Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.011
Filtrar
2.
Nat Immunol ; 22(10): 1210-1217, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34545250

RESUMO

When helper T (TH) cell polarization was initially described three decades ago, the TH cell universe grew dramatically. New subsets were described based on their expression of few specific cytokines. Beyond TH1 and TH2 cells, this led to the coining of various TH17 and regulatory (Treg) cell subsets as well as TH22, TH25, follicular helper (TFH), TH3, TH5 and TH9 cells. High-dimensional single-cell analysis revealed that a categorization of TH cells into a single-cytokine-based nomenclature fails to capture the complexity and diversity of TH cells. Similar to the simple nomenclature used to describe innate lymphoid cells (ILCs), we propose that TH cell polarization should be categorized in terms of the help they provide to phagocytes (type 1), to B cells, eosinophils and mast cells (type 2) and to non-immune tissue cells, including the stroma and epithelium (type 3). Studying TH cells based on their helper function and the cells they help, rather than phenotypic features such as individual analyzed cytokines or transcription factors, better captures TH cell plasticity and conversion as well as the breadth of immune responses in vivo.


Assuntos
Citocinas/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Linfócitos B/imunologia , Plasticidade Celular/imunologia , Eosinófilos/imunologia , Epitélio/imunologia , Humanos , Imunidade Inata/imunologia , Linfócitos/imunologia , Fagócitos/imunologia
3.
Sci Immunol ; 6(62)2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376481

RESUMO

To understand how a protective immune response against SARS-CoV-2 develops over time, we integrated phenotypic, transcriptional and repertoire analyses on PBMCs from mild and severe COVID-19 patients during and after infection, and compared them to healthy donors (HD). A type I IFN-response signature marked all the immune populations from severe patients during the infection. Humoral immunity was dominated by IgG production primarily against the RBD and N proteins, with neutralizing antibody titers increasing post infection and with disease severity. Memory B cells, including an atypical FCRL5+ T-BET+ memory subset, increased during the infection, especially in patients with mild disease. A significant reduction of effector memory, CD8+ T cells frequency characterized patients with severe disease. Despite such impairment, we observed robust clonal expansion of CD8+ T lymphocytes, while CD4+ T cells were less expanded and skewed toward TCM and TH2-like phenotypes. MAIT cells were also expanded, but only in patients with mild disease. Terminally differentiated CD8+ GZMB+ effector cells were clonally expanded both during the infection and post-infection, while CD8+ GZMK+ lymphocytes were more expanded post-infection and represented bona fide memory precursor effector cells. TCR repertoire analysis revealed that only highly proliferating T cell clonotypes, which included SARS-CoV-2-specific cells, were maintained post-infection and shared between the CD8+ GZMB+ and GZMK+ subsets. Overall, this study describes the development of immunity against SARS-CoV-2 and identifies an effector CD8+ T cell population with memory precursor-like features.


Assuntos
COVID-19/genética , COVID-19/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunofenotipagem , SARS-CoV-2/imunologia , Transcriptoma , Adulto , Idoso , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , COVID-19/virologia , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Evolução Clonal/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Isotipos de Imunoglobulinas/imunologia , Memória Imunológica , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
4.
Postepy Biochem ; 67(2): 95-103, 2021 06 30.
Artigo em Polonês | MEDLINE | ID: mdl-34378893

RESUMO

Metastasis is of great clinical importance as it is responsible for more than 90% of cancer-related mortality. Therefore, there is a strong need to prevent metastasis formation or to target existing metastases. It is currently assumed that initiating the epithelial-mesenchymal transition (EMT) process in differentiated cancers may strongly increase the migration potential and invasiveness of cancer cells. Molecular changes occurring during EMT are accompanied by morphological changes, the effect of which is the change of the epithelial phenotype to the mesenchymal one and the acquisition by cancer cells of increased mobility and the ability to invade. After metastasis is formed at a site distant from the primary tumor, cancer cells undergo the reverse process, the mesenchymal-epithelial transition (MET), regaining the epithelial phenotype. This ability of the tumour cell to switch from one state to the other allows permanent adaptations to the demanding conditions of a changing environment and promotes the formation of metastasis. In this review, I discuss two principle types of metastatic progression: phenotypic plasticity involving transient EMTâMET processes and intrinsic genetic alterations keeping cells in an EMT and stemness state. This simplified classification integrates clinically relevant aspects of dormancy, metastatic tropism and therapy resistance, and implies perspectives on treatment strategies against metastasis


Assuntos
Carcinoma , Plasticidade Celular , Diferenciação Celular , Transição Epitelial-Mesenquimal , Humanos , Metástase Neoplásica
5.
J Immunol ; 207(5): 1388-1400, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34380649

RESUMO

Acute viral infection generates lineage-committed Th1 and T follicular helper (Tfh) memory cells that recall their lineage-specific functions following secondary challenge with virus. However, the lineage commitment of effector and memory Th cells in vivo following protein vaccination is poorly understood. In this study, we analyzed effector and memory CD4+ T cell differentiation in mice (Mus musculus) following adjuvanted glycoprotein immunization compared with acute lymphocytic choriomeningitis virus infection. Glycoprotein immunization induced CXCR5- non-Tfh effector and memory CD4+ T cells that surprisingly had not undergone polarization toward any particular Th cell lineage but had undergone memory differentiation. However, upon challenge with virus, these Th lineage-nonpolarized memory CD4+ T cells were able to generate Th1 secondary effector cells, demonstrating their lineage plasticity. In addition, Tfh and memory Tfh cells were generated in response to protein immunization, and these cells differed from infection-induced Tfh cells by their lack of the transcription factor Tbet. Rechallenge experiments demonstrated that viral infection, but not protein immunization, during either the primary or secondary immune response, restricts the recall of Bcl6 expression and the generation of germinal center Tfh cells. Together, these data demonstrate that protein immunization generates a combination of nonpolarized memory cells that are highly plastic and memory Tfh cells that can undergo further Th1-like modulation during a secondary response to viral infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Centro Germinativo/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Subpopulações de Linfócitos T/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Plasticidade Celular , Células Cultivadas , Imunização , Memória Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Vacinação
6.
Nat Immunol ; 22(9): 1140-1151, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34426691

RESUMO

Tissue-resident memory T (TRM) cells are non-recirculating cells that exist throughout the body. Although TRM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze TRM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM cell function, durability and malleability. We find that unequal responsiveness to TGFß is a major driver of this diversity. Notably, dampened TGFß signaling results in CD103- TRM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFß-responsive CD103+ TRM counterparts. Furthermore, whereas CD103- TRM cells readily modified their phenotype upon relocation, CD103+ TRM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for TRM cell development, tissue adaptation of these cells confers discrete functional properties such that TRM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Plasticidade Celular/imunologia , Microambiente Celular/imunologia , Memória Imunológica/imunologia , Animais , Antígenos CD/imunologia , Linfócitos T CD8-Positivos/citologia , Feminino , Cadeias alfa de Integrinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/metabolismo
7.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299340

RESUMO

Unlike some lower vertebrates which can completely regenerate their heart, the human heart is a terminally differentiated organ. Cardiomyocytes lost during cardiac injury and heart failure cannot be replaced due to their limited proliferative capacity. Therefore, cardiac injury generally leads to progressive failure. Here, we summarize the latest progress in research on methods to induce cardiomyocyte cell cycle entry and heart repair through the alteration of cardiomyocyte plasticity, which is emerging as an effective strategy to compensate for the loss of functional cardiomyocytes and improve the impaired heart functions.


Assuntos
Proliferação de Células/fisiologia , Insuficiência Cardíaca/terapia , Miócitos Cardíacos/metabolismo , Animais , Ciclo Celular , Plasticidade Celular/genética , Plasticidade Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Coração/fisiologia , Insuficiência Cardíaca/fisiopatologia , Traumatismos Cardíacos/terapia , Humanos , Miócitos Cardíacos/fisiologia , Regeneração/fisiologia , Transdução de Sinais
8.
Arterioscler Thromb Vasc Biol ; 41(9): 2399-2416, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34289702

RESUMO

Objective: Vascular smooth muscle cell (VSMC) plasticity plays a critical role in the development of atherosclerosis. Long noncoding RNAs (lncRNAs) are emerging as important regulators in the vessel wall and impact cellular function through diverse interactors. However, the role of lncRNAs in regulating VSMCs plasticity and atherosclerosis remains unclear. Approach and Results: We identified a VSMC-enriched lncRNA cardiac mesoderm enhancer-associated noncoding RNA (CARMN) that is dynamically regulated with progression of atherosclerosis. In both mouse and human atherosclerotic plaques, CARMN colocalized with VSMCs and was expressed in the nucleus. Knockdown of CARMN using antisense oligonucleotides in Ldlr−/− mice significantly reduced atherosclerotic lesion formation by 38% and suppressed VSMCs proliferation by 45% without affecting apoptosis. In vitro CARMN gain- and loss-of-function studies verified effects on VSMC proliferation, migration, and differentiation. TGF-ß1 (transforming growth factor-beta) induced CARMN expression in a Smad2/3-dependent manner. CARMN regulated VSMC plasticity independent of the miR143/145 cluster, which is located in close proximity to the CARMN locus. Mechanistically, lncRNA pulldown in combination with mass spectrometry analysis showed that the nuclear-localized CARMN interacted with SRF (serum response factor) through a specific 600­1197 nucleotide domain. CARMN enhanced SRF occupancy on the promoter regions of its downstream VSMC targets. Finally, knockdown of SRF abolished the regulatory role of CARMN in VSMC plasticity. Conclusions: The lncRNA CARMN is a critical regulator of VSMC plasticity and atherosclerosis. These findings highlight the role of a lncRNA in SRF-dependent signaling and provide implications for a range of chronic vascular occlusive disease states.


Assuntos
Aterosclerose/metabolismo , Plasticidade Celular , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , RNA Longo não Codificante/metabolismo , Fator de Resposta Sérica/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/patologia , Linhagem Celular , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fenótipo , Placa Aterosclerótica , RNA Longo não Codificante/genética , Receptores de LDL/deficiência , Receptores de LDL/genética , Fator de Resposta Sérica/genética , Transdução de Sinais
9.
Urol Clin North Am ; 48(3): 339-347, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34210489

RESUMO

Androgen receptor function, tumor cell plasticity, loss of tumor suppressors, and defects in DNA repair genes affect aggressive features of prostate cancer. Prostate cancer development, progression, and aggressive behavior are often attributable to function of the androgen receptor. Tumor cell plasticity, neuroendocrine features, and loss of tumor suppressors lend aggressive behavior to prostate cancer cells. DNA repair defects have ramifications for prostate cancer cell behavior.


Assuntos
Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Antagonistas de Androgênios/uso terapêutico , Biomarcadores Tumorais/genética , Plasticidade Celular , Reparo do DNA , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Masculino , Medicina de Precisão , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia
11.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067929

RESUMO

Cutaneous melanoma (CM) tissue represents a network constituted by cancer cells and tumor microenvironment (TME). A key feature of CM is the high structural and cellular plasticity of TME, allowing its evolution with disease and adaptation to cancer cell and environmental alterations. In particular, during melanoma development and progression each component of TME by interacting with each other and with cancer cells is subjected to dramatic structural and cellular modifications. These alterations affect extracellular matrix (ECM) remodelling, phenotypic profile of stromal cells, cancer growth and therapeutic response. The stromal fibroblast populations of the TME include normal fibroblasts and melanoma-associated fibroblasts (MAFs) that are highly abundant and flexible cell types interacting with melanoma and stromal cells and differently influencing CM outcomes. The shift from the normal microenvironment to TME and from normal fibroblasts to MAFs deeply sustains CM growth. Hence, in this article we review the features of the normal microenvironment and TME and describe the phenotypic plasticity of normal dermal fibroblasts and MAFs, highlighting their roles in normal skin homeostasis and TME regulation. Moreover, we discuss the influence of MAFs and their secretory profiles on TME remodelling, melanoma progression, targeted therapy resistance and immunosurveillance, highlighting the cellular interactions, the signalling pathways and molecules involved in these processes.


Assuntos
Fibroblastos/fisiologia , Melanoma/metabolismo , Microambiente Tumoral/fisiologia , Fibroblastos Associados a Câncer/metabolismo , Comunicação Celular , Plasticidade Celular/fisiologia , Matriz Extracelular/metabolismo , Humanos , Melanoma/patologia , Melanoma/fisiopatologia , Transdução de Sinais , Neoplasias Cutâneas/patologia , Células Estromais/metabolismo
12.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062912

RESUMO

Schwann cells (SCs) are a highly plastic cell type capable of undergoing phenotypic changes following injury or disease. SCs are able to upregulate genes associated with nerve regeneration and ultimately achieve functional recovery. During the regeneration process, the extracellular matrix (ECM) and cell morphology play a cooperative, critical role in regulating SCs, and therefore highly impact nerve regeneration outcomes. However, the roles of the ECM and mechanotransduction relating to SC phenotype are largely unknown. Here, we describe the role that matrix stiffness and cell morphology play in SC phenotype specification via known mechanotransducers YAP/TAZ and RhoA. Using engineered microenvironments to precisely control ECM stiffness, cell shape, and cell spreading, we show that ECM stiffness and SC spreading downregulated SC regenerative associated proteins by the activation of RhoA and YAP/TAZ. Additionally, cell elongation promoted a distinct SC regenerative capacity by the upregulation of Rac1/MKK7/JNK, both necessary for the ECM and morphology changes found during nerve regeneration. These results confirm the role of ECM signaling in peripheral nerve regeneration as well as provide insight to the design of future biomaterials and cellular therapies for peripheral nerve regeneration.


Assuntos
Plasticidade Celular/genética , Forma Celular/genética , Matriz Extracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Animais , Proliferação de Células/genética , Regulação da Expressão Gênica/genética , Humanos , MAP Quinase Quinase 4/genética , Mecanotransdução Celular/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Regeneração Nervosa/genética , Ratos , Células de Schwann/citologia , Células de Schwann/metabolismo , Transdução de Sinais/genética , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/genética
13.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071193

RESUMO

Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.


Assuntos
Plasticidade Celular/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Melanoma/metabolismo , Crista Neural/metabolismo , Neoplasias Cutâneas/metabolismo , Acrilonitrila/análogos & derivados , Acrilonitrila/farmacologia , Compostos de Anilina/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Diferenciação Celular , Movimento Celular , Resistencia a Medicamentos Antineoplásicos/genética , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator de Transcrição MSX1/genética , Melanócitos/metabolismo , Melanoma/tratamento farmacológico , Melanoma/patologia , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição PAX3/genética , Fenótipo , Pirimidinonas/farmacologia , Fatores de Transcrição SOXE/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia
14.
Commun Biol ; 4(1): 747, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135460

RESUMO

Tumour recurrence is a serious impediment to cancer treatment, but the mechanisms involved are poorly understood. The most frequently used anti-tumour therapies-chemotherapy and radiotherapy-target highly proliferative cancer cells. However non- or slow-proliferative dormant cancer cells can persist after treatment, eventually causing tumour relapse. Whereas the reversible growth arrest mechanism allows quiescent cells to re-enter the cell cycle, senescent cells are largely thought to be irreversibly arrested, and may instead contribute to tumour growth and relapse through paracrine signalling mechanisms. Thus, due to the differences in their growth arrest mechanism, metabolic features, plasticity and adaptation to their respective tumour microenvironment, dormant-senescent and -quiescent cancer cells could have different but complementary roles in fuelling tumour growth. In this review article, we discuss the implication of dormant cancer cells in tumour relapse and the need to understand how quiescent and senescent cells, respectively, may play a part in this process.


Assuntos
Plasticidade Celular/fisiologia , Proliferação de Células/fisiologia , Senescência Celular/fisiologia , Recidiva Local de Neoplasia/patologia , Neoplasias/patologia , Ciclo Celular/fisiologia , Humanos , Neoplasias/terapia , Transdução de Sinais , Microambiente Tumoral/fisiologia
15.
EMBO Rep ; 22(7): e51921, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34096150

RESUMO

Epithelial tissues respond to a wide variety of environmental and genotoxic stresses. As an adaptive mechanism, cells can deviate from their natural paths to acquire new identities, both within and across lineages. Under extreme conditions, epithelial tissues can utilize "shape-shifting" mechanisms whereby they alter their form and function at a tissue-wide scale. Mounting evidence suggests that in order to acquire these alternate tissue identities, cells follow a core set of "tissue logic" principles based on developmental paradigms. Here, we review the terminology and the concepts that have been put forward to describe cell plasticity. We also provide insights into various cell intrinsic and extrinsic factors, including genetic mutations, inflammation, microbiota, and therapeutic agents that contribute to cell plasticity. Additionally, we discuss recent studies that have sought to decode the "syntax" of plasticity-i.e., the cellular and molecular principles through which cells acquire new identities in both homeostatic and malignant epithelial tissues-and how these processes can be manipulated for developing novel cancer therapeutics.


Assuntos
Plasticidade Celular , Neoplasias , Células Epiteliais , Homeostase , Humanos , Inflamação , Neoplasias/genética
16.
Front Immunol ; 12: 624746, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149687

RESUMO

Mesenchymal stem cells (MSCs) are multipotent adult stromal cells widely studied for their regenerative and immunomodulatory properties. They are capable of modulating macrophage plasticity depending on various microenvironmental signals. Current studies have shown that metabolic changes can also affect macrophage fate and function. Indeed, changes in the environment prompt phenotype change. Therefore, in this review, we will discuss how MSCs orchestrate macrophage's metabolic plasticity and the impact on their function. An improved understanding of the crosstalk between macrophages and MSCs will improve our knowledge of MSC's therapeutic potential in the context of inflammatory diseases, cancer, and tissue repair processes in which macrophages are pivotal.


Assuntos
Comunicação Celular , Plasticidade Celular , Reprogramação Celular , Metabolismo Energético , Macrófagos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Microambiente Celular , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Células-Tronco Mesenquimais/imunologia , Fenótipo , Transdução de Sinais
17.
Front Immunol ; 12: 652488, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34084163

RESUMO

Background: Excessive alcohol intake is associated with adverse immune response-related effects, however, acute and chronic abuse differently modulate monocyte activation. In this study, we have evaluated the phenotypic and functional changes of monocytes in acutely intoxicated healthy volunteers (HV). Methods: Twenty-two HV consumed individually adjusted amounts of alcoholic beverages until reaching a blood alcohol level of 1‰ after 4h (T4). Peripheral blood was withdrawn before and 2h (T2), 4h (T4), 6h (T6), 24h (T24), and 48h (T48) after starting the experiment and stained for CD14, CD16 and TLR4. CD14brightCD16-, CD14brightCD16+ and CD14dimCD16+ monocyte subsets and their TLR4 expression were analyzed by flow cytometry. Inflammasome activation via caspase-1 in CD14+ monocytes was measured upon an ex vivo in vitro LPS stimulation. Systemic IL-1ß and adhesion capacity of isolated CD14+ monocytes upon LPS stimulation were evaluated. Results: The percentage of CD14+ monocyte did not change following alcohol intoxication, whereas CD14brightCD16- monocyte subset significantly increased at T2 and T24, CD14brightCD16+ at T2, T4 and T6 and CD14dimCD16+ at T4 and T6. The relative fraction of TLR4 expressing CD14+ monocytes as well as the density of TLR4 surface presentation increased at T2 and decreased at T48 significantly. TLR4+CD14+ monocytes were significantly enhanced in all subsets at T2. TLR4 expression significantly decreased in CD14brightCD16- at T48, in CD14brightCD16+ at T24 and T48, increased in CD14dimCD16+ at T2. IL-1ß release upon LPS stimulation decreased at T48, correlating with TLR4 receptor expression. Alcohol downregulated inflammasome activation following ex vivo in vitro stimulation with LPS between T2 and T48 vs. T0. The adhesion capacity of CD14+ monocytes decreased from T2 with significance at T4, T6 and T48. Following LPS administration, a significant reduction of adhesion was observed at T4 and T6. Conclusions: Alcohol intoxication immediately redistributes monocyte subsets toward the pro-inflammatory phenotype with their subsequent differentiation into the anti-inflammatory phenotype. This is paralleled by a significant functional depression, suggesting an alcohol-induced time-dependent hyporesponsiveness of monocytes to pathogenic triggers.


Assuntos
Intoxicação Alcoólica/imunologia , Intoxicação Alcoólica/metabolismo , Plasticidade Celular , Monócitos/imunologia , Monócitos/metabolismo , Adolescente , Adulto , Biomarcadores , Plasticidade Celular/imunologia , Voluntários Saudáveis , Humanos , Imunofenotipagem , Interleucina-1beta/metabolismo , Pessoa de Meia-Idade , Fatores de Tempo , Receptor 4 Toll-Like/metabolismo , Adulto Jovem
18.
Front Immunol ; 12: 658681, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093546

RESUMO

Fusobacterium nucleatum (Fn) has been considered as a significant contributor in promoting colorectal carcinoma (CRC) development by suppressing host anti-tumor immunity. Recent studies demonstrated that the aggregation of M2 macrophage (Mφ) was involved in CRC progress driven by Fn infection. However, the underlying molecular mechanisms are poorly characterized. Here, we investigated the role of Fn in Mφ polarization as well as its effect on CRC malignancy. Fn infection facilitated differentiation of Mφ into the M2-like Mφ phenotype by in vitro study. Histological observation from Fn-positive CRC tissues confirmed the abundance of tumor-infiltrating M2-like Mφ. Fn-induced M2-like Mφ polarization was weakened once inhibiting a highly expressed damage-associated molecular pattern (DAMP) molecule S100A9 mainly derived from Fn-challenged Mφ and CRC cells. In addition, Fn-challenged M2-like Mφ conferred CRC cells a more malignant phenotype, showing stronger proliferation and migration characteristics in vitro and significantly enhanced tumor growth in vivo, all of which were partially inhibited when S100A9 was lost. Mechanistic studies further demonstrated that activation of TLR4/NF-κB signaling pathway mediated Fn-induced S100A9 expression and subsequent M2-like Mφ activation. Collectively, these findings indicate that elevated S100A9 in Fn-infected CRC microenvironment participates in M2-like Mφ polarization, thereby facilitating CRC malignancy. Furthermore, targeting TLR4/NF-κB/S100A9 cascade may serve as promising immunotherapeutic strategy for Fn-associated CRC.


Assuntos
Calgranulina B/metabolismo , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/imunologia , Plasticidade Celular/imunologia , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Infecções por Fusobacterium/imunologia , Infecções por Fusobacterium/microbiologia , Fusobacterium nucleatum/imunologia , Xenoenxertos , Humanos , Camundongos , Modelos Biológicos , Transdução de Sinais , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
19.
Mol Immunol ; 136: 138-149, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34146759

RESUMO

Gamma-delta (γδ) T cells are a heterogeneous population of immune cells, which constitute <5% of total T cells in mice lymphoid tissue and human peripheral blood. However, they comprise a higher proportion of T cells in the epithelial and mucosal barrier, where they perform immune functions, help in tissue repair, and maintaining homeostasis. These tissues resident γδ T cells possess properties of innate and adaptive immune cells which enables them to perform a variety of functions during homeostasis and disease. Emerging data suggest the involvement of γδ T cells during transplant rejection and survival. Interestingly, several functions of γδ T cells can be modulated through their interaction with other immune cells. This review provides an overview of development, differentiation plasticity into regulatory and effector phenotypes of γδ T cells during homeostasis and various diseases.


Assuntos
Rejeição de Enxerto/imunologia , Tolerância Imunológica/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa/imunologia , Animais , Plasticidade Celular/imunologia , Humanos , Imunidade Inata/imunologia , Camundongos , Linfócitos T/citologia
20.
Nat Cell Biol ; 23(7): 692-703, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34168324

RESUMO

It is generally accepted that epiblast cells ingress into the primitive streak by epithelial-to-mesenchymal transition (EMT) to give rise to the mesoderm; however, it is less clear how the endoderm acquires an epithelial fate. Here, we used embryonic stem cell and mouse embryo knock-in reporter systems to combine time-resolved lineage labelling with high-resolution single-cell transcriptomics. This allowed us to resolve the morphogenetic programs that segregate the mesoderm from the endoderm germ layer. Strikingly, while the mesoderm is formed by classical EMT, the endoderm is formed independent of the key EMT transcription factor Snail1 by mechanisms of epithelial cell plasticity. Importantly, forkhead box transcription factor A2 (Foxa2) acts as an epithelial gatekeeper and EMT suppressor to shield the endoderm from undergoing a mesenchymal transition. Altogether, these results not only establish the morphogenetic details of germ layer formation, but also have broader implications for stem cell differentiation and cancer metastasis.


Assuntos
Blastocisto/fisiologia , Plasticidade Celular , Endoderma/fisiologia , Células Epiteliais/fisiologia , Transição Epitelial-Mesenquimal , Gastrulação , Células-Tronco Embrionárias Murinas/fisiologia , Animais , Blastocisto/citologia , Blastocisto/metabolismo , Diferenciação Celular , Linhagem Celular , Endoderma/citologia , Endoderma/metabolismo , Células Epiteliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Idade Gestacional , Fator 3-beta Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/metabolismo , Camundongos , Camundongos Transgênicos , Células-Tronco Embrionárias Murinas/metabolismo , Fenótipo , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...