriptome analysis in a variety of mammals. However, the transcriptome profile of rat genes in bone marrow-derived macrophages (BMM) at different activation statuses has not been reported. Therefore, we performed RNA-Sequencing to identify gene expression signatures of rat BMM polarized in vitro with different stimuli. The differentially expressed genes (DEGs) among unactivated (M0), classically activated pro-inflammatory (M1), and alternatively activated anti-inflammatory macrophages (M2) were analyzed by using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In this study, not only we have identified the changes of global gene expression in rat M0, M1 and M2, but we have also made clear systematically the key genes and signaling pathways in the differentiation process of M0 to M1 and M2. These will provide a foundation for future researches of macrophage polarization.


Assuntos
Ativação de Macrófagos/genética , Macrófagos/imunologia , Transcriptoma , Animais , Células Cultivadas , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA , Transdução de Sinais
6.
Int J Mol Sci ; 20(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336892

RESUMO

BACKGROUND: Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP-4). It plays an important role in macrophage inflammatory responses through the negative regulation of Mitogen activated protein kinase (MAPK) signalling. However, information on the effect of MKP-2 on other aspect of macrophage function is limited. METHODS: We investigated the impact of MKP-2 in the regulation of several genes that are involved in function while using comparative whole genome microarray analysis in macrophages from MKP-2 wild type (wt) and knock out (ko) mice. RESULTS: Our data showed that the lack of MKP-2 caused a significant down-regulation of colony-stimulating factor-2 (Csf2) and monocyte to macrophage-associated differentiation (Mmd) genes, suggesting a role of MKP-2 in macrophage development. When treated with macrophage colony stimulating factor (M-CSF), Mmd and Csf2 mRNA levels increased but significantly reduced in ko cells in comparison to wt counterparts. This effect of MKP-2 deletion on macrophage function was also observed by cell counting and DNA measurements. On the signalling level, M-CSF stimulation induced extracellular signal-regulated kinases (ERK) phosphorylation, which was significantly enhanced in the absence of MKP-2. Pharmacological inhibition of ERK reduced both Csf2 and Mmd genes in both wild type and ko cultures, which suggested that enhanced ERK activation in ko cultures may not explain effects on gene expression. Interestingly other functional markers were also shown to be reduced in ko macrophages in comparison to wt mice; the expression of CD115, which is a receptor for M-CSF, and CD34, a stem/progenitor cell marker, suggesting global regulation of gene expression by MKP-2. CONCLUSIONS: Transcriptome profiling reveals that MKP-2 regulates macrophage development showing candidate targets from monocyte-to-macrophage differentiation and macrophage proliferation. However, it is unclear whether effects upon ERK signalling are able to explain the effects of DUSP-4 deletion on macrophage function.


Assuntos
Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Macrófagos/metabolismo , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/metabolismo , Deleção de Sequência , Transdução de Sinais , Animais , Biomarcadores , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Imunofenotipagem , Lipopolissacarídeos/imunologia , Sistema de Sinalização das MAP Quinases , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Análise em Microsséries
7.
Nat Immunol ; 20(7): 793-801, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31213715

RESUMO

Unlike other cells in the body, immune cells have to be able to enter and adapt to life within diverse tissues. Immune cells develop within dedicated immune system organs, such as the bone marrow, thymus and lymphoid tissues, but also inhabit other tissues, wherein they not only provide defense against infection and malignancies but also contribute to homeostatic tissue function. Because different tissues have widely divergent metabolic rates and fuel requirements, this raises interesting questions about the adaptation of immune cells in specific tissues. When immune cells take up residence in different tissues, they develop a transcriptional signature that reflects adaptation to life and function within that tissue. Genes encoding metabolic-pathway proteins are strongly represented within these signatures, reflective of the importance of metabolic adaptation to tissue residence. In this Review, we discuss the available data on the metabolic adaptation of immune cells to life in different tissue sites, within the broader framework of how functional adaptation versus maladaptation in the niche can affect tissue homeostasis.


Assuntos
Adaptação Biológica , Metabolismo Energético , Sistema Imunitário/citologia , Sistema Imunitário/fisiologia , Especificidade de Órgãos/imunologia , Animais , Biomarcadores , Homeostase , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Transdução de Sinais
8.
EBioMedicine ; 44: 60-70, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31130476

RESUMO

BACKGROUND: Mature myeloid cells play a crucial role in Crohn's disease (CD) but the molecular players that regulate their functions in CD are not fully characterized. We and others have shown that TRIM33 is involved in the innate immune response and in the inflammatory response but TRIM33 role in intestinal inflammation is not known. In this study, we investigated the role of TRIM33 in myeloid cells during dextran sulfate sodium (DSS)-induced colitis. METHODS: We study the role of TRIM33 during DSS-induced colitis which mimics intestinal inflammation using mice deleted for Trim33 only in mature myeloid cells (Trim33-/- mice) FINDINGS: We first show that Trim33 mRNA level is decreased in CD patient's blood monocytes suggesting a role of TRIM33 in CD. Using Trim33-/- mice, we show that these mice display an impaired resolution of colonic inflammation with an increased number of blood and colon monocytes and a decreased number of colonic macrophages. Trim33-/- monocytes are less competent for recruitment and macrophage differentiation. Finally, during resolution of inflammation, Trim33-/- colonic macrophages display an impaired M1/M2 switch and express a low level of membrane-bound TNF that is associated with an increased number of colonic neutrophils. INTERPRETATION: Our study shows an important role of TRIM33 in monocytes/macrophages during DSS-induced colitis and suggests that the decreased expression of TRIM33 in CD patient's blood monocytes might not be a consequence but might be involved in CD progression. FUND: La Ligue contre le Cancer (équipe labelisée), INSERM, CEA, Université Paris-Diderot, Université Paris-Sud.


Assuntos
Colite/etiologia , Macrófagos/metabolismo , Monócitos/metabolismo , Fatores de Transcrição/deficiência , Animais , Biomarcadores , Colite/metabolismo , Colite/patologia , Doença de Crohn/etiologia , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , RNA Mensageiro
9.
EBioMedicine ; 43: 562-575, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31060902

RESUMO

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death worldwide with no curative therapy. A non-canonical Notch ligand, DNER, has been recently identified in GWAS to associate with COPD severity, but its function and contribution to COPD is unknown. METHODS: DNER localisation was assessed in lung tissue from healthy and COPD patients, and cigarette smoke (CS) exposed mice. Microarray analysis was performed on WT and DNER deficient M1 and M2 bone marrow-derived macrophages (BMDM), and gene set enrichment undertaken. WT and DNER deficient mice were exposed to CS or filtered air for 3 day and 2 months to assess IFNγ-expressing macrophages and emphysema development. Notch and NFKB active subunits were quantified in WT and DNER deficient LPS-treated and untreated BMDM. FINDINGS: Immunofluorescence staining revealed DNER localised to macrophages in lung tissue from COPD patients and mice. Human and murine macrophages showed enhanced DNER expression in response to inflammation. Interestingly, pro-inflammatory DNER deficient BMDMs exhibited impaired NICD1/NFKB dependent IFNγ signalling and reduced nuclear NICD1/NFKB translocation. Furthermore, decreased IFNγ production and Notch1 activation in recruited macrophages from CS exposed DNER deficient mice were observed, protecting against emphysema and lung dysfunction. INTERPRETATION: DNER is a novel protein induced in COPD patients and 6 months CS-exposed mice that regulates IFNγ secretion via non-canonical Notch in pro-inflammatory recruited macrophages. These results provide a new pathway involved in COPD immunity that could contribute to the discovery of innovative therapeutic targets. FUNDING: This work was supported from the Helmholtz Alliance 'Aging and Metabolic Programming, AMPro'.


Assuntos
Interferon gama/biossíntese , Macrófagos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores Notch/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Imunofluorescência , Expressão Gênica , Humanos , Imunofenotipagem , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Modelos Biológicos , Monócitos/imunologia , Monócitos/metabolismo , Proteínas do Tecido Nervoso/genética , Doença Pulmonar Obstrutiva Crônica/etiologia , Receptores de Superfície Celular/genética , Transdução de Sinais
10.
EMBO J ; 38(11)2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31028084

RESUMO

Alternatively activated M2 macrophages play an important role in maintenance of tissue homeostasis by scavenging dead cells, cell debris and lipoprotein aggregates via phagocytosis. Using proteomics, we investigated how alternative activation, driven by IL-4, modulated the phagosomal proteome to control macrophage function. Our data indicate that alternative activation enhances homeostatic functions such as proteolysis, lipolysis and nutrient transport. Intriguingly, we identified the enhanced recruitment of the TAK1/MKK7/JNK signalling complex to phagosomes of IL-4-activated macrophages. The recruitment of this signalling complex was mediated through K63 polyubiquitylation of the macrophage scavenger receptor 1 (MSR1). Triggering of MSR1 in IL-4-activated macrophages leads to enhanced JNK activation, thereby promoting a phenotypic switch from an anti-inflammatory to a pro-inflammatory state, which was abolished upon MSR1 deletion or JNK inhibition. Moreover, MSR1 K63 polyubiquitylation correlated with the activation of JNK signalling in ovarian cancer tissue from human patients, suggesting that it may be relevant for macrophage phenotypic shift in vivo Altogether, we identified that MSR1 signals through JNK via K63 polyubiquitylation and provides evidence for the receptor's involvement in macrophage polarization.


Assuntos
Inflamação , Interleucina-4/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Ativação de Macrófagos , Receptores Depuradores Classe A/agonistas , Receptores Depuradores Classe A/genética , Animais , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/genética , Células Cultivadas , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Mediadores da Inflamação/fisiologia , Lipólise/efeitos dos fármacos , Lipólise/genética , Lipoproteínas LDL/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/genética , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/efeitos dos fármacos , Fagocitose/genética , Polissacarídeos/farmacologia , Processamento de Proteína Pós-Traducional/genética , Células RAW 264.7 , Receptores Depuradores Classe A/química , Receptores Depuradores Classe A/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ubiquitinação/genética
11.
Nat Immunol ; 20(5): 571-580, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936493

RESUMO

Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity. We found that the hyporesponsiveness of AlvMs to IL-4 depended upon the lung environment but was independent of the host microbiota or the lung extracellular matrix components surfactant protein D (SP-D) and mucin 5b (Muc5b). AlvMs showed severely dysregulated metabolism relative to that of cavity macrophages. After removal from the lungs, AlvMs regained responsiveness to IL-4 in a glycolysis-dependent manner. Thus, impaired glycolysis in the pulmonary niche regulates AlvM responsiveness during type 2 inflammation.


Assuntos
Inflamação/imunologia , Pulmão/imunologia , Ativação de Macrófagos/imunologia , Macrófagos Alveolares/imunologia , Animais , Inflamação/genética , Inflamação/metabolismo , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-4/metabolismo , Larva/imunologia , Larva/fisiologia , Pulmão/metabolismo , Pulmão/patologia , Ativação de Macrófagos/genética , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/parasitologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mucina-5B/genética , Mucina-5B/imunologia , Mucina-5B/metabolismo , Nippostrongylus/imunologia , Nippostrongylus/fisiologia , Proteína D Associada a Surfactante Pulmonar/genética , Proteína D Associada a Surfactante Pulmonar/imunologia , Proteína D Associada a Surfactante Pulmonar/metabolismo , Infecções por Strongylida/genética , Infecções por Strongylida/imunologia , Infecções por Strongylida/parasitologia
12.
Dev Comp Immunol ; 98: 20-33, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30974109

RESUMO

We previously demonstrated that the most bioactive vitamin A metabolite, all-trans retinoic acid (ATRA), increased T helper 2-associated responses induced in pigs by infection with the parasitic nematode Ascaris suum We also showed that ATRA potentiated the mRNA expression of several IL-4 induced chemokines (chemokine (CC motif) ligand 11 [(CCL11), CCL17, CCL22 and CCL26] associated with alternative activation (M2a) in porcine macrophages in vitro. Herein, several mechanisms whereby ATRA affects IL-4 signaling are profiled using large-scale real time PCR and RNA-Seq analysis. Twenty-three genes associated with M2a markers in other species were independently upregulated by both IL-4 and ATRA, including the adenosine receptor A2B (ADORA2B), cysteinyl leukotriene receptor 2 (CYSLTR2) and the vitamin D receptor (VDR). ATRA synergistically enhanced IL-4 up-regulation of Hepatitis A virus cellular receptor 2 (HAVCR2) and transglutaminase 2 (TGM2) and further repressed IL-4 down-regulated CD163 and Cytochrome b-245, beta polypeptide (CYBB) mRNA. Macrophages treated with ATRA exhibited a dose-dependent reduction in phagocytosis of opsonized Staphylococcus aureus. In addition, the combination of IL-4 and ATRA up-regulated the anti-inflammatory protein, IL-1R antagonist (IL1RN) and TGM2. These data indicate that ATRA induces a state of partial alternative activation in porcine macrophages, and amplifies certain aspects of M2a activation induced by IL-4. Given the prevalence of allergic and parasitic diseases worldwide and the close similarities in the porcine and human immune responses, these findings have important implications for the nutritional regulation of allergic inflammation at mucosal surfaces.


Assuntos
Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Fagocitose/efeitos dos fármacos , Tretinoína/farmacologia , Animais , Células Cultivadas , Quimiocinas/genética , Quimiocinas/imunologia , Humanos , Interleucina-4/farmacologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/classificação , Macrófagos/metabolismo , Fagocitose/imunologia , Staphylococcus aureus/imunologia , Suínos , Transcriptoma/efeitos dos fármacos , Transcriptoma/imunologia
13.
Artif Cells Nanomed Biotechnol ; 47(1): 833-843, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30862190

RESUMO

We aimed to explore the mediating role of Notch signal in macrophage polarization. This signal was knocked out from macrophages of Lyz2 cre and RBP-J flox mice. Bone marrow-derived macrophages (BMDMs) were isolated and polarized. The expressions of polarization markers in BMDMs 24 h after transfection were detected by qPCR. After Notch knockout, the expressions of M1 markers decreased but those of M2 markers increased significantly. MiR-125a/miR-99b and Spaca6 were highly and lowly expressed upon M1 and M2 polarizations, respectively. The expressions of experimental group were significantly lower than those of control group. Overexpression of miR-125a significantly promoted the expressions of M1 markers, whereas inhibited those of M2 markers. NO release in the culture supernatant of miR-125a overexpression group significantly exceeded that of control group. Transfection with miR-125a inhibitor significantly down-regulated IL-12 expression but up-regulated MR expression in BMDMs. The supernatant secreted by M1 macrophages significantly facilitated BS524 cell apoptosis, which was enhanced after miR-125a overexpression. The TNF-α expression of miR-99b overexpression group increased whereas that of MR decreased significantly. The miR-125a/miR-99b cluster contained an RBP-J specific recognition site in the first intron of initial transcript. The Notch signalling pathway promoted macrophage polarization into M1 phenotype by up-regulating miR-125a/miR-99b expression.


Assuntos
Regulação da Expressão Gênica , Macrófagos/imunologia , MicroRNAs/genética , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Ativação de Macrófagos/genética , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/antagonistas & inibidores , Fenótipo , Receptores Notch/genética , Proteínas de Plasma Seminal/genética
14.
Pathog Dis ; 77(2)2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30916767

RESUMO

We aimed to investigate the relationship of intestinal dysbiosis (IDB) and ovarian cancer progression, and understand its underlying signaling mechanisms. IDB was induced with high dose antibiotics. The xenograft mouse model was used to assess the tumor progression. Real-time polymerase chain reaction and immunoblotting are commonly used quantitative methods, and they were used to quantify epithelial-mesenchymal transition (EMT) markers in this paper. Meanwhile, cellular proliferation was also measured. First, IDB could promote the growth of xenograft tumors and induce the EMT. Serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 also increased remarkably. In addition, the production and secretion of TNF-α and IL-6 in macrophages isolated from IDB model mice were observably higher. In vitro, conditioned medium could significantly stimulate the development of EMT in ovarian cancer cells. Loss of macrophages completely offset the pro-tumor effects of IDB. IDB can stimulate the activation of tumor-associated macrophages in ovarian cancer, which is achieved by secreting pro-inflammatory cytokines IL-6 and TNF-α, and ultimately induces the development of EMT.


Assuntos
Disbiose , Transição Epitelial-Mesenquimal , Microbioma Gastrointestinal , Macrófagos/imunologia , Macrófagos/metabolismo , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/metabolismo , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/imunologia , Feminino , Xenoenxertos , Humanos , Interleucina-6/sangue , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Neoplasias Ovarianas/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/sangue
15.
Mol Med Rep ; 19(4): 2740-2748, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816473

RESUMO

The peroxisome proliferator­activated receptor γ (PPARγ) agonist pioglitazone has been widely used in previous studies to ameliorate diabetes mellitus and regulate inflammation. However, the present study aimed to investigate the effect of pioglitazone on macrophages and determine its impact on renal fibrosis in vivo. Firstly, bone marrow­derived macrophages (BMDM) were used to detect the effects of pioglitazone on macrophages in vitro. It was demonstrated that pioglitazone promoted M2 macrophage activation and induced vascular endothelial growth factor receptor 3 (VEGFR3) upregulation in a PPARγ­dependent manner. Furthermore, pioglitazone increased macrophage proliferation and macrophage VEGFR3 expression in a murine unilateral ureteral obstruction (UUO) model; however, it had no therapeutic effect on renal fibrosis in vivo. Therefore, the results in the present study implied that presence of M2 macrophages may inhibit pioglitazone's ability to attenuate UUO­induced renal fibrosis. In addition, the results demonstrated that macrophage­associated VEGFR3 could be induced by pioglitazone, although it is still unclear what role VEGFR3+ M2 macrophages have in renal fibrosis.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , PPAR gama/metabolismo , Pioglitazona/farmacologia , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Animais , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Fibrose , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Lipopolissacarídeos/imunologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Masculino , Camundongos
16.
Auris Nasus Larynx ; 46(5): 716-723, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30827793

RESUMO

OBJECTIVE: Microglia are highly specialized tissue macrophages in the central nervous system. Their activation in the auditory system has been reported in adult hearing loss models, but their status in the developing auditory system is less understood. Therefore, we investigated microglial status in the cochlear nucleus (CN) during normal developing periods and after exposing rats to amikacin, a potent ototoxin, around the time of hearing onset. METHODS: To develop the deafness model, rats were administered with a daily intraperitoneal injection of amikacin (500 mg/kg) from postnatal day 7 (P7) to P15. To evaluate the expression of ionized calcium binding adaptor molecule 1 (Iba1), we performed immunohistochemical analysis using rat brains from P10-60. To compare the expression of microglia-related gene, reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis were performed. RESULTS: Immunohistochemical analysis revealed that, under normal conditions, microglia had relatively large cell bodies with several extended processes that surrounded other cells at P10, while the sizes and number of these cells gradually decreased afterward. In contrast, when amikacin was administered from P7 to P15, microglia maintained large cell bodies with relatively shorter processes at both P15 and P21. Furthermore, RT-qPCR analysis revealed upregulation of genes including phagocytotic and anti-inflammatory markers after amikacin administration. CONCLUSION: These results suggest that microglia are activated in the CN, and they may contribute to tissue remodeling after early hearing loss in the developing auditory system.


Assuntos
Núcleo Coclear/imunologia , Perda Auditiva/imunologia , Ativação de Macrófagos/genética , Microglia/imunologia , Amicacina/toxicidade , Animais , Animais Recém-Nascidos , Antibacterianos/toxicidade , Proteínas de Ligação ao Cálcio/metabolismo , Potenciais Evocados Auditivos do Tronco Encefálico , Perda Auditiva/induzido quimicamente , Inflamação/genética , Ativação de Macrófagos/imunologia , Proteínas dos Microfilamentos/metabolismo , Microglia/metabolismo , Fagocitose/genética , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Kidney Int ; 95(4): 760-773, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30827512

RESUMO

Tissue macrophages are crucial players in homeostasis, inflammation, and immunity. They are characterized by heterogeneity and plasticity, due to which they display a continuum of phenotypes with M1/M2 presenting 2 extremes of this continuum. M2 macrophages are usually termed in the literature as anti-inflammatory and wound healing. Substantial progress has been made in elucidating the biology of M2 macrophages and their potential for clinical translation. In this review we discuss the current state of knowledge in M2 macrophage research with an emphasis on kidney disease. We explore their therapeutic potential and the challenges in using them as cellular therapies. Some new regulators that shape macrophage polarization and potential areas for future research are also examined.


Assuntos
Nefropatias/terapia , Ativação de Macrófagos/imunologia , Macrófagos/transplante , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Nefropatias/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/genética , Macrófagos/imunologia , Macrófagos/metabolismo
18.
Am J Physiol Cell Physiol ; 316(5): C731-C740, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30811223

RESUMO

This study aims to explore the mechanism of the signal transmission between oral squamous cell carcinoma (OSCC) and unpolarized stromal immune macrophages mediated by OSCC-derived exosomes (OSCC-Exo). Polarization of macrophages was found by detection of the level of protein markers or specific components for M1 subtype or M2 subtype macrophages, respectively. Exosomes extracted from two OSCC cell lines, which might have been transfected with micro-RNA (miR)-29a-3p inhibitor or mimic, were cocultured with macrophages to ensure the effect of exosome-enclosed miR-29a-3p on the polarization of macrophages. miR-29a-3p is highly expressed, suppressor of cytokine signaling 1 (SOCS1) is low expressed and phosphorylated signal transduction and transcriptional activator 6 (p-STAT6) is highly expressed in OSCC tissues. Upregulation of miR-29a-3p is observed in OSCC-derived exosomes. When cocultured, OSCC-derived exosomes promote M2 subtype macrophage polarization and the medium of the coculture promotes the proliferation and invasion of SCC-9 and CAL-27 cells. After interfered silencing miR-29a-3p of OSCCs, SCC-9- and CAL-27 cell-derived exosomes inhibit M2 subtype macrophage polarization. On the other hand, cellular highly expressed miR-29a-3p of macrophages enhances M2 subtype macrophage polarization. Moreover, such macrophages promote the proliferation and invasion of SCC-9 and CAL-27. SOCS1 is a direct target for miR-29a-3p and could be negatively regulated by miR-29a-3p. Moreover, SOCS1 overexpression reverses the activity of SOCS1/STAT6 signals of macrophages and cell proliferation and invasion of OSCCs induced by miR-29a-3p overexpression. Also, overexpressed SOCS1 in macrophages counteracts the impact of OSCC-derived exosomes in M2 subtype macrophage polarization. Exosome-enclosed miR-29a-3p promotes tumor growth in nude mice with xenograft. OSCC-derived exosomes promote M2 subtype macrophage polarization mediated by exosome-enclosed miR-29a-3p, and the mechanism by miR-29a-3p is the activity of SOCS1/STAT6 signals in macrophages.


Assuntos
Carcinoma de Células Escamosas/genética , Exossomos/genética , Macrófagos/patologia , MicroRNAs/genética , Neoplasias Bucais/genética , Animais , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Ativação de Macrófagos/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Bucais/patologia , Invasividade Neoplásica/genética , Transdução de Sinais/genética , Proteína 1 Supressora da Sinalização de Citocina/genética , Células THP-1 , Regulação para Cima/genética
19.
Immunol Cell Biol ; 97(3): 268-278, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30779212

RESUMO

Macrophages are a critical component of the innate immune response, and compose the first response to perturbations in tissue homeostasis. Their unique ability to dynamically integrate diverse stimuli underlies their important role in the healing response from first insult to re-establishment of tissue homeostasis. While the roles of macrophages in tissue repair have been well-described in vitro and in vivo, the influence of cellular metabolism on macrophage function during tissue repair remains an unexplored area of immunometabolism. In this review, we will explore the unique metabolic requirements of inflammatory and anti-inflammatory macrophages and the potential contribution of macrophage metabolism to each phase of wound healing.


Assuntos
Metabolismo Energético , Macrófagos/imunologia , Macrófagos/metabolismo , Animais , Biomarcadores , Microambiente Celular/genética , Microambiente Celular/imunologia , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Homeostase , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Redes e Vias Metabólicas , Transdução de Sinais , Cicatrização
20.
Immunol Cell Biol ; 97(3): 258-267, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30746824

RESUMO

Macrophages are critically involved in wound healing, from dampening inflammation to clearing cell debris and coordinating tissue repair. Within the wound, the complexity of macrophage function is increasingly recognized, with adverse outcomes when macrophages are inappropriately activated, such as in fibrosis or chronic non-healing wounds. Recent advances in in vivo and translational wound models, macrophage-specific deletions and new technologies to distinguish macrophage subsets, have uncovered the vast spectrum of macrophage activation and effector functions. Here, we summarize the main players in wound-healing macrophage activation and function, including cytokines, apoptotic cells, nucleotides and mechanical stimuli. We highlight recent studies demonstrating cooperation between these factors for optimal wound healing. Next, we describe recent technologies such as cell tracking and single-cell RNA-seq, which have uncovered remarkable plasticity and heterogeneity in blood-derived or tissue-resident macrophages and discuss the implications for wound healing. Lastly, we evaluate macrophage dysfunction in aberrant wound healing that occurs in aging, diabetes and fibrosis. A better understanding of the longevity and plasticity of wound-healing macrophages, and identification of unique macrophage subsets or specific effector molecules in wound healing, would shed light on the therapeutic potential of manipulating macrophage function for optimal wound healing.


Assuntos
Plasticidade Celular , Macrófagos/imunologia , Macrófagos/metabolismo , Cicatrização , Animais , Apoptose , Biomarcadores , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Citocinas/metabolismo , Suscetibilidade a Doenças , Fibrose , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Transdução de Sinais , Cicatrização/imunologia
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