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1.
Phys Rev Lett ; 125(8): 088103, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32909804

RESUMO

The ability of humans and animals to quickly adapt to novel tasks is difficult to reconcile with the standard paradigm of learning by slow synaptic weight modification. Here, we show that fixed-weight neural networks can learn to generate required dynamics by imitation. After appropriate weight pretraining, the networks quickly and dynamically adapt to learn new tasks and thereafter continue to achieve them without further teacher feedback. We explain this ability and illustrate it with a variety of target dynamics, ranging from oscillatory trajectories to driven and chaotic dynamical systems.


Assuntos
Aprendizagem/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Animais , Comunicação Celular/fisiologia , Humanos , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Neurônios/citologia
2.
J Biomed Nanotechnol ; 16(4): 399-418, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32970974

RESUMO

Exosomes are small extracellular vesicles of 30-150 nm diameter secreted by almost all cells. In recent years, with continuous deeper understanding of exosomes physiological functions, different reports have proven that exosomes can facilitate cell-to-cell communication by binding to target cells and transferring their contents, together with RNAs, DNAs, proteins, and lipids between cells and tissues. With advantages that exosomes can be involved in various types of physiological processes, such as blood coagulation, cellular homeostasis, inflammation, immune surveillance, stem cell differentiation, neuroprotection, and tissue regeneration and angiogenesis. Exosomes have been demonstrated that they can be applied in identification and treatment of multiple disorders such as cancers, cerebral ischemia, and respiratory infectious diseases. Importantly, researchers utilize application of exosomes in the treatment of various respiratory infectious diseases that have made some breakthrough progress. However, with the global pandemic of Coronavirus Disease 2019 (COVID-19), we have focused on applications of exosomes in respiratory infectious diseases and their serious complications, including influenza, TB, ARDS and sepsis. In this review, we explain the use of exosomes in various respiratory infectious diseases and their serious complications, and hope to provide new ideas for the treatment of new coronavirus infections.


Assuntos
Infecções por Coronavirus/terapia , Exossomos , Pneumonia Viral/terapia , Infecções Respiratórias/terapia , Betacoronavirus , Comunicação Celular , Humanos , Pandemias
3.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(4): 440-448, 2020 Apr 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-32879070

RESUMO

Exosomes are in a size of 30-100 nm vesicles released by various cells, with a double-layered lipid membrane containing DNA, RNA, and protein. In the past, exosomes were considered to be molecular waste, and recently exosomes have been shown to be involved in many pathophysiological processes, including intercellular communication, immune response, nerve repair, and tumorigenesis. Exosomes are present in numerous body fluids, and urinary exosomes have been shown to be biomarkers of a variety of kidney diseases.


Assuntos
Exossomos , Nefropatias , Biomarcadores , Comunicação Celular , Humanos , Proteínas
4.
Nat Commun ; 11(1): 4855, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978390

RESUMO

The atypical chemokine receptor 3 (ACKR3) plays a pivotal role in directing the migration of various cellular populations and its over-expression in tumors promotes cell proliferation and invasiveness. The intracellular signaling pathways transducing ACKR3-dependent effects remain poorly characterized, an issue we addressed by identifying the interactome of ACKR3. Here, we report that recombinant ACKR3 expressed in HEK293T cells recruits the gap junction protein Connexin 43 (Cx43). Cx43 and ACKR3 are co-expressed in mouse brain astrocytes and human glioblastoma cells and form a complex in embryonic mouse brain. Functional in vitro studies show enhanced ACKR3 interaction with Cx43 upon ACKR3 agonist stimulation. Furthermore, ACKR3 activation promotes ß-arrestin2- and dynamin-dependent Cx43 internalization to inhibit gap junctional intercellular communication in primary astrocytes. These results demonstrate a functional link between ACKR3 and gap junctions that might be of pathophysiological relevance.


Assuntos
Astrócitos/metabolismo , Comunicação Celular/fisiologia , Conexina 43/metabolismo , Junções Comunicantes/patologia , Receptores CXCR/metabolismo , Animais , Proliferação de Células , Conexina 43/efeitos dos fármacos , Conexinas/metabolismo , Técnicas de Introdução de Genes , Glioblastoma/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Domínios e Motivos de Interação entre Proteínas , Receptores CXCR/agonistas , Receptores CXCR/genética , Transdução de Sinais/fisiologia
5.
Nat Commun ; 11(1): 4458, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895383

RESUMO

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.


Assuntos
Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fator 1 de Crescimento de Fibroblastos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Hipotálamo/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteína Relacionada com Agouti/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Glicemia/análise , Comunicação Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/administração & dosagem , Sacarose na Dieta/efeitos adversos , Humanos , Hipotálamo/citologia , Hipotálamo/patologia , Injeções Intraventriculares , Leptina/genética , Masculino , Melanocortinas/metabolismo , Hormônios Estimuladores de Melanócitos/administração & dosagem , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , RNA-Seq , Receptor Tipo 4 de Melanocortina/genética , Receptores de Melanocortina/antagonistas & inibidores , Receptores de Melanocortina/metabolismo , Indução de Remissão/métodos , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Técnicas Estereotáxicas , Transcriptoma/efeitos dos fármacos
6.
Nat Commun ; 11(1): 4666, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938943

RESUMO

Intercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart. Mutations in genes encoding ICD components are linked to cardiovascular diseases. Here, we show that loss of Xinß, a newly-identified component of ICDs, results in cardiomyocyte proliferation defects and cardiomyopathy. We uncovered a role for Xinß in signaling via the Hippo-YAP pathway by recruiting NF2 to the ICD to modulate cardiac function. In Xinß mutant hearts levels of phosphorylated NF2 are substantially reduced, suggesting an impairment of Hippo-YAP signaling. Cardiac-specific overexpression of YAP rescues cardiac defects in Xinß knock-out mice-indicating a functional and genetic interaction between Xinß and YAP. Our study reveals a molecular mechanism by which cardiac-expressed intercalated disc protein Xinß modulates Hippo-YAP signaling to control heart development and cardiac function in a tissue specific manner. Consequently, this pathway may represent a therapeutic target for the treatment of cardiovascular diseases.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas com Domínio LIM/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Cardiomiopatia Dilatada/genética , Comunicação Celular , Proteínas de Ciclo Celular/genética , Proliferação de Células , Proteínas do Citoesqueleto/genética , Proteínas de Ligação a DNA/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Ventrículos do Coração/crescimento & desenvolvimento , Proteínas com Domínio LIM/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Miócitos Cardíacos/citologia , Miócitos Cardíacos/patologia , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Proteínas Nucleares/genética , Transdução de Sinais
7.
Nat Commun ; 11(1): 4226, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839450

RESUMO

Intercellular signaling is indispensable for single cells to form complex biological structures, such as biofilms, tissues and organs. The genetic tools available for engineering intercellular signaling, however, are quite limited. Here we exploit the chemical diversity of biological small molecules to de novo design a genetic toolbox for high-performance, multi-channel cell-cell communications and biological computations. By biosynthetic pathway design for signal molecules, rational engineering of sensing promoters and directed evolution of sensing transcription factors, we obtain six cell-cell signaling channels in bacteria with orthogonality far exceeding the conventional quorum sensing systems and successfully transfer some of them into yeast and human cells. For demonstration, they are applied in cell consortia to generate bacterial colony-patterns using up to four signaling channels simultaneously and to implement distributed bio-computation containing seven different strains as basic units. This intercellular signaling toolbox paves the way for engineering complex multicellularity including artificial ecosystems and smart tissues.


Assuntos
Comunicação Celular/genética , Biologia Computacional/métodos , Transdução de Sinais/genética , Fatores de Transcrição/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Microscopia de Fluorescência , Mutação , Reprodutibilidade dos Testes , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo
8.
Phys Rev Lett ; 125(4): 048103, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32794792

RESUMO

A ubiquitous way that cells share information is by exchanging molecules. Yet, the fundamental ways that this information exchange is influenced by intracellular dynamics remain unclear. Here we use information theory to investigate a simple model of two interacting cells with internal feedback. We show that cell-to-cell molecule exchange induces a collective two-cell critical point and that the mutual information between the cells peaks at this critical point. Information can remain large far from the critical point on a manifold of cellular states but scales logarithmically with the correlation time of the system, resulting in an information-correlation time trade-off. This trade-off is strictly imposed, suggesting the correlation time as a proxy for the mutual information.


Assuntos
Comunicação Celular/fisiologia , Modelos Biológicos , Análise de Célula Única , Termodinâmica
9.
Nat Commun ; 11(1): 4239, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843640

RESUMO

How stem cells give rise to epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation. Here we use single cell-RNA sequencing to interrogate basal stem cell heterogeneity of human interfollicular epidermis and find four spatially distinct stem cell populations at the top and bottom of rete ridges and transitional positions between the basal and suprabasal epidermal layers. Cell-cell communication modeling suggests that basal cell populations serve as crucial signaling hubs to maintain epidermal communication. Combining pseudotime, RNA velocity, and cellular entropy analyses point to a hierarchical differentiation lineage supporting multi-stem cell interfollicular epidermal homeostasis models and suggest that transitional basal stem cells are stable states essential for proper stratification. Finally, alterations in differentially expressed transitional basal stem cell genes result in severe thinning of human skin equivalents, validating their essential role in epidermal homeostasis and reinforcing the critical nature of basal stem cell heterogeneity.


Assuntos
Diferenciação Celular , Células Epidérmicas/citologia , Homeostase , Células-Tronco/citologia , Comunicação Celular/genética , Diferenciação Celular/genética , Linhagem da Célula/genética , Células Epidérmicas/metabolismo , Epiderme/metabolismo , Prepúcio do Pênis/citologia , Prepúcio do Pênis/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Recém-Nascido , Queratinócitos/citologia , Queratinócitos/metabolismo , Masculino , Modelos Biológicos , Transdução de Sinais , Células-Tronco/metabolismo
10.
Nat Commun ; 11(1): 4261, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848136

RESUMO

Metastasis, the spread of malignant cells from a primary tumour to distant sites, causes 90% of cancer-related deaths. The integrin ITGB3 has been previously described to play an essential role in breast cancer metastasis, but the precise mechanisms remain undefined. We have now uncovered essential and thus far unknown roles of ITGB3 in vesicle uptake. The functional requirement for ITGB3 derives from its interactions with heparan sulfate proteoglycans (HSPGs) and the process of integrin endocytosis, allowing the capture of extracellular vesicles and their endocytosis-mediated internalization. Key for the function of ITGB3 is the interaction and activation of focal adhesion kinase (FAK), which is required for endocytosis of these vesicles. Thus, ITGB3 has a central role in intracellular communication via extracellular vesicles, proposed to be critical for cancer metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Comunicação Celular/fisiologia , Vesículas Extracelulares/metabolismo , Integrina beta3/metabolismo , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Meios de Cultivo Condicionados , Endocitose , Feminino , Quinase 1 de Adesão Focal/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Células MCF-7 , Camundongos , Camundongos Nus , Modelos Biológicos , Metástase Neoplásica/patologia , Transplante de Neoplasias
11.
PLoS Comput Biol ; 16(8): e1008076, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745094

RESUMO

We consider how a signalling system can act as an information hub by multiplexing information arising from multiple signals. We formally define multiplexing, mathematically characterise which systems can multiplex and how well they can do it. While the results of this paper are theoretical, to motivate the idea of multiplexing, we provide experimental evidence that tentatively suggests that the NF-κB transcription factor can multiplex information about changes in multiple signals. We believe that our theoretical results may resolve the apparent paradox of how a system like NF-κB that regulates cell fate and inflammatory signalling in response to diverse stimuli can appear to have the low information carrying capacity suggested by recent studies on scalar signals. In carrying out our study, we introduce new methods for the analysis of large, nonlinear stochastic dynamic models, and develop computational algorithms that facilitate the calculation of fundamental constructs of information theory such as Kullback-Leibler divergences and sensitivity matrices, and link these methods to a new theory about multiplexing information. We show that many current models such as those of the NF-κB system cannot multiplex effectively and provide models that overcome this limitation using post-transcriptional modifications.


Assuntos
Comunicação Celular/fisiologia , Modelos Biológicos , Transdução de Sinais/fisiologia , Algoritmos , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Regulação da Expressão Gênica , Humanos , Teoria da Informação , NF-kappa B/metabolismo , Análise de Célula Única , Processos Estocásticos
12.
Nature ; 585(7823): 91-95, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32788726

RESUMO

Signalling between cells of the neurovascular unit, or neurovascular coupling, is essential to match local blood flow with neuronal activity. Pericytes interact with endothelial cells and extend processes that wrap capillaries, covering up to 90% of their surface area1,2. Pericytes are candidates to regulate microcirculatory blood flow because they are strategically positioned along capillaries, contain contractile proteins and respond rapidly to neuronal stimulation3,4, but whether they synchronize microvascular dynamics and neurovascular coupling within a capillary network was unknown. Here we identify nanotube-like processes that connect two bona fide pericytes on separate capillary systems, forming a functional network in the mouse retina, which we named interpericyte tunnelling nanotubes (IP-TNTs). We provide evidence that these (i) have an open-ended proximal side and a closed-ended terminal (end-foot) that connects with distal pericyte processes via gap junctions, (ii) carry organelles including mitochondria, which can travel along these processes, and (iii) serve as a conduit for intercellular Ca2+ waves, thus mediating communication between pericytes. Using two-photon microscope live imaging, we demonstrate that retinal pericytes rely on IP-TNTs to control local neurovascular coupling and coordinate light-evoked responses between adjacent capillaries. IP-TNT damage following ablation or ischaemia disrupts intercellular Ca2+ waves, impairing blood flow regulation and neurovascular coupling. Notably, pharmacological blockade of Ca2+ influx preserves IP-TNTs, rescues light-evoked capillary responses and restores blood flow after reperfusion. Our study thus defines IP-TNTs and characterizes their critical role in regulating neurovascular coupling in the living retina under both physiological and pathological conditions.


Assuntos
Nanotubos , Acoplamento Neurovascular , Pericitos/metabolismo , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Cálcio/metabolismo , Sinalização do Cálcio , Capilares/fisiopatologia , Capilares/efeitos da radiação , Comunicação Celular , Feminino , Junções Comunicantes/metabolismo , Hemodinâmica , Masculino , Camundongos , Mitocôndrias/metabolismo , Acoplamento Neurovascular/fisiologia , Pericitos/citologia , Pericitos/patologia , Retina/citologia , Retina/patologia
13.
Yakugaku Zasshi ; 140(8): 969-977, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741870

RESUMO

We developed a method of video-rate bioluminescence imaging to visualize proteins secreted from living cells. A protein of interest was fused to Gaussia luciferase (GLase), and the luminescence signals of secreted GLase with coelenterazine (luciferin) were visualized at a video-rate of 30-500 ms/frame by using a water-cooled EM-CCD camera. We established a subclonal rat INS-1E cell line, named iGL cells, stably expressing the fusion protein of insulin and GLase (Insulin-GLase). By stimulation with high glucose, 3D-cultured iGL cells showed synchronized oscillatory secretion of insulin for over 1 h, as similarly observed in an isolated rat pancreatic islet. In 2D-cultured iGL cells, the luminescence images indicated that synchronized insulin secretion was localized in intercellular spaces between cells. Further, the relative amount of insulin secretion from iGL cells was easily determined with a luminometer, and we demonstrated that cell-cell interaction of beta cells is fundamental to increase glucose-stimulated insulin secretion by synchronization. Thus, iGL cells would be valuable for studying oscillatory insulin secretion and evaluating anti-diabetic drugs. Our bioluminescence imaging method with GLase could be generally used for investigating protein secretion in 2D and 3D cell culture systems.


Assuntos
Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Medições Luminescentes/métodos , Imagem Molecular/métodos , Animais , Comunicação Celular , Linhagem Celular , Células Cultivadas , Humanos , Imidazóis , Luciferases , Pirazinas , Ratos
14.
Cells ; 9(9)2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32859053

RESUMO

Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising of exosomes, apoptotic bodies, and microvesicles. Of the extracellular vesicles, exosomes are the most widely sorted and extensively explored for their contents and function. The size of the nanovesicular structures (exosomes) range from 30 to 140 nm and are present in various biological fluids such as saliva, plasma, urine etc. These cargo-laden extracellular vesicles arise from endosome-derived multivesicular bodies and are known to carry proteins and nucleic acids. Exosomes are involved in multiple physiological and pathological processes, including cellular senescence. Exosomes mediate signaling crosstalk and play a critical role in cell-cell communications. Exosomes have evolved as potential biomarkers for aging-related diseases. Aging, a physiological process, involves a progressive decline of function of organs with a loss of homeostasis and increasing probability of illness and death. The review focuses on the classic view of exosome biogenesis, biology, and age-associated changes. Owing to their ability to transport biological information among cells, the review also discusses the interplay of senescent cell-derived exosomes with the aging process, including the susceptibility of the aging population to COVID-19 infections.


Assuntos
Envelhecimento/metabolismo , Doenças Cardiovasculares/metabolismo , Comunicação Celular , Senescência Celular , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/metabolismo , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Doenças Neurodegenerativas/metabolismo , Pneumonia Viral/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Betacoronavirus , Biomarcadores/metabolismo , Infecções por Coronavirus/virologia , Humanos , Camundongos , Pandemias , Pneumonia Viral/virologia
15.
PLoS One ; 15(8): e0237795, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32833989

RESUMO

Extracellular vesicles (EVs) are small membrane-limited structures derived from outward budding of the plasma membrane or endosomal system that participate in cellular communication processes through the transport of bioactive molecules to recipient cells. To date, there are no published methodological works showing step-by-step the isolation, characterization and internalization of small EVs secreted by human primary macrophages derived from circulating monocytes (MDM-derived sEVs). Thus, here we aimed to provide an alternative protocol based on differential ultracentrifugation (dUC) to describe small EVs (sEVs) from these cells. Monocyte-derived macrophages were cultured in EV-free medium during 24, 48 or 72 h and, then, EVs were isolated from culture supernatants by (dUC). Macrophages secreted a large amount of sEVs in the first 24 h, with size ranging from 40-150 nm, peaking at 105 nm, as evaluated by nanoparticle tracking analysis and scanning electron microscopy. The markers Alix, CD63 and CD81 were detected by immunoblotting in EV samples, and the co-localization of CD63 and CD81 after sucrose density gradient ultracentrifugation (S-DGUC) indicated the presence of sEVs from late endosomal origin. Confocal fluorescence revealed that the sEVs were internalized by primary macrophages after three hours of co-culture. The methodology here applied aims to contribute for enhancing reproducibility between the limited number of available protocols for the isolation and characterization of MDM-derived sEVs, thus providing basic knowledge in the area of EV methods that can be useful for those investigators working with sEVs released by human primary macrophages derived from circulating monocytes.


Assuntos
Comunicação Celular , Vesículas Extracelulares/metabolismo , Macrófagos/metabolismo , Buffy Coat/citologia , Diferenciação Celular , Fracionamento Celular/métodos , Centrifugação com Gradiente de Concentração/métodos , Técnicas de Cocultura , Voluntários Saudáveis , Humanos , Microscopia Intravital , Macrófagos/citologia , Macrófagos/ultraestrutura , Microscopia Confocal , Microscopia Eletrônica de Varredura , Microscopia de Fluorescência , Monócitos/fisiologia , Cultura Primária de Células
16.
BMC Bioinformatics ; 21(1): 346, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778050

RESUMO

BACKGROUND: While technological advances have made it possible to profile the immune system at high resolution, translating high-throughput data into knowledge of immune mechanisms has been challenged by the complexity of the interactions underlying immune processes. Tools to explore the immune network are critical for better understanding the multi-layered processes that underlie immune function and dysfunction, but require a standardized network map of immune interactions. To facilitate this we have developed ImmunoGlobe, a manually curated intercellular immune interaction network extracted from Janeway's Immunobiology textbook. RESULTS: ImmunoGlobe is the first graphical representation of the immune interactome, and is comprised of 253 immune system components and 1112 unique immune interactions with detailed functional and characteristic annotations. Analysis of this network shows that it recapitulates known features of the human immune system and can be used uncover novel multi-step immune pathways, examine species-specific differences in immune processes, and predict the response of immune cells to stimuli. ImmunoGlobe is publicly available through a user-friendly interface at www.immunoglobe.org and can be downloaded as a computable graph and network table. CONCLUSION: While the fields of proteomics and genomics have long benefited from network analysis tools, no such tool yet exists for immunology. ImmunoGlobe provides a ground truth immune interaction network upon which such tools can be built. These tools will allow us to predict the outcome of complex immune interactions, providing mechanistic insight that allows us to precisely modulate immune responses in health and disease.


Assuntos
Comunicação Celular , Curadoria de Dados , Espaço Extracelular/metabolismo , Sistema Imunitário/metabolismo , Mapas de Interação de Proteínas , Software , Biologia de Sistemas , Animais , Humanos , Camundongos , Modelos Imunológicos
17.
PLoS One ; 15(8): e0237095, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756599

RESUMO

Regular exercise is an effective strategy that is used to prevent and treat obesity as well as type 2 diabetes. Exercise-induced myokine secretion is considered a mechanism that coordinates communication between muscles and other organs. In order to examine the possibility of novel communications from muscle to adipose tissue mediated by myokines, we treated 3T3-L1 adipocytes with C2C12 myotube electrical pulse stimulation-conditioned media (EPS-CM), using a C2C12 myotube contraction system stimulated by an electrical pulse. Continuous treatment with myotube EPS-CM promoted adipogenesis of 3T3-L1 pre-adipocytes via the upregulation of the peroxisome proliferator-activated receptor-gamma (PPARγ) 2 and PPARγ-regulated gene expression. Furthermore, our results revealed that myotube EPS-CM induces lipolysis and secretion of adiponectin in mature adipocytes. EPS-CM obtained from a C2C12 myoblast culture did not induce such changes in these genes, suggesting that contraction-induced myokine(s) secretion occurs particularly in differentiated myotubes. Thus, contraction-induced secretion of myokine(s) promotes adipogenesis and lipid metabolism in 3T3-L1 adipocytes. These findings suggest the possibility that skeletal muscle communicates to adipose tissues during exercise, probably by the intermediary of unidentified myokines.


Assuntos
Adipócitos/citologia , Diferenciação Celular , Lipólise , Fibras Musculares Esqueléticas/metabolismo , Células 3T3 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia , Adiponectina/metabolismo , Animais , Comunicação Celular , Meios de Cultivo Condicionados/farmacologia , Camundongos , PPAR gama/metabolismo
18.
Korean J Parasitol ; 58(3): 217-227, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32615735

RESUMO

Trichomonas vaginalis causes inflammation of the prostate and has been detected in tissues of prostate cancers (PCa), prostatitis and benign prostatic hyperplasia. Obesity is a risk factor for PCa and causes a chronic subclinical inflammation. This chronic inflammation further exacerbates adipose tissue inflammation as results of migration and activation of macrophages. Macrophages are the most abundant immune cells in the PCa microenvironment. M2 macrophages, known as Tumor-Associated Macrophages, are involved in increasing cancer malignancy. In this study, conditioned medium (TCM) of PCa cells infected with live trichomonads contained chemokines that stimulated migration of the mouse preadipocytes (3T3-L1 cells). Conditioned medium of adipocytes incubated with TCM (ATCM) contained Th2 cytokines (IL-4, IL-13). Macrophage migration was stimulated by ATCM. In macrophages treated with ATCM, expression of M2 markers increased, while M1 markers decreased. Therefore, it is suggested that ATCM induces polarization of M0 to M2 macrophages. In addition, conditioned medium from the macrophages incubated with ATCM stimulates the proliferation and invasiveness of PCa. Our findings suggest that interaction between inflamed PCa treated with T. vaginalis and adipocytes causes M2 macrophage polarization, so contributing to the progression of PCa.


Assuntos
Adipócitos/imunologia , Macrófagos/imunologia , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/parasitologia , Trichomonas vaginalis , Animais , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Quimiocinas/imunologia , Inflamação , Masculino , Camundongos , Obesidade , Neoplasias da Próstata/patologia , Fatores de Risco
19.
Nat Commun ; 11(1): 3421, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647184

RESUMO

The OX40-OX40L pathway provides crucial co-stimulatory signals for CD4 T cell responses, however the precise cellular interactions critical for OX40L provision in vivo and when these occur, remains unclear. Here, we demonstrate that provision of OX40L by dendritic cells (DCs), but not T cells, B cells nor group 3 innate lymphoid cells (ILC3s), is critical specifically for the effector Th1 response to an acute systemic infection with Listeria monocytogenes (Lm). OX40L expression by DCs is regulated by cross-talk with NK cells, with IFNγ signalling to the DC to enhance OX40L in a mechanism conserved in both mouse and human DCs. Strikingly, DC expression of OX40L is redundant in a chronic intestinal Th1 response and expression by ILC3s is necessary. Collectively these data reveal tissue specific compartmentalisation of the cellular provision of OX40L and define a mechanism controlling DC expression of OX40L in vivo.


Assuntos
Microambiente Celular , Ligante OX40/metabolismo , Células Th1/imunologia , Animais , Comunicação Celular , Sinais (Psicologia) , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Humanos , Interferon gama/biossíntese , Interleucina-12/farmacologia , Intestinos/citologia , Antígeno Ki-1/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Listeria monocytogenes/fisiologia , Camundongos Endogâmicos C57BL , Receptores CXCR5/metabolismo , Receptores OX40/metabolismo , Baço/metabolismo , Regulação para Cima/efeitos dos fármacos
20.
Nat Commun ; 11(1): 3366, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632165

RESUMO

CD4+ T lymphocytes consist of naïve, antigen-specific memory, and memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells exert innate-like effector function during host defense, but whether MP CD4+ T cells are functionally heterogeneous and, if so, what signals specify the differentiation of MP cell subpopulations under homeostatic conditions is still unclear. Here we characterize MP lymphocytes as consisting of T-bethigh, T-betlow, and T-bet- subsets, with innate, Th1-like effector activity exclusively associated with T-bethigh cells. We further show that the latter population depends on IL-12 produced by CD8α+ type 1 dendritic cells (DC1) for its differentiation. Finally, our data demonstrate that this tonic IL-12 production requires TLR-MyD88 signaling independent of foreign agonists, and is further enhanced by CD40-CD40L interactions between DC1 and CD4+ T lymphocytes. We propose that optimal differentiation of T-bethigh MP lymphocytes at homeostasis is driven by self-recognition signals at both the DC and Tcell levels.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Homeostase/imunologia , Memória Imunológica/imunologia , Proteínas com Domínio T/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Ligante de CD40/genética , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Antígenos CD8/imunologia , Antígenos CD8/metabolismo , Comunicação Celular/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-12/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Transdução de Sinais/imunologia , Proteínas com Domínio T/metabolismo , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo
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