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1.
Adv Exp Med Biol ; 1226: 73-86, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030677

RESUMO

The term "adipose tissue" represents a multicellular and multifunctional organ involved in lipid storage, in hormone and temperature regulation, and in the protection of bones and vital organs from impact-based damage. Emerging evidence now suggests a more malignant role of adipose tissue in promoting cancer onset and progression via the release of secreted factors such as interleukin-6 (IL6) and extracellular vesicles (EVs). These adipose-source factors subsequently affect various aspects of tumorigenesis and/or cancer progression by either directly enhancing the tumor cell oncogenic phenotype or indirectly by the stimulating adjacent normal cells to adopt a more pro-cancer phenotype. Due to the recent growing interest in the role of IL6 and EVs released by adipose tissue in cancer promotion and progression, we are focusing on the protumorigenic impact of fat tissue via IL6 and EV secretion.


Assuntos
Tecido Adiposo/metabolismo , Carcinogênese , Vesículas Extracelulares/metabolismo , Interleucina-6/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Microambiente Tumoral , Humanos
2.
Cell Physiol Biochem ; 54(1): 88-109, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31990489

RESUMO

Extracellular vesicles (EVs) are important mediators of intercellular communication. Since EVs are also released during pathological conditions, there has been considerable interest in their potential as sensitive biomarkers of cellular stress and/or injury. In the context of kidney disease, urinary EVs are promising indicators of glomerular and tubular damage. In the present review we discuss the role of urinary EVs in kidney health and disease. Our focus is to explore urinary large EVs (lEVs, often referred to as microparticles or microvesicles) as direct and noninvasive early biomarkers of renal injury. In this regard, studies have been demonstrating altered levels of urinary lEVs, especially podocyte-derived lEVs, preceding the decrease of renal function assessed by classical markers. In addition, we discuss the role of small EVs (sEVs, often referred to as exosomes) and their contents in kidney pathophysiology. Even though results concerning the production of sEVs during diseased conditions are varied, there has been a consensus on the importance of urinary sEV content assessment in kidney disease. These mediators, including EV-released miRNAs and mRNAs, are responsible for EV-mediated signaling in the regulation of renal cellular homeostasis, pathogenesis and regeneration. Finally, steps necessary for the validation of EVs as reliable markers will be discussed.


Assuntos
Vesículas Extracelulares/patologia , Nefropatias/diagnóstico , Glomérulos Renais/patologia , Túbulos Renais/patologia , Animais , Biomarcadores/análise , Biomarcadores/urina , Humanos , Nefropatias/patologia , Nefropatias/urina
3.
Life Sci ; 240: 117094, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760101

RESUMO

The liver serves as a central participant in immune system owing to its particular blood supply and large amounts of immune cells, in which macrophages play a significant role in liver homeostasis and disorders. Extracellular vesicles (EVs), membrane-defined nanometer-sized vesicles released by cells in a tightly controlled manner, have attracted intensive research attention as a critical vehicle for cell-cell communication in the pathophysiology of liver. Accumulating evidence has proved that extracellular vesicles are frequently involved in macrophage-mediated biological behaviors. Not only can macrophages produce and secrete EVs containing multifarious cargo themselves to exert immunomodulatory functions, but also macrophages may serve as target cells of EVs from other cells eliciting the alteration of their phenotype and function. Since both macrophage as well as EVs show pleiotropic and central effects in the progression of liver diseases, their roles in adjusting innate immunity of liver often present a crossover. In this review we are dedicated to deciphering the complex immunological network constituted by macrophages and EVs in several common liver diseases, including acute liver injury or failure and a set of chronic liver diseases such as viral hepatitis B and C, metabolic and alcoholic liver diseases, as well as hepatocellular carcinoma (HCC). From the aspect of immunology, we integrate the mechanism of EVs and hepatic macrophages in the setting of liver diseases and show a promising significance of utilizing this association into clinical immunotherapy.


Assuntos
Vesículas Extracelulares/imunologia , Hepatopatias/imunologia , Macrófagos/imunologia , Animais , Humanos , Imunomodulação
4.
Cancer Sci ; 111(1): 98-111, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31715081

RESUMO

The role of long noncoding RNAs (lncRNAs) in the epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) is unclear. Some lncRNAs can be transferred by extracellular vesicles (EVs) and have potential as biomarkers. Here, we identify an lncRNA that could serve as a biomarker for PDAC and show the functional roles of the lncRNA. Expression profiling of lncRNAs revealed that highly upregulated in liver cancer (HULC) was highly expressed, and induced, by transforming growth factor-ß in PDAC cells and their EVs. Knockdown of HULC decreased PDAC cell invasion and migration by inhibiting the EMT. Thus, HULC could be transferred by EVs, and promote EMT, invasion, and migration in recipient PDAC cells. To assess the roles of HULC, PDAC cell xenografts in nude mice were established. Knockdown of HULC in PDAC cells implanted in mice inhibited tumor growth. Moreover, microRNA-133b suppressed PDAC cell invasion and migration by inhibiting the EMT through targeting HULC. Furthermore, serum samples were obtained from 20 PDAC and 22 intraductal papillary mucinous neoplasm (IPMN) patients, as well as 21 healthy individuals. Analysis of serum EV HULC expression by digital PCR showed that HULC expression was significantly increased in PDAC patients compared to healthy individuals or IPMN patients. Additionally, HULC showed good predictive performance for discriminating PDAC, suggesting that the analysis of EV-encapsulated HULC would contribute to the diagnosis for human PDAC. Extracellular vesicle-transported HULC promotes cell invasion and migration by inducing the EMT, and microRNA-133b suppresses the EMT by targeting HULC. Extracellular vesicle-encapsulated HULC could be a potential circulating biomarker for human PDAC.


Assuntos
Biomarcadores Tumorais/sangue , Vesículas Extracelulares/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/patologia , Regulação para Cima/genética , Adenocarcinoma/sangue , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/genética , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , RNA Longo não Codificante/genética , Ativação Transcricional/genética
5.
Recent Results Cancer Res ; 215: 319-344, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31605237

RESUMO

Extracellular micro- and nanoscale membrane vesicles produced by different cells progressively attract the attention of the scientific community. They function as mediators of intercellular communication and transport genetic material and signaling molecules between the cells. In the context of keeping homeostasis, the extracellular vesicles contribute to the regulation of various systemic and local processes. Vesicles released by the tumor and activated stromal cells exhibit multiple functions including support of tumor growth, preparation of the pre-metastatic niches, and immune suppression. Considerable progress has been made regarding the criteria of classification of the vesicles according to their origin, content, and function: Exosomes, microvesicles, also referred to as microparticles or ectosomes, and large oncosomes were defined as actively released vesicles. Additionally, apoptotic bodies represented by a highly heterogeneous population of particles produced during apoptosis, the programmed cell death, should be considered. Because the majority of isolation techniques do not allow the separation of different types of vesicles, a joined term "extracellular vesicles" (EVs) was recommended by the ISEV community for the definition of vesicles isolated from either the cell culture supernatants or the body fluids. Because EV content reflects the content of the cell of origin, multiple studies on EVs from body fluids in the context of cancer diagnosis, prediction, and prognosis were performed, actively supporting their high potential as a biomarker source. Here, we review the leading achievements in EV analysis from body fluids, defined as EV-based liquid biopsy, and provide an overview of the main EV constituents: EV surface proteins, intravesicular soluble proteins, EV RNA including mRNA and miRNA, and EV DNA as potential biomarkers. Furthermore, we discuss recent developments in technology for quantitative EV analysis in the clinical setting and future perspectives toward miniaturized high-precision liquid biopsy approaches.


Assuntos
Vesículas Extracelulares , Biópsia Líquida/métodos , Biópsia Líquida/tendências , Neoplasias/diagnóstico , Neoplasias/patologia , Apoptose , Micropartículas Derivadas de Células , Exossomos , Humanos
6.
Acta Trop ; 201: 105184, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31542374

RESUMO

Schistosomiasis is a chronic parasitic disease caused by the genus Schistosoma and poses a great threat to human and animal health. Identification of effective biomarkers would facilitate evaluation of drug efficacy and recognition of infected hosts, which are crucial for effective schistosomiasis control. Extracellular vesicle (EV) proteins are considered ideal biomarkers for developing invasive diagnostic tools. In this study, we evaluated the potential of Schistosoma japonicum EV (SjEV) proteins as biomarkers for diagnosing schistosomiasis. Several SjEV proteins were subject to epitope prediction using DNASTAR software, and the diagnostic potential of selected peptides was evaluated using enzyme-linked immunosorbent assay (ELISA). The results indicated that the sera showed detectable antibody levels against the two antigens in mice, rabbits, and humans infected with S. japonicum. Further analysis of the combined epitope protein demonstrated a modest sensitivity for detection of Schistosomiasis japonica. Our preliminary study suggests that S. japonicum EV proteins could serve as potential biomarkers for developing diagnostic tools for schistosomiasis.


Assuntos
Vesículas Extracelulares/química , Proteínas de Helminto/imunologia , Esquistossomose Japônica/diagnóstico , Animais , Anticorpos Anti-Helmínticos/sangue , Biomarcadores/sangue , Biologia Computacional , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Camundongos , Coelhos
8.
J Orthop Res ; 38(1): 117-127, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31286564

RESUMO

Adipose-derived stem cells (ASCs) have the potential to enhance tendon repair via paracrine regulation of the inflammatory response to injury. Extracellular vesicles (EVs), which are secreted by ASCs, have shown promise in mediating this process. This study was designed to evaluate the effect of ASC EVs on early tendon healing using a mouse Achilles tendon injury and repair model. EVs were isolated from the conditioned medium of naïve and interferonγ-primed ASCs and applied to the repair site via a collagen sheet. Tendon healing was assessed in nuclear factor-κB (NF-κB)-luciferase reporter mice up to 7 days after suture repair. As anticipated, repair site NF-κB activity increased greater than twofold following tendon repair. Treatment with EVs from primed but not naïve ASCs effectively suppressed the response. Accordingly, the pro-inflammatory genes Il1b and Ifng were both dramatically increased in repaired tendons, while primed, but not naïve ASC EVs attenuated the response. Compared with control repairs, primed ASC EVs further reduced the rate of post-repair tendon gap formation and rupture and facilitated collagen formation at the injury site. Additional experiments demonstrated that EVs target macrophages and that primed ASC EVs were most effective in blocking macrophage NF-κB activity. Collectively, the findings of this study demonstrate that primed ASC EVs, similar to ASCs, attenuate the early tendon inflammatory response after injury via modulation of the macrophage inflammatory response. Statement of clinical significance: These findings introduce a new cell-free therapy, derived from stem cells, for tendon repair with the potential for improved therapeutic efficacy and safety. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:117-127, 2020.


Assuntos
Vesículas Extracelulares/fisiologia , Células-Tronco Mesenquimais/fisiologia , Traumatismos dos Tendões , Cicatrização , Tendão do Calcâneo/lesões , Animais , Macrófagos/metabolismo , Camundongos Transgênicos , NF-kappa B/metabolismo
9.
Anticancer Res ; 39(12): 6701-6709, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810935

RESUMO

BACKGROUND/AIM: Extracellular vesicles (exosomes, EVs) (30-200 nm in diameter) are secreted by various cells in the body. Owing to the pharmaceutical advantages of EVs, an EV-based drug delivery system (DDS) for cancer therapy is expected to be the next-generation therapeutic system. However, preservation methods for functional and therapeutic EVs should be developed. Here, we developed the method of lyophilization of arginine-rich cell penetrating peptide (CPP)-modified EVs and investigated the effects of lyophilization on the characteristics of EVs. MATERIALS AND METHODS: Particle size, structure, zeta-potential, and cellular uptake efficacy of the arginine-rich CPP-modified EVs were analyzed. The model protein saporin (SAP), having anti-cancer effects, was encapsulated inside the EVs to assess the cytosolic release of EV content after cellular uptake. RESULTS: Lyophilization of the EVs did not affect their particle size, structure, zeta-potential, and cellular uptake efficacy; however, the biological activity of the encapsulated SAP was inhibited by lyophilization. CONCLUSION: Lyophilization of EVs may affect SAP structures and/or reduce the cytosolic release efficacy of EV's content after cellular uptake and needs attention in EV-based DDSs.


Assuntos
Arginina , Peptídeos Penetradores de Células/farmacocinética , Vesículas Extracelulares/metabolismo , Veículos Farmacêuticos , Saporinas/farmacocinética , Animais , Células CHO , Sobrevivência Celular , Peptídeos Penetradores de Células/administração & dosagem , Peptídeos Penetradores de Células/química , Cricetulus , Liofilização , Humanos , Tamanho da Partícula , Pinocitose , Preservação Biológica/métodos , Saporinas/administração & dosagem , Tetraspanina 30/metabolismo
10.
Adv Exp Med Biol ; 1185: 431-436, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884650

RESUMO

Extracellular vesicles (EVs) are membranous structures released by cells, including those of the retinal pigment epithelium (RPE) and photoreceptors. The cargo of EVs includes genetic material and proteins, making these vesicles essential in cell communication. Among the genetic materials, we find a large number of microRNAs (miRNAs), small chains of noncoding RNA. In the case of EVs from the retina, changes have also been observed in the number and cargo of EVs.Our group confirmed that damaged RPE cells in vitro release a greater number of EVs with a higher pro-angiogenic factor (VEGFR-1 and VEGFR-2) than control non-damaged cells, thus increasing neovascularization in endothelial cell cultures. This indicates that something similar could happen in patients suffering from some types of retinal degeneration that occur with angiogenesis, such as wet AMD or RD.Here, we investigated the role of EVs in photoreceptor degeneration, and we report for the first time on CD9 and CD81, closely related tetraspanins, in wild-type and rd1 retinae. Our study demonstrates the involvement of EVs in the process of inherited photoreceptor degeneration in a PDE6 mutation.


Assuntos
Vesículas Extracelulares , Degeneração Retiniana/patologia , Retinite Pigmentosa/patologia , Tetraspanina 28/metabolismo , Tetraspanina 29/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Humanos , Retina , Epitélio Pigmentado da Retina/patologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
11.
Mem Inst Oswaldo Cruz ; 114: e190217, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31851215

RESUMO

The protozoan Trypanosoma cruzi has the ability to spontaneously secrete extracellular vesicles (EVs). In this paper, T. cruzi EVs derived from epimastigote forms were evaluated during interaction with triatomine bugs Rhodnius prolixus and Triatoma infestans. T. cruzi EVs were purified and artificially offered to the insects prior to infection with epimastigote forms. No effect of EVs was detected in the parasite counts in the guts of both vectors after 49-50 days. On the other hand, pre-feeding with EVs delayed parasite migration to rectum only in the gut in R. prolixus after 21-22 days. Those data suggest a possible role of T. cruzi EVs during the earlier events of infection in the invertebrate host.


Assuntos
Vesículas Extracelulares , Insetos Vetores/parasitologia , Intestinos/parasitologia , Rhodnius/parasitologia , Triatoma/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Interações Hospedeiro-Parasita/fisiologia , Trypanosoma cruzi/citologia
12.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 31(5): 555-559, 2019 Jul 24.
Artigo em Chinês | MEDLINE | ID: mdl-31713395

RESUMO

Exosomes are tiny vesicles secreted by most endogenous cells, and the extracellular vesicles (EVs) are specifically secreted by cells. Recently, it was found that exosomes contain a large quantity of important substances such as proteins, nucleic acids, and lipids, which play important roles in material exchange and information transmission in cell-cell communication, and in modulating the immune response, metabolism, and expansion, metastasis, and drug resistance of tumors. This paper summarizes the recent researches on exosomes in parasites and parasitic diseases and hopes to be helpful for improving the researches of parasites and parasitic diseases.


Assuntos
Exossomos , Vesículas Extracelulares , Parasitos , Doenças Parasitárias , Animais , Vesículas Extracelulares/fisiologia , Interações Hospedeiro-Parasita/fisiologia , Parasitos/citologia , Doenças Parasitárias/parasitologia , Pesquisa/tendências
13.
Plast Reconstr Surg ; 144(4): 869-880, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31568294

RESUMO

BACKGROUND: The efficacy of autologous fat transplantation is reduced by fat absorption and fibrosis that are closely related to unsatisfactory vascularization. Extracellular vesicles are key components of the cell secretome, which can mirror the functional and molecular characteristics of their parental cells. Growing evidence has revealed that adipose-derived mesenchymal stem cells have the ability to enhance vascularization, which is partly ascribed to extracellular vesicles. The authors evaluated whether adipose-derived mesenchymal stem cell-derived extracellular vesicles improved vascularization of fat grafts and increased their retention rate. METHODS: To test the angiogenesis ability of adipose-derived mesenchymal stem cell-derived extracellular vesicles, they were isolated from the supernatant of cultured human adipose-derived mesenchymal stem cells and incubated with human umbilical vein endothelial cells in vitro. Then, the vesicles were co-transplanted with fat into nude mice subcutaneously. Three months after transplantation, the retention rate and inflammatory reaction of the grafts were analyzed by histologic assay. RESULTS: The experimental group could significantly promote migration and tube formation at the concentration of 20 µg/ml. At 3 months after transplantation, the volume of the experimental group (0.12 ± 0.03 mm) was larger compared with the blank group (0.05 ± 0.01 mm). Histology and immunohistology results demonstrated significantly fewer cysts and vacuoles, less fibrosis, and more neovessels in the extracelluar vesicle group. CONCLUSIONS: The authors co-transplanted adipose-derived mesenchymal stem cell-derived extracellular vesicles with fat into a nude mouse model and found that the vesicles improved volume retention by enhancing vascularization and regulating the inflammatory response.


Assuntos
Tecido Adiposo/transplante , Vesículas Extracelulares , Células-Tronco Mesenquimais/citologia , Neovascularização Fisiológica , Animais , Células Cultivadas , Humanos , Camundongos
17.
Nat Commun ; 10(1): 4333, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551417

RESUMO

RNA-based therapeutics hold great promise for treating diseases and lipid nanoparticles (LNPs) represent the most advanced platform for RNA delivery. However, the fate of the LNP-mRNA after endosome-engulfing and escape from the autophagy-lysosomal pathway remains unclear. To investigate this, mRNA (encoding human erythropoietin) was delivered to cells using LNPs, which shows, for the first time, a link between LNP-mRNA endocytosis and its packaging into extracellular vesicles (endo-EVs: secreted after the endocytosis of LNP-mRNA). Endosomal escape of LNP-mRNA is dependent on the molar ratio between ionizable lipids and mRNA nucleotides. Our results show that fractions of ionizable lipids and mRNA (1:1 molar ratio of hEPO mRNA nucleotides:ionizable lipids) of endocytosed LNPs were detected in endo-EVs. Importantly, these EVs can protect the exogenous mRNA during in vivo delivery to produce human protein in mice, detected in plasma and organs. Compared to LNPs, endo-EVs cause lower expression of inflammatory cytokines.


Assuntos
Endossomos/fisiologia , Eritropoetina/metabolismo , Vesículas Extracelulares/metabolismo , Metabolismo dos Lipídeos , Nanopartículas/metabolismo , RNA Mensageiro/metabolismo , Animais , Transporte Biológico , Linhagem Celular , Citoplasma/metabolismo , Endossomos/metabolismo , Endossomos/ultraestrutura , Eritropoetina/genética , Feminino , Humanos , Lipídeos/química , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química
18.
J Cancer Res Clin Oncol ; 145(11): 2725-2736, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31552489

RESUMO

PURPOSE: The identification of biomarkers characterizing the invasive potential of bladder cancer could enhance the clinical management of individual patients and therefore improve prognosis. The aim of this study was to define a miRNA panel in tumor tissues as well as in urinary extracellular vesicles (EVs) for discriminating muscle-invasive bladder cancer (MIBC) from non-muscle-invasive bladder cancer (NMIBC). METHODS: miRNA expression was analyzed in 24 formalin-fixed, paraffin-embedded (FFPE) tumor samples by microarray analysis and was further validated by qRT-PCR in 56 FFPE tumor samples as well as in 37 urinary EV samples. RESULTS: Microarray analysis revealed 63 miRNAs that were significantly differentially expressed (P < 0.05) between tissues from MIBC and NMIBC tumors. Five selected miRNAs (miR-146b-5p, miR-155-5p, miR-138-5p, miR-144-5p, and miR-200a-3p) were validated by qRT-PCR. The expression of all except miR-144-5p was significantly associated with high tumor grade. In urinary EVs, a different expression was verified for miR-146b-5p (P = 0.004) and miR-155-5p (P = 0.036), which exhibited significantly higher expression in urinary EVs from patients with MIBC. CONCLUSIONS: miRNAs are promising biomarkers for the identification of invasive bladder carcinomas. Tissue samples as well as urinary EVs may serve as sources for miRNA analysis. This method, in addition to histopathology, could provide a new diagnostic tool and facilitate individual therapeutic decisions to select patients for early cystectomy.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/urina , Vesículas Extracelulares/genética , MicroRNAs/genética , MicroRNAs/urina , Neoplasias Musculares/diagnóstico , Neoplasias da Bexiga Urinária/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/genética , Neoplasias Musculares/urina , Prognóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/urina
19.
EMBO J ; 38(20): e101266, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31544965

RESUMO

Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active IL-1ß by proteolytic cleavage via caspase-1. Although many principles of inflammasome activation have been described, mechanisms that limit inflammasome-dependent immune responses remain poorly defined. Here, we show that the thiol-specific peroxidase peroxiredoxin-4 (Prdx4) directly regulates IL-1ß generation by interfering with caspase-1 activity. We demonstrate that caspase-1 and Prdx4 form a redox-sensitive regulatory complex via caspase-1 cysteine 397 that leads to caspase-1 sequestration and inactivation. Mice lacking Prdx4 show an increased susceptibility to LPS-induced septic shock. This effect was phenocopied in mice carrying a conditional deletion of Prdx4 in the myeloid lineage (Prdx4-ΔLysMCre). Strikingly, we demonstrate that Prdx4 co-localizes with inflammasome components in extracellular vesicles (EVs) from inflammasome-activated macrophages. Purified EVs are able to transmit a robust IL-1ß-dependent inflammatory response in vitro and also in recipient mice in vivo. Loss of Prdx4 boosts the pro-inflammatory potential of EVs. These findings identify Prdx4 as a critical regulator of inflammasome activity and provide new insights into remote cell-to-cell communication function of inflammasomes via macrophage-derived EVs.


Assuntos
Caspase 1/metabolismo , Vesículas Extracelulares/metabolismo , Inflamassomos/imunologia , Macrófagos/imunologia , Peroxirredoxinas/fisiologia , Choque Séptico/prevenção & controle , Animais , Caspase 1/genética , Citocinas/metabolismo , Feminino , Inflamassomos/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Choque Séptico/induzido quimicamente , Choque Séptico/imunologia , Choque Séptico/patologia , Transdução de Sinais
20.
Int J Mol Sci ; 20(18)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500278

RESUMO

Extracellular vesicles (EVs) are nanometer-sized membranous vesicles used for primitive cell-to-cell communication. We previously reported that colon cancer-derived EVs contain abundant miR-92a-3p and have a pro-angiogenic function. We previously identified Dickkopf-3 (Dkk-3) as a direct target of miR-92a-3p; however, the pro-angiogenic function of miR-92a-3p cannot only be attributed to downregulation of Dkk-3. Therefore, the complete molecular mechanism by which miR-92a-3p exerts pro-angiogenic effects is still unclear. Here, we comprehensively analyzed the gene sets affected by ectopic expression of miR-92a-3p in endothelial cells to elucidate processes underlying EV-induced angiogenesis. We found that the ectopic expression of miR-92a-3p upregulated cell cycle- and mitosis-related gene expression and downregulated adhesion-related gene expression in endothelial cells. We also identified a novel target gene of miR-92a-3p, claudin-11. Claudin-11 belongs to the claudin gene family, which encodes essential components expressed at tight junctions (TJs). Disruption of TJs with a concomitant loss of claudin expression is a significant event in the process of epithelial-to-mesenchymal transition. Our findings have unveiled a new EV-mediated mechanism for tumor angiogenesis through the induction of partial endothelial-to-mesenchymal transition in endothelial cells.


Assuntos
Claudinas/genética , Neoplasias do Colo/irrigação sanguínea , Vesículas Extracelulares/genética , MicroRNAs/genética , Neovascularização Patológica/genética , Linhagem Celular Tumoral , Claudinas/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Células Endoteliais/química , Células Endoteliais/citologia , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Neovascularização Patológica/metabolismo , Mapas de Interação de Proteínas , Junções Íntimas/genética , Junções Íntimas/metabolismo
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