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1.
Nat Commun ; 11(1): 4909, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999291

RESUMO

Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.


Assuntos
Micropartículas Derivadas de Células/imunologia , Imunoterapia/métodos , Macrófagos/imunologia , Melanoma/terapia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antígeno CD47/metabolismo , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Melanoma/imunologia , Melanoma/secundário , Proteínas de Membrana/agonistas , Proteínas de Membrana/imunologia , Camundongos , Nanopartículas/administração & dosagem , Recidiva Local de Neoplasia/imunologia , Nucleotídeos Cíclicos/administração & dosagem , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia
2.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 32(4): 432-435, 2020 Feb 24.
Artigo em Chinês | MEDLINE | ID: mdl-32935525

RESUMO

Macrophages are important members of innate immunity and play an extremely important role in the host defense against pathogenic infections, tumors, and allergic diseases. Macrophages have a high degree of plasticity, and may be polarized into classical activated macrophages (M1 macrophages) and alternative activated macrophages (M2 macrophages) under the stimulation of different environments. M1 macrophages are found to promote inflammatory responses, which facilitates the clearance of pathogens, while M2 macrophages may inhibit inflammatory responses, which facilitates the survival and reproduction of pathogens. This review summarizes the role of macrophage polarization in parasitic infections, so as to provide insights into the prevention and treatment of parasitic diseases.


Assuntos
Ativação de Macrófagos , Doenças Parasitárias , Humanos , Ativação de Macrófagos/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Doenças Parasitárias/imunologia
3.
Asian Pac J Allergy Immunol ; 38(3): 170-177, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32990448

RESUMO

The disease course of coronavirus disease 2019 (COVID-19) is usually mild and self-limiting in previously healthy children, but they may also develop severe disease. Severe COVID-19 infection is especially observed in very young children or those with underlying comorbidities. Moreover, a multisystem inflammatory syndrome that mimics the Kawasaki disease shock syndrome can develop in children that are genetically predisposed to displaying an overactive immune response to SARS-CoV-2 infection. In this review, we describe the clinical phenotypes of mild and severe COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We also discuss the possible immunobiological mechanisms that may be involved in the protection of children against COVID-19 and the development of multisystem inflammatory syndrome.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/virologia , Pneumonia Viral/virologia , Síndrome de Resposta Inflamatória Sistêmica/virologia , Adolescente , Idade de Início , Betacoronavirus/imunologia , Criança , Pré-Escolar , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Suscetibilidade a Doenças , Feminino , Interações Hospedeiro-Patógeno , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/virologia , Lactente , Recém-Nascido , Ativação Linfocitária , Ativação de Macrófagos , Masculino , Pandemias , Fenótipo , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Prognóstico , Fatores de Risco , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia
4.
Anim Sci J ; 91(1): e13443, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32779259

RESUMO

Obesity stimulates the macrophage infiltration and senescence state in adipose tissues of humans and rodents. The adipogenesis capacity of Japanese Black cattle (Wagyu) is higher than that of Holsteins. We hypothesized that breed differences between Wagyu and Holsteins may affect the level of macrophage infiltration and senescence state in adipose tissues. The macrophage infiltration, senescence marker gene expression and activity of senescence-associated ß-galactosidase (SA-ßgal) in visceral and intramuscular adipose tissue of Wagyu were higher than those of Holsteins. In contrast, there were no differences in macrophage infiltration, senescence marker gene expression and activity of SA-ßgal in subcutaneous adipose tissue between the breeds. Expression of p53 gene, the master regulator of macrophage infiltration and senescence state, in visceral and intramuscular adipose tissue of Wagyu was higher than that of Holsteins. In contrast, there was no difference in the expression of p53 gene in subcutaneous adipose tissue between the breeds. These results suggest that breed differences in macrophage infiltration and senescence state in adipose tissues of Wagyu and Holsteins are affected by p53 expression.


Assuntos
Tecido Adiposo/imunologia , Cruzamento , Bovinos/imunologia , Ativação de Macrófagos , Animais
5.
Nat Commun ; 11(1): 4064, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792542

RESUMO

Regulation of the programming of tumour-associated macrophages (TAMs) controls tumour growth and anti-tumour immunity. We examined the role of FGF2 in that regulation. Tumours in mice genetically deficient in low-molecular weight FGF2 (FGF2LMW) regress dependent on T cells. Yet, TAMS not T cells express FGF receptors. Bone marrow derived-macrophages from Fgf2LMW-/- mice co-injected with cancer cells reduce tumour growth and express more inflammatory cytokines. FGF2 is induced in the tumour microenvironment following fractionated radiation in murine tumours consistent with clinical reports. Combination treatment of in vivo tumours with fractionated radiation and a blocking antibody to FGF2 prolongs tumour growth delay, increases long-term survival and leads to a higher iNOS+/CD206+ TAM ratio compared to irradiation alone. These studies show for the first time that FGF2 affects macrophage programming and is a critical regulator of immunity in the tumour microenvironment.


Assuntos
Fator 2 de Crescimento de Fibroblastos/metabolismo , Radioterapia/métodos , Animais , Linhagem Celular Tumoral , Fator 2 de Crescimento de Fibroblastos/genética , Células HT29 , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/efeitos da radiação , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
6.
PLoS One ; 15(8): e0233818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857777

RESUMO

Macrophages serve as a first line of defense against infection with the facultative intracellular pathogen, Cryptococcus neoformans (Cn). However, the ability of these innate phagocytic cells to destroy ingested Cn is strongly influenced by polarization state with classically (M1) activated macrophages better able to control cryptococcal infections than alternatively (M2) activated cells. While earlier studies have demonstrated that intracellular Cn minimally affects the expression of M1 and M2 markers, the impact on the broader transcriptome associated with these states remains unclear. To investigate this, an in vitro cell culture model of intracellular infection together with RNA sequencing-based transcriptome profiling was used to measure the impact of Cn infection on gene expression in both polarization states. The gene expression profile of both M1 and M2 cells was extensively altered to become more like naive (M0) macrophages. Gene ontology analysis suggested that this involved changes in the activity of the Janus kinase-signal transducers and activators of transcription (JAK-STAT), p53, and nuclear factor-κB (NF-κB) pathways. Analyses of the principle polarization markers at the protein-level also revealed discrepancies between the RNA- and protein-level responses. In contrast to earlier studies, intracellular Cn was found to increase protein levels of the M1 marker iNos. In addition, common gene expression changes were identified that occurred post-Cn infection, independent of polarization state. This included upregulation of the transcriptional co-regulator Cited1, which was also apparent at the protein level in M1-polarized macrophages. These changes constitute a transcriptional signature of macrophage Cn infection and provide new insights into how Cn impacts gene expression and the phenotype of host phagocytes.


Assuntos
Cryptococcus neoformans/patogenicidade , Macrófagos/metabolismo , Macrófagos/microbiologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Cryptococcus neoformans/imunologia , Ontologia Genética , Redes Reguladoras de Genes , Imunidade Inata/genética , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Transativadores/genética , Transativadores/metabolismo , Transcriptoma
7.
Life Sci ; 258: 118166, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739471

RESUMO

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/patologia , Animais , Betacoronavirus/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Humanos , Imunidade Inata , Inflamação/etiologia , Inflamação/imunologia , Inflamação/fisiopatologia , Inflamação/terapia , Ativação de Macrófagos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Ativação de Neutrófilo , Pandemias , Ativação Plaquetária , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/terapia , Trombofilia/etiologia , Trombofilia/imunologia , Trombofilia/fisiopatologia , Trombofilia/terapia
8.
Int J Nanomedicine ; 15: 4125-4138, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606668

RESUMO

Purpose: To investigate the effect and mechanism of macrophage membrane-coated nanoparticles (M-NPs) on hepatic ischemia-reperfusion injury (I/RI) caused by orthotopic liver transplantation. In addition, the advantages of TLR4+/M-NPs compared to M-NPs are discussed. Materials and Methods: We prepared biomimetic M-NPs and identified their characteristics. M-NPs were injected into an SD rat model of orthotopic liver transplantation, and the anti-inflammatory and anti-I/RI activities of M-NPs were studied in vivo and in vitro. In addition, we overexpressed macrophage membrane Toll-like receptor 4 (TLR4) in vitro and prepared TLR4+/M-NPs. Then, we assessed the characteristics and advantages of TLR4+/M-NPs. Results: The M-NPs neutralized endotoxin, inhibited the overactivation of Kupffer cells (KCs) and suppressed the secretion of inflammatory factors by inhibiting the endotoxin-mediated TLR4/MyD88/IRAK1/NF-κB signaling pathway. In an orthotopic liver transplantation model in SD rats, M-NPs showed significant therapeutic efficacy by neutralizing endotoxin and suppressing the secretion of inflammatory factors. Moreover, overexpression of TLR4 on the macrophage membrane by using a TLR4+-plasmid in vitro effectively reduced the amount of M-NPs needed to neutralize an equivalent dose of endotoxin, reducing the potential risks of NP overuse. Conclusion: This study indicates that M-NPs can effectively alleviate I/RI induced by liver transplantation.


Assuntos
Membrana Celular/metabolismo , Endotoxinas/metabolismo , Transplante de Fígado/efeitos adversos , Fígado/irrigação sanguínea , Macrófagos/metabolismo , Nanopartículas/química , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/terapia , Animais , Anti-Inflamatórios/farmacologia , Fluorescência , Lipopolissacarídeos/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Nanopartículas/ultraestrutura , Células RAW 264.7 , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo
9.
Nat Commun ; 11(1): 3631, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686670

RESUMO

Macrophages are a major immune cell type infiltrating tumors and promoting tumor growth and metastasis. To elucidate the mechanism of macrophage recruitment, we utilize an overgrowth tumor model ("undead" model) in larval Drosophila imaginal discs that are attached by numerous macrophages. Here we report that changes to the microenvironment of the overgrown tissue are important for recruiting macrophages. First, we describe a correlation between generation of reactive oxygen species (ROS) and damage of the basement membrane (BM) in all neoplastic, but not hyperplastic, models examined. ROS and the stress kinase JNK mediate the accumulation of matrix metalloproteinase 2 (Mmp2), damaging the BM, which recruits macrophages to the tissue. We propose a model where macrophage recruitment to and activation at overgrowing tissue is a multi-step process requiring ROS- and JNK-mediated Mmp2 upregulation and BM damage. These findings have implications for understanding the role of the tumor microenvironment for macrophage activation.


Assuntos
Membrana Basal/patologia , Ativação de Macrófagos/fisiologia , Metaloproteinase 2 da Matriz , Microambiente Tumoral/fisiologia , Animais , Membrana Basal/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Expressão Gênica , Discos Imaginais/imunologia , Discos Imaginais/metabolismo , Larva/metabolismo , MAP Quinase Quinase 4/metabolismo , Macrófagos/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Espécies Reativas de Oxigênio/metabolismo
10.
Anticancer Res ; 40(8): 4681-4685, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727792

RESUMO

BACKGROUND/AIM: The functions of macrophages change in response to environmental factors such as lipopolysaccharide (LPS). LPS derived from Pantoea agglomerans (LPSp) is involved in macrophage activation and tissue repair when administered dermally. LPSp-activated macrophages may be useful for restoring and maintaining homeostasis of the skin. MATERIALS AND METHODS: Phorbol myristate acetate-treated human monocytes (THP-1 cells) were activated with LPSp. The medium of LPSp-activated THP-1 cells was added to normal human dermal fibroblasts (NHDF cells). After 24 h, the expression of hyaluronan (HA) synthase (HAS)2, hyaluronidase (HYAL)1, and tropoelastin in NHDF cells was analyzed using quantitative real-time PCR. RESULTS: The expression of HAS2 and tropoelastin was significantly increased, but that of HYAL1 was significantly decreased. It was demonstrated that the abilities of HA and elastin synthesis in NHDF cells increased through LPSp-activated THP-1 cells. CONCLUSION: LPSp-activated macrophages may be useful for enhancing the abilities of HA and elastin synthesis in fibroblasts, subsequently improving dysfunction and reducing various age-related disorders.


Assuntos
Elastina/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Ácido Hialurônico/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Linhagem Celular , Humanos , Ativação de Macrófagos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Pantoea/metabolismo , Fagocitose/efeitos dos fármacos , Células Th1
11.
Anticancer Res ; 40(8): 4707-4710, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727796

RESUMO

BACKGROUND/AIM: Serum-derived macrophage activating factor (serum-MAF) can rapidly activate macrophage phagocytic activity by inducing characteristic membrane ruffles designated as Frill-like structures. Serum-MAF contains γ-globulin, an activator of phagocytosis. This study examined whether serum-MAF and γ-globulin activate macrophages similarly. MATERIALS AND METHODS: Morphological changes in macrophages were observed by time-lapse imaging and the efficiency of engulfment was analysed quantitatively. Immunological staining of talin-1 and a calpain inhibitor were performed. RESULTS: The engulfment efficiency of serum-MAF- and γ-globulin-activated macrophages was significantly different. Talin-1 showed weak co-localisation with the Frill-like structures. Treatment with a calpain inhibitor similarly down-regulated phagocytosis irrespective of the activation factor. CONCLUSION: There was a difference between macrophage activation mechanisms by γ-globulin and serum-MAF. Talin may slightly contribute to serum-MAF activation. It is possible to distinguish between the calpain-dependent fundamental 'mechanism of phagocytosis' and the activating factor-dependent rapid 'activation mechanism'.


Assuntos
Ativação de Macrófagos/efeitos dos fármacos , Fatores Ativadores de Macrófagos/farmacologia , Macrófagos/efeitos dos fármacos , gama-Globulinas/farmacologia , Calpaína/farmacologia , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Humanos , Fagocitose/efeitos dos fármacos , Células THP-1
12.
PLoS One ; 15(7): e0236038, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32658933

RESUMO

The attenuation of hyper-inflammation in sepsis with the administration of anti-inflammatory macrophages is an interesting adjuvant therapy for sepsis. Because the induction of anti-inflammatory macrophages by microRNA (miR), a regulator of mRNA, has been mentioned, the exploration on miR-induced anti-inflammatory macrophages was performed. The over-expression of miR-223 and miR-146a in RAW264.7 induced M2 macrophage-polarization (anti-inflammatory macrophages) as evaluated by the enhanced expression of Arginase-1 and Fizz. However, miR-223 over-expressed cells demonstrated the more potent anti-inflammatory property against LPS stimulation as lesser iNOS expression, lower supernatant IL-6 and higher supernatant IL-10 compared with miR-146a over-expressed cells. Interestingly, LPS stimulation in miR-223 over-expressed cells, compared with LPS-stimulated control cells, demonstrated lower activity of glycolysis pathway and higher mitochondrial respiration, as evaluated by the extracellular flux analysis, and also down-regulated HIF-1α, an important enzyme of glycolysis pathway. In addition, the administration of miR-223 over-expressed macrophages with IL-4 pre-conditioning, but not IL-4 stimulated control cells, attenuated sepsis severity in LPS injected mice as evaluated by serum creatinine, liver enzymes, lung histology and serum cytokines. In conclusion, miR-223 interfered with the glycolysis pathway through the down-regulation of HIF-1α, resulting in the anti-inflammatory status. The over-expression of miR-223 in macrophages prevented the conversion into M1 macrophage polarization after LPS stimulation. The administration of miR-223 over-expressed macrophages, with IL-4 preconditioning, attenuated sepsis severity in LPS model. Hence, a proof of concept in the induction of anti-inflammatory macrophages through the cell-energy interference for sepsis treatment was proposed as a basis of cell-based therapy in sepsis.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Glicólise , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Macrófagos/transplante , MicroRNAs/genética , Sepse/prevenção & controle , Animais , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Ativação de Macrófagos , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/induzido quimicamente , Sepse/metabolismo , Sepse/patologia
13.
Front Immunol ; 11: 1580, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670297

RESUMO

SARS-CoV-2 might directly activate NLRP3 inflammasome resulting in an endogenous adjuvant activity necessary to mount a proper adaptive immune response against the virus. Heterogeneous response of COVID-19 patients could be attributed to differences in not being able to properly downregulate NLRP3 inflammasome activation. This relates to the fitness of the immune system of the individual challenged by the virus. Patients with a reduced immune fitness can demonstrate a dysregulated NLRP3 inflammasome activity resulting in severe COVID-19 with tissue damage and a cytokine storm. We sketch the outlines of five possible scenarios for COVID-19 in medical practice and provide potential treatment options targeting dysregulated endogenous adjuvant activity in severe COVID-19 patients.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Proteína HMGB1/metabolismo , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Citocinas/metabolismo , Humanos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/patologia
14.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(6): 765-768, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32684228

RESUMO

Macrophages are important innate immune cells that play essential roles in the inflammatory response. The phenotypic plasticity of macrophages enables them to be polarized into distinct gene phenotypes under different immune microenvironments to regulate the process of inflammation. The study of macrophage metabolic reprogramming aims to clarify the influence of key metabolic pathways on the regulation of different polarization states and related functions of macrophages. This review focuses on the relationship between the four key metabolic pathways [glycolysis, tricarboxylic acid (TCA) cycle, fatty acid metabolism and amino acid metabolism] and the distinct gene phenotypes of macrophages. It also reveals the metabolic regulation of the immune function of macrophage cells thus to provide new ideas and methods for the study of macrophage polarization-related process of inflammation.


Assuntos
Ativação de Macrófagos , Macrófagos , Glicólise , Humanos , Inflamação , Fenótipo
15.
Mol Immunol ; 125: 104-114, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659595

RESUMO

Leishmania are obligate protozoan parasites responsible for substantial public health problems in tropical and subtropical regions around the world, with L. braziliensis being one of the causative agents of American Tegumentary Leishmaniasis. Macrophages, fundamental cells in the innate inflammatory response against Leishmania, constitute a heterogeneous group with multiple activation phenotypes and functions. The outcome of this infection depends largely on the activation status of macrophages, the first line of mammalian defense and the major target cells for parasite replication. The importance of lipids, the major components of cell membranes, goes beyond their basic structural functions. Lipid bioactive molecules have been described in Leishmania spp., and in the recent years the knowledge about the biological relevance of lipids in particular and their relationship with the immune response is expanding. The present work analyzes the biological effects of L. braziliensis lipids from lysed promastigotes (PRO) to mimic rapid modulatory processes that could occur in the initial steps of infection or the effects of lipids from lysed and incubated promastigotes (PROinc), simulating the parasite lipid degradation processes triggered after parasite lysis that might occur in the mammalian host. To perform these studies, lipid profiles of PRO and PROinc were compared with lipids from amastigotes under similar conditions (AMA and AMAinc), and the effect of these lipid extracts were analyzed on the induction of an inflammatory response in murine peritoneal macrophages: LB induction, COX-2, iNOS and Arginase expression, TNF-α, IL-10 and NO production, Arginase activity and M1/M2 markers mRNA induction.


Assuntos
Antígenos de Protozoários/imunologia , Leishmania braziliensis/imunologia , Leishmaniose/imunologia , Lipídeos/imunologia , Ativação de Macrófagos/imunologia , Animais , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C
16.
PLoS One ; 15(7): e0235776, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645059

RESUMO

Macrophages are key phagocytic cells and play an important role in eliminating external microorganisms and endogenous danger signals. Dysregulation in macrophage functions have been reported in patients with asthma. Zinc homeostasis is critical in maintaining macrophage functions. The solute carrier (SLC) protein SLC39A7, a Zn2+ importer, has recently been linked to asthma. However, the roles of SLC39A7 in macrophage phagocytosis are not well understood. Here we found that phagocytosis efficiency was significantly decreased in SLC39A7-knockdown THP-1 cells, however the phagocytosis capability could be reversed with zinc supplementation. SLC39A7 deficiency skewed macrophages towards alternative activation, as indicated by increased expression of M2 activation marker CD206 and decreased expression of M1 activation marker NOS2. Consistent to this result, SLC39A7-knockdown cells produced reduced amounts of proinflammatory cytokines TNF- and IL-6. Furthermore, the mRNA level of receptor Clec4e previously known to be involved in phagocytosis of BCG was significantly reduced in SLC39A7 knockdown cells. Importantly, all these defects due to SLC39A7 deficiency could be reversed by zinc supplementation. Thus, zinc transporter SLC39A7 provide support for phagocytosis and classical macrophage activation.


Assuntos
Proteínas de Transporte de Cátions/imunologia , Ativação de Macrófagos , Fagocitose , Zinco/deficiência , Linhagem Celular , Humanos , Macrófagos/imunologia , Zinco/imunologia
17.
Diab Vasc Dis Res ; 17(4): 1479164120945675, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722929

RESUMO

Activation of the prostaglandin E2 receptor EP4 alters polarization of adipose tissue macrophages towards the anti-inflammatory M2 phenotype to suppress chronic inflammation. However, the role of EP4 signalling in pancreatic macrophages that affect insulin secretion is unclear. We examined the role of EP4 signalling in islet inflammation in vitro and in vivo. Obese diabetic db/db mice were treated with an EP4-selective agonist or vehicle for 4 weeks. Islet morphology did not significantly differ and glucose-stimulated insulin secretion was increased, whereas the pancreatic M1/M2 ratio was decreased in the EP4 agonist-treated group compared to the vehicle group. Because EP4 activation in MIN6 cells did not affect insulin secretion, we used a MIN6/macrophage co-culture system to evaluate the role of EP4 signalling in islet inflammation and subsequent inhibition of insulin release. Co-culture with M1-polarized macrophages markedly suppressed insulin expression in MIN6 cells; however, modulation of M1 polarization by the EP4 agonist significantly reversed the negative impact of co-cultivation on insulin production. The enhanced expression levels of pro-inflammatory cytokines in co-cultured MIN6 cells were markedly inhibited by EP4 agonist treatment of M1 macrophages. Thus, EP4 activation may suppress islet inflammation and protect ß-cell function by altering inflammatory macrophages in the diabetic pancreas.


Assuntos
Plasticidade Celular , Diabetes Mellitus Tipo 2/metabolismo , Inflamação/metabolismo , Células Secretoras de Insulina/metabolismo , Macrófagos Peritoneais/metabolismo , Obesidade/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ativação de Macrófagos , Macrófagos Peritoneais/patologia , Camundongos , Obesidade/patologia , Fenótipo , Via Secretória , Transdução de Sinais
18.
Med Hypotheses ; 143: 110117, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32721809

RESUMO

With rapid spread of severe acute respiratory syndrome- corona virus-2 (SARS-COV-2) globally, some new aspects of the disease have been reported. Recently, it has been reported the incidence of Kawasaki-like disease among children with COVID-19. Since, children had been known to be less severely affected by the virus in part due to the higher concentration of Angiotensin converting enzyme (ACE)-2 receptor, this presentation has emerged concerns regarding the infection of children with SARS-COV2. ACE2 has anti-inflammatory, anti-fibrotic and anti-proliferative characteristics through converting angiotensin (Ag)-II to Ang (1-7). ACE2 receptor is downregulated by the SARS-COV through the spike protein of SARS-CoV (SARS-S) via a process that is tightly coupled with Tumor necrosis factor (TNF)-α production. TNF-α plays a key role in aneurysmal formation of coronary arteries in Kawasaki disease (KD). Affected children by COVID-19 with genetically-susceptible to KD might have genetically under-expression of ACE2 receptor that might further decrease the expression of ACE2 due to the downregulation of the receptor by the virus in these patients. It appears that TNF- α might be the cause and the consequence of the ACE2 receptor downregulation which results in arterial walls aneurysm. Conclusion: Genetically under-expression of ACE2 receptor in children with genetically-susceptible to KD who are infected with SARS-CoV-2 possibly further downregulates the ACE2 expression by TNF-α and leads to surge of inflammation including TNF-α and progression to Kawasaki-like disease.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/complicações , Modelos Imunológicos , Síndrome de Linfonodos Mucocutâneos/etiologia , Pandemias , Pneumonia Viral/complicações , Ásia/epidemiologia , Criança , Vasos Coronários/imunologia , Vasos Coronários/patologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Síndrome da Liberação de Citocina/etiologia , Progressão da Doença , Endotélio Vascular/virologia , Predisposição Genética para Doença , Humanos , Inflamação , Ativação de Macrófagos , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Síndrome de Linfonodos Mucocutâneos/genética , Síndrome de Linfonodos Mucocutâneos/imunologia , Países Baixos/epidemiologia , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Receptores Virais/biossíntese , Receptores Virais/genética , Receptores Virais/fisiologia , Estações do Ano , Glicoproteína da Espícula de Coronavírus/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Estados Unidos/epidemiologia
19.
Arterioscler Thromb Vasc Biol ; 40(9): 2265-2278, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32673525

RESUMO

OBJECTIVE: Macrophages are immune cells, capable to remodel the extracellular matrix, which can harbor extracellular DNA incorporated into neutrophil extracellular traps (NETs). To study the breakdown of NETs we studied the capability of macrophage subsets to degrade these structures in vitro and in vivo in a murine thrombosis model. Furthermore, we analyzed human abdominal aortic aneurysm samples in support of our in vitro and in vivo results. Approach and Results: Macrophages were seeded onto blood clots or isolated NETs and polarized. All macrophages were capable to degrade NETs. For initial breakdown, macrophages relied on extracellular deoxyribonucleases. Proinflammatory polarization enhanced NET degradation. The boost in degradation was because of increased macropinocytosis, as inhibition by imipramine diminished their NET breakdown. Inhibition of macropinocytosis in a murine thrombosis model led to increased NET burden and reduced thrombus resolution in vivo. When analyzing abdominal aortic aneurysm samples, macrophage density furthermore corresponded negatively with the amount of local NETs in the intraluminal thrombi as well as in the vessel wall, as increased macrophage density was associated with a reduction in NET burden. CONCLUSIONS: We provide evidence that macrophages degrade NETs by extracellular predigestion and subsequent uptake. Furthermore, we show that proinflammatory macrophages increase NET degradation through enhanced macropinocytosis, priming them for NET engulfment. Based on our findings, that inhibition of macropinocytosis in mice corresponded to increased NET amounts in thrombi and that local macrophage density in human abdominal aortic aneurysm is negatively associated with surrounding NETs, we hypothesize, that macrophages are able to degrade NETs in vivo.


Assuntos
Endodesoxirribonucleases/metabolismo , Armadilhas Extracelulares/metabolismo , Ativação de Macrófagos , Macrófagos/enzimologia , Neutrófilos/metabolismo , Pinocitose , Animais , Aneurisma da Aorta Abdominal/metabolismo , Células Cultivadas , Desoxirribonuclease I/metabolismo , Desoxirribonucleases/metabolismo , Modelos Animais de Doenças , Exodesoxirribonucleases/metabolismo , Feminino , Humanos , Imipramina/farmacologia , Interferon gama/farmacologia , Interleucina-13/farmacologia , Interleucina-4/farmacologia , Cinética , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Fagocitose , Fenótipo , Fosfoproteínas/metabolismo , Pinocitose/efeitos dos fármacos , Veia Cava Inferior/metabolismo , Trombose Venosa/metabolismo
20.
Med Hypotheses ; 143: 110073, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32645660

RESUMO

COVID-19 (coronavirus disease 2019) pandemic due to infection with SARS-CoV-2 has led to the death of thousands of adults worldwide. It is now clear that the hyper-inflammatory response triggered by SARS-CoV-2 plays a major role in disease severity and lethality of the infection. Macrophages are innate immune cells that sense and respond to infections by producing a plethora of inflammatory molecules and by interacting with other inflammatory cells. Therefore, macrophages may be diriment on eliminating pathogens and promoting organ repair. However, macrophages can be a major player of the so called cytokine storm and may be damaging to the tissues. It is believed that macrophage activation syndrome is induced by SARS-CoV to be lethal. Surprisingly and fortunately few children die from COVID-19. For instance, in Italy, out of more than 30.000 deaths for COVID-19, three are children. Therefore, we must wonder why? Are macrophages different in children compared to adults? In my opinion they are different. It has been demonstrated that macrophages populate the lung in three "developmental waves", and it has been suggested that similar waves may be observed in other important organs, such as the heart and kidney. It is most likely that macrophages heterogeneity is involved in determining the severity. There are no doubts that macrophages are important in determining life or death in these patients. Comparing macrophages of children with those of adults with different degrees of disease severity is, therefore, mandatory.


Assuntos
Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Macrófagos/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Adulto , Fatores Etários , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Criança , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/etiologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Pulmão/imunologia , Ativação de Macrófagos , Síndrome de Ativação Macrofágica/etiologia , Macrófagos/classificação , Modelos Biológicos , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações
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