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1.
Nat Immunol ; 21(6): 660-670, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32341509

RESUMO

Within germinal centers (GCs), complex and highly orchestrated molecular programs must balance proliferation, somatic hypermutation and selection to both provide effective humoral immunity and to protect against genomic instability and neoplastic transformation. In contrast to this complexity, GC B cells are canonically divided into two principal populations, dark zone (DZ) and light zone (LZ) cells. We now demonstrate that, following selection in the LZ, B cells migrated to specialized sites within the canonical DZ that contained tingible body macrophages and were sites of ongoing cell division. Proliferating DZ (DZp) cells then transited into the larger DZ to become differentiating DZ (DZd) cells before re-entering the LZ. Multidimensional analysis revealed distinct molecular programs in each population commensurate with observed compartmentalization of noncompatible functions. These data provide a new three-cell population model that both orders critical GC functions and reveals essential molecular programs of humoral adaptive immunity.


Assuntos
Microambiente Celular/genética , Microambiente Celular/imunologia , Centro Germinativo/citologia , Centro Germinativo/fisiologia , Animais , Biomarcadores , Biologia Computacional/métodos , Imunofluorescência , Perfilação da Expressão Gênica , Genômica/métodos , Camundongos , Fosforilação , Proteoma , Proteômica/métodos , Transcriptoma
2.
Proc Natl Acad Sci U S A ; 117(18): 9896-9905, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32321834

RESUMO

The extracellular matrix (ECM) initiates mechanical cues that activate intracellular signaling through matrix-cell interactions. In blood vessels, additional mechanical cues derived from the pulsatile blood flow and pressure play a pivotal role in homeostasis and disease development. Currently, the nature of the cues from the ECM and their interaction with the mechanical microenvironment in large blood vessels to maintain the integrity of the vessel wall are not fully understood. Here, we identified the matricellular protein thrombospondin-1 (Thbs1) as an extracellular mediator of matrix mechanotransduction that acts via integrin αvß1 to establish focal adhesions and promotes nuclear shuttling of Yes-associated protein (YAP) in response to high strain of cyclic stretch. Thbs1-mediated YAP activation depends on the small GTPase Rap2 and Hippo pathway and is not influenced by alteration of actin fibers. Deletion of Thbs1 in mice inhibited Thbs1/integrin ß1/YAP signaling, leading to maladaptive remodeling of the aorta in response to pressure overload and inhibition of neointima formation upon carotid artery ligation, exerting context-dependent effects on the vessel wall. We thus propose a mechanism of matrix mechanotransduction centered on Thbs1, connecting mechanical stimuli to YAP signaling during vascular remodeling in vivo.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Integrina beta1/genética , Trombospondina 1/genética , Fatores de Transcrição/genética , Remodelação Vascular/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Aorta/crescimento & desenvolvimento , Aorta/metabolismo , Artérias Carótidas/crescimento & desenvolvimento , Artérias Carótidas/metabolismo , Microambiente Celular/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Adesões Focais/genética , Humanos , Integrina beta1/metabolismo , Mecanotransdução Celular , Camundongos , Neointima/genética , Neointima/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética , Trombospondina 1/metabolismo , Fatores de Transcrição/metabolismo , Proteínas rap de Ligação ao GTP/genética
3.
Soft Matter ; 16(13): 3234-3244, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32163061

RESUMO

Vesicles composed of diblock copolymers, or polymersomes, have proven to possess numerous applications ranging from drug delivery to catalytically driven nano-motors. The shape of a polymersome can be responsive to external stimuli, such as light or solvent. Molecular dynamics simulations reveal that the shape change upon the contraction of the inner volume of a polymersome vesicle occurs in two separate regimes-a stretching regime and a bending regime. The barrier is shown to be dependent on the solvent environment. These results suggest that tailoring the bending modulus of polymer membranes can be used as a design methodology to engineer new stimuli-responsive vesicles.


Assuntos
Sistemas de Liberação de Medicamentos , Vesículas Extracelulares/química , Simulação de Dinâmica Molecular , Polímeros/química , Forma Celular/efeitos dos fármacos , Microambiente Celular/genética , Polimerização , Solventes/química
4.
Sci Adv ; 6(10): eaax1909, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32181337

RESUMO

Transduction of extracellular matrix mechanics affects cell migration, proliferation, and differentiation. While this mechanotransduction is known to depend on the regulation of focal adhesion kinase phosphorylation on Y397 (FAKpY397), the mechanism remains elusive. To address this, we developed a mathematical model to test the hypothesis that FAKpY397-based mechanosensing arises from the dynamics of nanoscale integrin clustering, stiffness-dependent disassembly of integrin clusters, and FAKY397 phosphorylation within integrin clusters. Modeling results predicted that integrin clustering dynamics governs how cells convert substrate stiffness to FAKpY397, and hence governs how different cell types transduce mechanical signals. Existing experiments on MDCK cells and HT1080 cells, as well as our new experiments on 3T3 fibroblasts, confirmed our predictions and supported our model. Our results suggest a new pathway by which integrin clusters enable cells to calibrate responses to their mechanical microenvironment.


Assuntos
Microambiente Celular/genética , Células Epiteliais/metabolismo , Matriz Extracelular/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Integrinas/metabolismo , Mecanotransdução Celular , Animais , Adesão Celular , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Cães , Células Epiteliais/ultraestrutura , Matriz Extracelular/ultraestrutura , Quinase 1 de Adesão Focal/genética , Expressão Gênica , Humanos , Integrinas/genética , Células Madin Darby de Rim Canino , Camundongos , Células NIH 3T3 , Fosforilação , Especificidade da Espécie
5.
Nat Immunol ; 21(3): 309-320, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31953534

RESUMO

Tissue-resident memory T cells (TRM cells) are critical for cellular immunity to respiratory pathogens and reside in both the airways and the interstitium. In the present study, we found that the airway environment drove transcriptional and epigenetic changes that specifically regulated the cytolytic functions of airway TRM cells and promoted apoptosis due to amino acid starvation and activation of the integrated stress response. Comparison of airway TRM cells and splenic effector-memory T cells transferred into the airways indicated that the environment was necessary to activate these pathways, but did not induce TRM cell lineage reprogramming. Importantly, activation of the integrated stress response was reversed in airway TRM cells placed in a nutrient-rich environment. Our data defined the genetic programs of distinct lung TRM cell populations and show that local environmental cues altered airway TRM cells to limit cytolytic function and promote cell death, which ultimately leads to fewer TRM cells in the lung.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Reprogramação Celular/genética , Reprogramação Celular/imunologia , Epigênese Genética/imunologia , Memória Imunológica/genética , Pulmão/imunologia , Animais , Apoptose/imunologia , Linfócitos T CD8-Positivos/citologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Microambiente Celular/genética , Microambiente Celular/imunologia , Feminino , Pulmão/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia
6.
Biochim Biophys Acta Biomembr ; 1862(4): 183176, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31923411

RESUMO

Bacterial mechanosensitive channels gate in response to membrane tension, driven by shifts in environmental osmolarity. The mechanosensitive channels of small conductance (MscS) and large conductance (MscL) from Escherichia coli (Ec) gate in response to mechanical force applied to the membrane. Ec-MscS is the foundational member of the MscS superfamily of ion channels, a diverse family with at least fifteen subfamilies identified by homology to the pore lining helix of Ec-MscS, as well as significant diversity on the N- and C-termini. The MscL family of channels are homologous to Ec-MscL. In a rhizosphere associated bacterium, Paraburkholderia graminis C4D1M, mechanosensitive channels are essential for cell survival during changing osmotic environments such as a rainstorm. Utilizing bioinformatics, we predicted six MscS superfamily members and a single MscL homologue. The MscS superfamily members fall into at least three subfamilies: bacterial cyclic nucleotide gated, multi-TM, and extended N-terminus. Osmotic downshock experiments show that wildtype P. graminis cells contain a survival mechanism that prevents cell lysis in response to hypoosmotic shock. To determine if this rescue is due to mechanosensitive channels, we developed a method to create giant spheroplasts of P. graminis to explore the single channel response to applied mechanical tension. Patch clamp electrophysiology on these spheroplasts shows two unique conductances: MscL-like and MscS-like. These conductances are due to likely three unique proteins. This indicates that channels that gate in response to mechanical tension are present in the membrane. Here, we report the first single channel evidence of mechanosensitive ion channels from P. graminis membranes.


Assuntos
Burkholderiaceae/genética , Mecanotransdução Celular/genética , Concentração Osmolar , Esferoplastos/genética , Burkholderiaceae/metabolismo , Sobrevivência Celular/genética , Microambiente Celular/genética , Biologia Computacional , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Canais Iônicos/genética , Canais Iônicos de Abertura Ativada por Ligante/genética , Pressão Osmótica , Rizosfera , Homologia de Sequência de Aminoácidos
7.
J Biosci ; 452020.
Artigo em Inglês | MEDLINE | ID: mdl-31965997

RESUMO

Epigenetic changes play a crucial role in sensing signals and responding to fluctuations in the extracellular environment. How the cellular micro-environment affects DNA damage response signalling in chromatin context is not extensively studied. Histone acetylation is dynamic and very sensitive to changes in the extracellular environment. Existing literature on H3 lysine 56 acetylation (H3K56ac) levels upon DNA damage in mammals presents a conflicting picture. The occurrence of both increased and decreased H3K56ac upon DNA damage in our experiments led us to investigate the role of the micro-environment on H3K56ac. Here, we show that the global levels of H3K56ac increase as cells grow from low density to high density while SIRT1 and SIRT6 expression decrease. Additionally, rising lactic acid levels increase H3K56ac. Our results show that cell density and accumulation of metabolites affect dynamics of H3K56ac in response to DNA damage. Upon DNA damage, H3K56ac increases in low density cells with low initial acetylation, while acetylation decreases in high cell density cells. These results highlight that H3K56ac levels upon DNA damage are dependent on the metabolites in the extracellular milieu which impact chromatin structure by regulating chromatin modifying enzymes. Accumulation of lactic acid at high cell density reflects conditions similar to the tumour micro-environment. As H3K56ac increases in tumours, lactic acid and low pH might alter H3K56ac in tumours, leading to deregulated gene expression, contributing to tumour progression.


Assuntos
Epigênese Genética , Histonas/genética , Sirtuína 1/genética , Sirtuínas/genética , Acetilação , Animais , Microambiente Celular/genética , Cromatina/genética , Meios de Cultivo Condicionados/farmacologia , Dano ao DNA/genética , Histona Desacetilases/genética , Humanos , Lisina/genética , Mamíferos , Processamento de Proteína Pós-Traducional/genética
8.
Biochim Biophys Acta Biomembr ; 1862(4): 183193, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31945321

RESUMO

Intramembrane proteases (IMPs) are proteolytic enzymes embedded in the lipid bilayer, where they cleave transmembrane substrates. The importance of IMPs relies on their role in a wide variety of cellular processes and diseases. In order to study the activity and function of IMPs, their purified form is often desired. The production of pure and active IMPs has proven to be a challenging task. This process unavoidably requires the use of solubilizing agents that will, to some extent, alter the native environment of these proteases. In this review we present the current solubilization and reconstitution techniques that have been applied to IMPs. In addition, we describe how these techniques had an influence on the activity and structural studies of IMPs, focusing on rhomboid proteases and γ-secretase.


Assuntos
Secretases da Proteína Precursora do Amiloide/isolamento & purificação , Proteínas de Membrana/isolamento & purificação , Peptídeo Hidrolases/isolamento & purificação , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/genética , Membrana Celular/química , Membrana Celular/enzimologia , Membrana Celular/genética , Microambiente Celular/genética , Proteínas de Membrana/química , Proteínas de Membrana/genética , Peptídeo Hidrolases/química , Peptídeo Hidrolases/genética
9.
Biochim Biophys Acta Mol Cell Res ; 1867(3): 118436, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-30742931

RESUMO

The composition and the stiffness of cardiac microenvironment change during development and/or in heart disease. Cardiomyocytes (CMs) and their progenitors sense these changes, which decides over the cell fate and can trigger CM (progenitor) proliferation, differentiation, de-differentiation or death. The field of mechanobiology has seen a constant increase in output that also includes a wealth of new studies specific to cardiac or cardiomyocyte mechanosensing. As a result, mechanosensing and transduction in the heart is increasingly being recognised as a main driver of regulating the heart formation and function. Recent work has for instance focused on measuring the molecular, physical and mechanical changes of the cellular environment - as well as intracellular contributors to the passive stiffness of the heart. On the other hand, a variety of new studies shed light into the molecular machinery that allow the cardiomyocytes to sense these properties. Here we want to discuss the recent work on this topic, but also specifically focus on how the different components are regulated at various stages during development, in health or disease in order to highlight changes that might contribute to disease progression and heart failure.


Assuntos
Cardiopatias/genética , Coração/crescimento & desenvolvimento , Mecanotransdução Celular/genética , Miócitos Cardíacos/metabolismo , Morte Celular/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Microambiente Celular/genética , Coração/fisiopatologia , Cardiopatias/patologia , Humanos , Miócitos Cardíacos/patologia
10.
Cell Mol Life Sci ; 77(10): 1919-1932, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31720740

RESUMO

The presence of macrophages within the plaque is a defining hallmark of atherosclerosis. Macrophages are exposed to various microenvironments such as oxidized lipids and cytokines which effect their phenotypic differentiation and activation. Classically, macrophages have been divided into two groups: M1 and M2 macrophages induced by T-helper 1 and T-helper 2 cytokines, respectively. However, for a decade, greater phenotypic heterogeneity and plasticity of these cells have since been reported in various models. In addition to M1 and M2 macrophage phenotypes, the concept of additional macrophage phenotypes such as M (Hb), Mox, and M4 has emerged. Understanding the mechanisms and functions of distinct phenotype of macrophages can lead to determination of their potential role in atherosclerotic plaque pathogenesis. However, there are still many unresolved controversies regarding their phenotype and function with respect to atherosclerosis. Here, we summarize and focus on the differential subtypes of macrophages in atherosclerotic plaques and their differing functional roles based upon microenvironments such as lipid, intraplaque hemorrhage, and plaque regression.


Assuntos
Aterosclerose/metabolismo , Metabolismo dos Lipídeos/genética , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Aterosclerose/patologia , Diferenciação Celular/genética , Linhagem da Célula/genética , Microambiente Celular/genética , Citocinas/metabolismo , Humanos , Ativação de Macrófagos/genética , Macrófagos/classificação , Fenótipo , Placa Aterosclerótica/patologia
11.
Cell Rep ; 29(10): 3313-3330.e4, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31801092

RESUMO

Bone marrow (BM) stromal cells provide the regulatory framework for hematopoiesis and contribute to developmental stage-specific niches, such as those preserving hematopoietic stem cells. Despite advances in our understanding of stromal function, little is known about the transcriptional changes that this compartment undergoes throughout lifespan and during adaptation to stress. Using RNA sequencing, we perform transcriptional analyses of four principal stromal subsets, namely CXCL12-abundant reticular, platelet-derived growth factor receptor (PDGFR)-α+Sca1+, sinusoidal, and arterial endothelial cells, from early postnatal, adult, and aged mice. Our data reveal (1) molecular fingerprints defining cell-specific anatomical and functional features, (2) a radical reprogramming of pro-hematopoietic, immune, and matrisomic transcriptional programs during the transition from juvenile stages to adulthood, and (3) the aging-driven progressive upregulation of pro-inflammatory gene expression in stroma. We further demonstrate that transcriptomic pathways elicited in vivo by prototypic microbial molecules are largely recapitulated during aging, thereby supporting the inflammatory basis of age-related adaptations of BM hematopoietic function.


Assuntos
Envelhecimento/genética , Medula Óssea/fisiologia , Microambiente Celular/genética , Desenvolvimento Embrionário/genética , Inflamação/genética , Células-Tronco Mesenquimais/fisiologia , Transcriptoma/genética , Animais , Células da Medula Óssea/fisiologia , Diferenciação Celular/genética , Células Cultivadas , Quimiocina CXCL12/genética , Células Endoteliais/fisiologia , Perfilação da Expressão Gênica/métodos , Hematopoese/genética , Células-Tronco Hematopoéticas/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nicho de Células-Tronco/genética
12.
Sci Rep ; 9(1): 18400, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804547

RESUMO

Vinculin is an essential component of cell adhesion complexes, where it regulates the strength and stability of adhesions. Whilst the role of vinculin in cell motility is well established, it remains unclear how vinculin contributes to other aspects of tissue function. Here we examine the role of vinculin in mammary epithelial cell phenotype. In these cells, correct adhesion to the extracellular matrix is essential for both the formation of polarised secretory acini and for the transcription of tissue-specific milk protein genes. We show that vinculin, through its interaction with talin, controls milk protein gene expression. However, vinculin is not required for the formation of polarised acini. This work reveals new roles for vinculin that are central to cellular differentiation, and for the ability of cells to interpret their extracellular microenvironment.


Assuntos
Células Epiteliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Glândulas Mamárias Animais/metabolismo , Proteínas do Leite/genética , Talina/genética , Vinculina/genética , Animais , Adesão Celular , Diferenciação Celular , Linhagem Celular Transformada , Microambiente Celular/genética , Células Epiteliais/citologia , Feminino , Células HEK293 , Humanos , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Camundongos , Camundongos Transgênicos , Proteínas do Leite/metabolismo , Fenótipo , Gravidez , Cultura Primária de Células , Ligação Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transdução de Sinais , Talina/metabolismo , Vinculina/metabolismo
13.
Genome Med ; 11(1): 73, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771646

RESUMO

BACKGROUND: Acute myeloid leukemia (AML), caused by the abnormal proliferation of immature myeloid cells in the blood or bone marrow, is one of the most common hematologic malignancies. Currently, the interactions between malignant myeloid cells and the immune microenvironment, especially T cells and B cells, remain poorly characterized. METHODS: In this study, we systematically analyzed the T cell receptor and B cell receptor (TCR and BCR) repertoires from the RNA-seq data of 145 pediatric and 151 adult AML samples as well as 73 non-tumor peripheral blood samples. RESULTS: We inferred over 225,000 complementarity-determining region 3 (CDR3) sequences in TCR α, ß, γ, and δ chains and 1,210,000 CDR3 sequences in B cell immunoglobulin (Ig) heavy and light chains. We found higher clonal expansion of both T cells and B cells in the AML microenvironment and observed many differences between pediatric and adult AML. Most notably, adult AML samples have significantly higher level of B cell activation and more secondary Ig class switch events than pediatric AML or non-tumor samples. Furthermore, adult AML with highly expanded IgA2 B cells, which might represent an immunosuppressive microenvironment, are associated with regulatory T cells and worse overall survival. CONCLUSIONS: Our comprehensive characterization of the AML immune receptor repertoires improved our understanding of T cell and B cell immunity in AML, which may provide insights into immunotherapies in hematological malignancies.


Assuntos
Suscetibilidade a Doenças , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Adulto , Fatores Etários , Linfócitos B/imunologia , Linfócitos B/metabolismo , Microambiente Celular/genética , Microambiente Celular/imunologia , Criança , Regiões Determinantes de Complementaridade , Humanos , Leucemia Mieloide Aguda/patologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Análise de Sequência de RNA , Linfócitos T/imunologia , Linfócitos T/metabolismo
14.
Autoimmunity ; 52(7-8): 242-250, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31661985

RESUMO

Salivary and lacrimal gland involvement is a characteristic feature of primary Sjögren's syndrome (pSS), where tissue destruction is mediated by mononuclear cell infiltration, resulting in lacrimal and salivary gland impairment. We have previously shown distinct prevalence of adipose tissue replacement in the minor salivary gland tissue from pSS patients. The salivary gland microenvironment was further examined through microarray analysis, identifying signalling pathways that promoted adipose tissue development, inflammation, and lymphoma. As B cells may also contribute to disease progression, we now aimed to study the B cell pattern with regard to adipocyte development in pSS. Double immunohistochemical staining of paraffin-embedded salivary gland tissue from 22 pSS patients and 11 non-SS tissue controls was employed, using the characteristic pSS autoantigens Ro52 or Ro60, alongside CD27. Additional CD138/CD20 double staining was also performed to identify the plasma- and general B- cell pattern. Our results demonstrated CD27-positive Ro52 and Ro60 specific cells observed within and in close proximity to the adipose tissue. CD138-positive plasma cells were also seen in areas of adipose tissue replacement, while the CD20+ cells were located within focal infiltrates, forming distinct B cell zones. The quantification of CD138+ and CD20+ cells revealed elevated numbers of CD138+ cells in areas of fatty infiltration, and also interstitially, in the salivary glands of pSS patients when compared to non-SS controls. A significant increase (p < .01) in CD138+ cells close to areas of fatty infiltration, and interstitially, with increasing fatty infiltration and focus score was further observed in pSS patients. A correlation between the number of CD20+ B cell zones/mm2 of salivary gland tissue and focus score values was also witnessed in the patients (r2 = 0.6047, p < .001). In conclusion, autoantigen-specific B cells and plasma cells appear prominent in areas of fatty infiltration in salivary glands of pSS patients, where an increase in CD138+ plasma cells and CD20+ B cells, in relation to both fatty and focal infiltration, suggests their active involvement in promoting inflammation. Further studies are needed to assess whether these adipocytes are also a result of tissue repair.


Assuntos
Adipócitos/patologia , Autoantígenos/genética , Linfócitos B/patologia , Glândulas Salivares/patologia , Síndrome de Sjogren/patologia , Adipócitos/imunologia , Adulto , Idoso , Antígenos CD20/genética , Antígenos CD20/imunologia , Autoantígenos/imunologia , Autoimunidade , Linfócitos B/imunologia , Estudos de Casos e Controles , Movimento Celular , Microambiente Celular/genética , Microambiente Celular/imunologia , Feminino , Expressão Gênica , Humanos , Pessoa de Meia-Idade , Saliva/química , Saliva/imunologia , Glândulas Salivares/imunologia , Transdução de Sinais , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Sindecana-1/genética , Sindecana-1/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
15.
J Immunol Res ; 2019: 2164017, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565659

RESUMO

Inflammation is a well-known feature of heart failure. Studies have shown that while some inflammation is required for repair during injury and is protective, prolonged inflammation leads to myocardial remodeling and apoptosis of cardiac myocytes. Various types of immune cells are implicated in myocardial inflammation and include neutrophils, macrophages, eosinophils, mast cells, natural killer cells, T cells, and B cells. Recent clinical trials have targeted inflammatory cascades as therapy for heart failure with limited success. A better understanding of the temporal course of the infiltration of the different immune cells and their contribution to the inflammatory process may improve the success for therapy. This brief review outlines the major cell types involved in heart failure, and some of their actions are summarized in the supplementary figure.


Assuntos
Microambiente Celular , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Miocárdio/imunologia , Miocárdio/metabolismo , Animais , Microambiente Celular/genética , Microambiente Celular/imunologia , Suscetibilidade a Doenças , Insuficiência Cardíaca/diagnóstico , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Leucócitos/patologia , Miocárdio/patologia , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/metabolismo
16.
Stem Cells Dev ; 28(23): 1540-1551, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31595840

RESUMO

Red blood cell (RBC) differentiation from human induced pluripotent stem cells (hiPSCs) offers great potential for developmental studies and innovative therapies. However, ex vivo erythropoiesis from hiPSCs is currently limited by low efficiency and unphysiological conditions of common culture systems. Especially, the absence of a physiological niche may impair cell growth and lineage-specific differentiation. We here describe a simplified, xeno- and feeder-free culture system for prolonged RBC generation that uses low numbers of supporting cytokines [stem cell factor (SCF), erythropoietin (EPO), and interleukin 3 (IL-3)] and is based on the intermediate development of a "hematopoietic cell forming complex (HCFC)." From this HCFC, CD43+ hematopoietic cells (purity >95%) were continuously released into the supernatant and could be collected repeatedly over a period of 6 weeks for further erythroid differentiation. The released cells were mainly CD34+/CD45+ progenitors with high erythroid colony-forming potential and CD36+ erythroid precursors. A total of 1.5 × 107 cells could be harvested from the supernatant of one six-well plate, showing 100- to 1000-fold amplification during subsequent homogeneous differentiation into GPA+ erythroid cells. Mean enucleation rates near 40% (up to 60%) further confirmed the potency of the system. These benefits may be explained by the generation of a niche within the HCFC that mimics the spatiotemporal signaling of the physiological microenvironment in which erythropoiesis occurs. Compared to other protocols, this method provides lower complexity, less cytokine and medium consumption, higher cellular output, and better enucleation. In addition, slight modifications in cytokine addition shift the system toward continuous generation of granulocytes and macrophages.


Assuntos
Técnicas de Cultura de Células/métodos , Diferenciação Celular/genética , Células Eritroides/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Antígenos CD36/genética , Linhagem da Célula/genética , Microambiente Celular/genética , Citocinas/genética , Eritrócitos/citologia , Eritropoese/genética , Células-Tronco Hematopoéticas/citologia , Humanos , Leucossialina/genética
17.
Front Immunol ; 10: 2284, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616442

RESUMO

Autoimmune diseases are a physiological state wherein immune responses are directed against and damage the body's own tissues. Cytokines secreted by infiltrated inflammatory cells contribute to the pathogenesis of autoimmune diseases. TIPE2, one of the four family members of Tumor necrosis factor-α induced protein-8 (TNFAIP8), is a negative regulator of innate and adaptive immunity and plays essential roles in the maintenance of immune tolerance. However, studies on the role of TIPE2 during the development of autoimmune diseases have generated contradictory results. In the current study, we sought to determine the role of TIPE2 during the development of IMQ-induced psoriasis and Experimental Autoimmune Uveitis (EAU) in mice. Our study revealed that, while TIPE2-deficiency alleviates psoriasis, it exacerbates the development of EAU. Further studies demonstrated that, although TIPE2-deficient T cells produced more IL-17A, they do not migrate efficiently to the local inflammatory site, i.e., the skin. This in turn led to the decreased IL-17A production in the skin and consequently reduced the severity of psoriasis in TIPE2-deficient mice. However, although TIPE2-deficient T cells still produced more IL-17A in EAU model, they migrate into the inflamed eye as efficient as TIPE2-sufficient T cells, and consequently exacerbates the development of EAU in TIPE2-deficient mice. Taken together, these results indicate that TIPE2 may either promote or suppress autoimmunity depending on the specific inflammatory microenvironment in different types of autoimmune diseases.


Assuntos
Doenças Autoimunes/imunologia , Movimento Celular/imunologia , Microambiente Celular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Linfócitos T/imunologia , Uveíte/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Movimento Celular/genética , Microambiente Celular/genética , Modelos Animais de Doenças , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-17/genética , Interleucina-17/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Camundongos , Camundongos Knockout , Linfócitos T/patologia , Uveíte/genética , Uveíte/patologia
18.
Front Immunol ; 10: 1889, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507585

RESUMO

In the last decades, immunologists have started to consider intracellular metabolism in relation with the dynamics and functions of immune cells, especially when it became clear that microenvironmental alterations were associated with immune dysfunctions. Regulatory T cells (Tregs) are equipped with a variety of immunological and metabolic sensors, and encompass circulating as well as tissue-resident cells, being therefore particularly susceptible to microenvironmental cues. Moreover, Tregs undergo metabolic reprogramming over the course of an immune response, allowing the use of alternate substrates and engaging different metabolic pathways for energetic demands. The study of metabolic mechanisms supporting Treg dynamics has led to puzzling results, due to several limitations, including the heterogeneity of population in the same tissues and between different tissues, the difficulty in considering all the interconnected metabolic pathways during a cellular process, and the differences between in vitro and in vivo conditions. Therefore, Treg reliance on different metabolic routes (oxidation rather than glycolysis) has been a matter of controversy in recent years. Metabolic reprogramming and altered bioenergetics are now identified as hallmarks in cancer, and are employed by cancer cells to determine the availability of metabolites and molecules, thus affecting the fate of tumor-infiltrating immune cells. In particular, the tumor microenvironment forces a metabolic restriction and a plethora of synergistic intrinsic and extrinsic stresses, leading to an impaired anti-tumor immunity and favoring Treg generation, expansion, and suppressive function. This leads to the understanding that Tregs and conventional T cells have different capability to adapt to metabolic hurdles. Considering the role of Tregs in dictating the outcome of tumor-specific responses, it would be important to understand the specific Treg metabolic profile that provides an advantage at the tumor site, to finally identify new targets for therapy. In this review, we will report and discuss the major recent findings about the metabolic pathways required for Treg development, expansion, migration and functions, in relation to tissue-derived signals. We will focus on the adipose tissue and the liver, where Tregs are exposed to a variety of metabolites, and on the tumor microenvironment as the context where Tregs develop the ability to adapt to perturbations in nutrient accessibility.


Assuntos
Metabolismo Energético , Imunomodulação , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adaptação Biológica/imunologia , Animais , Microambiente Celular/genética , Microambiente Celular/imunologia , Espaço Extracelular/metabolismo , Humanos , Ativação Linfocitária/imunologia , Redes e Vias Metabólicas , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
19.
Exp Cell Res ; 384(1): 111559, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31425691

RESUMO

Altered expression of miRNAs is evident in the islets of diabetic human donors, but the effects of specific aspects of the diabetic microenvironment and identity of gene ontology pathways demonstrating target gene enrichment in response to each is understudied. We assessed changes in the miRNA milieu in response to high/low glucose, hypoxia, dyslipidaemia and inflammatory factors in a humanised EndoC-ßH1 beta cell culture system and performed miRPath analysis for each treatment individually. The 10 miRNAs demonstrating the greatest dysregulation across treatments were then independently validated and Gene Set Enrichment Analysis to confirm targeted pathways undertaken. 171 of 392 miRNAs displayed altered expression in response to one or more cellular stressors. miRNA changes were treatment specific, but their target genes were enriched in conserved pathways. 5 miRNAs (miR-136-5p, miR299-5p, miR-454-5p, miR-152 and miR-185) were dysregulated in response to multiple stressors and survived validation in independent samples (p = 0.008, 0.002, 0.012, 0.005 and 0.024 respectively). Target genes of dysregulated miRNAs were clustered into FOXO1, HIPPO and Lysine degradation pathways (p = 0.02, p = 5.84 × 10-5 and p = 3.00 × 10-3 respectively). We provide evidence that the diabetic microenvironment may induce changes to the expression of miRNAs targeting genes enriched in pathways involved in cell stress response and cell survival.


Assuntos
Microambiente Celular/genética , Diabetes Mellitus/metabolismo , Proteína Forkhead Box O1/metabolismo , Células Secretoras de Insulina/metabolismo , Lisina/metabolismo , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Linhagem Celular , Sobrevivência Celular/fisiologia , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Redes Reguladoras de Genes/fisiologia , Humanos
20.
Autoimmun Rev ; 18(9): 102349, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31323359

RESUMO

Myasthenia gravis (MG) is a rare autoimmune disease characterized by muscle weakness and abnormal fatigability. Like many other autoimmune diseases, genetic contribution to MG has been studied where the HLA system appears to play the most vital role. Although many correlations have been revealed in these studies, the underlying mechanism for them is still in the veil. Based on current evidence, we propose two synergetic mechanisms underlying the MG predisposition via HLA. In brief, the first advocates specific MHC II-peptide patterns that influence the efficacy of antigen presentation, and the second emphasizes the role of classical MHC alleles in shaping the TCR repertoire for MG predisposition. Besides, possible explanations for unresolved or controversial MG-related epidemiological phenomenon or clinical problems are addressed as well. Then, we discuss three factors influencing the effect of HLA on MG: gender discrepancy, inflammatory microenvironment, and epigenetic regulation. Lastly, from a provisional angle, we introduce several precautious treatments for people highly predisposed to MG. Although this is a review focusing on MG, the underlying mechanisms might be applicable in other autoimmune diseases as well.


Assuntos
Antígenos HLA/fisiologia , Miastenia Gravis/genética , Alelos , Microambiente Celular/genética , Microambiente Celular/imunologia , Epigênese Genética/fisiologia , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Antígenos HLA/genética , Humanos , Miastenia Gravis/epidemiologia , Miastenia Gravis/imunologia , Miastenia Gravis/terapia , Fatores Sexuais , Transdução de Sinais
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