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1.
Int J Mol Sci ; 24(11)2023 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-37298236

RESUMEN

Despite not dividing, senescent cells acquire the ability to synthesize and secrete a plethora of bioactive molecules, a feature known as the senescence-associated secretory phenotype (SASP). In addition, senescent cells often upregulate autophagy, a catalytic process that improves cell viability in stress-challenged cells. Notably, this "senescence-related autophagy" can provide free amino acids for the activation of mTORC1 and the synthesis of SASP components. However, little is known about the functional status of mTORC1 in models of senescence induced by CDK4/6 inhibitors (e.g., Palbociclib), or the effects that the inhibition of mTORC1 or the combined inhibition of mTORC1 and autophagy have on senescence and the SASP. Herein, we examined the effects of mTORC1 inhibition, with or without concomitant autophagy inhibition, on Palbociclib-driven senescent AGS and MCF-7 cells. We also assessed the pro-tumorigenic effects of conditioned media from Palbociclib-driven senescent cells with the inhibition of mTORC1, or with the combined inhibition of mTORC1 and autophagy. We found that Palbociclib-driven senescent cells display a partially reduced activity of mTORC1 accompanied by increased levels of autophagy. Interestingly, further mTORC1 inhibition exacerbated the senescent phenotype, a phenomenon that was reversed upon autophagy inhibition. Finally, the SASP varied upon inhibiting mTORC1, or upon the combined inhibition of mTORC1 and autophagy, generating diverse responses in cell proliferation, invasion, and migration of non-senescent tumorigenic cells. Overall, variations in the SASP of Palbociclib-driven senescent cells with the concomitant inhibition of mTORC1 seem to depend on autophagy.


Asunto(s)
Senescencia Celular , Piperazinas , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Piperazinas/farmacología , Carcinogénesis , Autofagia
2.
Front Immunol ; 14: 1169601, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37275865

RESUMEN

Hepatitis B has become one of the major global health threats, especially in developing countries and regions. Hepatitis B virus infection greatly increases the risk for liver diseases such as cirrhosis and cancer. However, treatment for hepatitis B is limited when considering the huge base of infected people. The immune response against hepatitis B is mediated mainly by CD8+ T cells, which are key to fighting invading viruses, while regulatory T cells prevent overreaction of the immune response process. Additionally, follicular T helper cells play a key role in B-cell activation, proliferation, differentiation, and formation of germinal centers. The pathogenic process of hepatitis B virus is generally the result of a disorder or dysfunction of the immune system. Therefore, we present in this review the critical functions and related biological processes of regulatory T cells and follicular T helper cells during HBV infection.


Asunto(s)
Virus de la Hepatitis B , Hepatitis B , Humanos , Linfocitos T Reguladores , Linfocitos T Colaboradores-Inductores/patología
3.
Front Immunol ; 13: 988536, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36110861

RESUMEN

B cells secrete antibodies and mediate the humoral immune response, making them extremely important in protective immunity against SARS-CoV-2, which caused the coronavirus disease 2019 (COVID-19) pandemic. In this review, we summarize the positive function and pathological response of B cells in SARS-CoV-2 infection and re-infection. Then, we structure the immunity responses that B cells mediated in peripheral tissues. Furthermore, we discuss the role of B cells during vaccination including the effectiveness of antibodies and memory B cells, viral evolution mechanisms, and future vaccine development. This review might help medical workers and researchers to have a better understanding of the interaction between B cells and SARS-CoV-2 and broaden their vision for future investigations.


Asunto(s)
COVID-19 , Vacunas Virales , COVID-19/prevención & control , Humanos , Recuento de Linfocitos , SARS-CoV-2 , Vacunación
4.
Front Immunol ; 13: 841641, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35663931

RESUMEN

Lymphatic vasculature is a network of capillaries and vessels capable of draining extracellular fluid back to blood circulation and to facilitate immune cell migration. Although the role of the lymphatic vasculature as coordinator of fluid homeostasis has been extensively studied, the consequences of abnormal lymphatic vasculature function and impaired lymph drainage have been mostly unexplored. Here, by using the Prox1+/- mice with defective lymphatic vasculature and lymphatic leakage, we provide evidence showing that lymph leakage induces an immunosuppressive environment by promoting anti-inflammatory M2 macrophage polarization in different inflammatory conditions. In fact, by using a mouse model of tail lymphedema where lymphatic vessels are thermal ablated leading to lymph accumulation, an increasing number of anti-inflammatory M2 macrophages are found in the lymphedematous tissue. Moreover, RNA-seq analysis from different human tumors shows that reduced lymphatic signature, a hallmark of lymphatic dysfunction, is associated with increased M2 and reduced M1 macrophage signatures, impacting the survival of the patients. In summary, we show that lymphatic vascular leakage promotes an immunosuppressive environment by enhancing anti-inflammatory macrophage differentiation, with relevance in clinical conditions such as inflammatory bowel diseases or cancer.


Asunto(s)
Vasos Linfáticos , Linfedema , Antiinflamatorios , Humanos , Terapia de Inmunosupresión , Macrófagos
5.
FASEB J ; 36(5): e22276, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35344212

RESUMEN

The lymphatic vasculature is a unidirectional network of lymphatic endothelial cells, whose main role is to maintain fluid homeostasis along with the absorption of dietary fat in the gastrointestinal organs and management and coordination of immune cell trafficking into lymph nodes during homeostasis and under inflammatory conditions. In homeostatic conditions, immune cells, such as dendritic cells, macrophages, or T cells can enter into the lymphatic vasculature and move easily through the lymph reaching secondary lymph nodes where immune cell activation or peripheral tolerance can be modulated. However, under inflammatory conditions such as pathogen infection, increased permeabilization of lymphatic vessels allows faster immune cell migration into inflamed tissues following a chemokine gradient, facilitating pathogen clearance and the resolution of inflammation. Interestingly, since the re-discovery of lymphatic vasculature in the central nervous system, known as the meningeal lymphatic vasculature, the role of these lymphatics as a key player in several neurological disorders has been described, with emphasis on the neurodegenerative process. Alternatively, less has been discussed about meningeal lymphatics and its role in neuroinflammation. In this review, we discuss current knowledge about the anatomy and function of the meningeal lymphatic vasculature and specifically analyze its contribution to different neuroinflammatory processes, highlighting the potential therapeutic target of meningeal lymphatic vasculature in these pathological conditions.


Asunto(s)
Vasos Linfáticos , Enfermedades Neuroinflamatorias , Células Endoteliales , Humanos , Sistema Linfático , Meninges/patología
6.
Signal Transduct Target Ther ; 6(1): 345, 2021 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-34552055

RESUMEN

The SARS-CoV-2 infection causes severe immune disruption. However, it is unclear if disrupted immune regulation still exists and pertains in recovered COVID-19 patients. In our study, we have characterized the immune phenotype of B cells from 15 recovered COVID-19 patients, and found that healthy controls and recovered patients had similar B-cell populations before and after BCR stimulation, but the frequencies of PBC in patients were significantly increased when compared to healthy controls before stimulation. However, the percentage of unswitched memory B cells was decreased in recovered patients but not changed in healthy controls upon BCR stimulation. Interestingly, we found that CD19 expression was significantly reduced in almost all the B-cell subsets in recovered patients. Moreover, the BCR signaling and early B-cell response were disrupted upon BCR stimulation. Mechanistically, we found that the reduced CD19 expression was caused by the dysregulation of cell metabolism. In conclusion, we found that SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism, which may provide a new intervention target to cure COVID-19.


Asunto(s)
Antígenos CD19/inmunología , Linfocitos B/inmunología , COVID-19/inmunología , Regulación hacia Abajo/inmunología , Síndromes de Inmunodeficiencia/inmunología , SARS-CoV-2/inmunología , Animales , COVID-19/complicaciones , Chlorocebus aethiops , Femenino , Humanos , Síndromes de Inmunodeficiencia/etiología , Síndromes de Inmunodeficiencia/virología , Memoria Inmunológica , Masculino , Ratones , Ratones Transgénicos , Receptores de Antígenos de Linfocitos B/inmunología , Células Vero
7.
Int. j. morphol ; 39(3): 789-796, jun. 2021. ilus, tab, graf
Artículo en Inglés | LILACS | ID: biblio-1385422

RESUMEN

SUMMARY: Age-associated decline of immune system, termed immunosenescence, is characterized by low-grade systemic inflammation, known as inflammaging, together with T-cell functional dysregulation. Although affecting all individuals, different environmental as well genetic factors impinge on the individual´s susceptibility or resilience to immunosenescence. Physical activity has been shown to improve autonomy and functionality in older adults. However, if physical activity affects immunosenescence or inflammaging remains unknown. The purpose of this study was to analyze immunosenescence and inflammaging in elderly individuals by measuring peripheral naïve T cells and interleukin (IL) -6 from peripheral blood and evaluate the impact of physical activity on T cell dysregulation and inflammaging. Thirty (30) elderly volunteers (10 males and 20 females), and 7 young controls (2 males ad 7 females), were recruited for this study. A methodology questionnaire was used to evaluate different parameters such as physical activity, and peripheral naïve CD4+ and CD8+ T cells and serum IL-6 were measured by FACS and ELISA respectively. Our results shown that naïve T cells decline, and IL-6 levels increase as older people age. Interestingly, we observed strong negative correlation between naïve T cells numbers and IL-6 levels in older adults, suggesting a direct link between reduced naïve T cell pool and increased inflammaging. Continuous physical activity during youth did not affect immunosenescence and inflammaging in elderly, but physical activity during elderly increase naïve T cell numbers and reduce inflammaging in older subjects. Our results showed reduced number of naïve T cells and increased levels of IL-6 as elder people get older. Moreover, the strong negative correlation between these parameters suggest that naïve T cells can have a direct suppressive activity over innate immune components. Furthermore, physical activity during elderly can reduce immunosenescence and inflammaging in older subjects.


RESUMEN: El deterioro del sistema inmunológico asociado con la edad, denominado inmunosenescencia, se caracteriza por una inflamación sistémica de bajo grado, conocida como inflamaging, junto con una desregulación funcional de las células T. Aunque afectan a todos los individuos, diferentes factores ambientales y genéticos inciden en la susceptibilidad o resiliencia del individuo a la inmunosenescencia. Estudios anteriores han demostrado que la actividad física mejora la autonomía y la funcionalidad en los adultos mayores, aunque como la actividad física impacta a la inmunosenescencia e inflammaging es aún desconocido. El propósito de este estudio fue analizar la inmunosenescencia e inflammaging en personas de edad avanzada, midiendo las células T vírgenes y la interleucina (IL)-6 de sangre periférica, junto con evaluar el impacto de la actividad física sobre la inflamación basal y la inmunosenescencia. Treinta voluntarios ancianos (10 hombres y 20 mujeres) y 7 controles jóvenes (2 hombres y 5 mujeres) fueron incluidos en este estudio. Para medir actividad física, autonomía y dependencia se utilizó un cuestionario de metodología, junto con evaluar el número de células T CD4+ y CD8+ periféricas vírgenes e IL-6 sérica mediante FACS y ELISA, respectivamente. Nuestros resultados muestran que las células T vírgenes disminuyen y los niveles de IL-6 aumentan a medida que las personas mayores envejecen. Curiosamente, observamos una fuerte correlación negativa entre el número de células T vírgenes y los niveles de IL-6 en adultos mayores, lo que sugiere un vínculo directo entre la reducción de la reserva de células T vírgenes y el aumento de la inflamación. La actividad física durante la juventud no afectó la inmunosenescencia ni la inflamación en los ancianos, pero la actividad física durante la vejez aumenta el número de células T vírgenes y reduce la inflamación en los adultos mayores. Estos resultados sugieren que inmunosenescencia e inflammaging parecen estar directamente conectados, además de concluir que el desarrollo de actividad física durante la vejez reduce la inmunosenescencia y la inflamación basal en adultos mayores.


Asunto(s)
Humanos , Masculino , Femenino , Anciano , Anciano de 80 o más Años , Linfocitos T/inmunología , Ejercicio Físico/fisiología , Inflamación , Envejecimiento/inmunología , Interleucina-6 , Inmunosenescencia/inmunología
8.
Obes Rev ; 22(6): e13200, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33426811

RESUMEN

Obesity is an increasing problem in developed and developing countries. Individuals with obesity have a higher risk of several diseases, such as cardiovascular disease, increased risk of insulin resistance, type 2 diabetes, infertility, degenerative disorders, and also certain types of cancer. Adipose tissue (AT) is considered an extremely active endocrine organ, and the expansion of AT is accompanied by the infiltration of different types of immune cells, which induces a state of low-grade, chronic inflammation and metabolic dysregulation. Even though the exact mechanism of this low-grade inflammation is not fully understood, there is clear evidence that AT-infiltrating macrophages (ATMs) play a significant role in the pro-inflammatory state and dysregulated metabolism. ATMs represent the most abundant class of leukocytes in AT, constituting 5% of the cells in AT in individuals with normal weight. However, this percentage dramatically increases up to 50% in individuals with obesity, suggesting an important role of ATMs in obesity and its associated complications. In this review, we discuss current knowledge of the function of ATMs during steady-state and obesity and analyze its contribution to different obesity-associated diseases, highlighting the potential therapeutic target of ATMs in these pathological conditions.


Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Tejido Adiposo , Humanos , Inflamación , Macrófagos , Obesidad/complicaciones
9.
J Leukoc Biol ; 109(2): 395-405, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32816356

RESUMEN

Ubiquitinases are a select group of enzymes that modify target proteins through ubiquitination, which plays a crucial role in the regulation of protein degradation, location, and function. B lymphocytes that originated from bone marrow hematopoietic stem cells (HSC), exert humoral immune functions by differentiating into plasma cells and producing antibodies. Previous studies have shown that ubiquitination is involved in the regulation of the cell cycle and signal transduction important for B lymphocyte development and function. In this review, how ubiquitinases regulate B cell development, activation, apoptosis, and proliferation is discussed, which could help in understanding the physiological processes and diseases related to B cells and also provides potential new targets for further studies.


Asunto(s)
Enzimas/metabolismo , Ubiquitina/metabolismo , Animales , Apoptosis , Linfocitos B , Humanos , Activación de Linfocitos/inmunología , Ubiquitinación
10.
J Leukoc Biol ; 109(2): 383-394, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32542827

RESUMEN

The dedicator of cytokinesis (DOCK) family proteins consist of 11 members, each of which contains 2 domains, DOCK homology region (DHR)-1 and DHR-2, and as guanine nucleotide exchange factors, they mediate activation of small GTPases. Both DOCK2 and DOCK8 deficiencies in humans can cause severe combined immunodeficiency, but they have different characteristics. DOCK8 defect mainly causes high IgE, allergic disease, refractory skin virus infection, and increased incidence of malignant tumor, whereas DOCK2 defect mainly causes early-onset, invasive infection with less atopy and increased IgE. However, the underlying molecular mechanisms causing the disease remain unclear. This paper discusses the role of DOCK family proteins in regulating B and T cells, including development, survival, migration, activation, immune tolerance, and immune functions. Moreover, related signal pathways or molecule mechanisms are also described in this review. A greater understanding of DOCK family proteins and their regulation of lymphocyte functions may facilitate the development of new therapeutics for immunodeficient patients and improve their prognosis.


Asunto(s)
Linfocitos B/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Linfocitos T/metabolismo , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Factores de Intercambio de Guanina Nucleótido/química , Humanos , Tolerancia Inmunológica , Activación de Linfocitos/inmunología , Dominios Proteicos , Linfocitos T/citología , Linfocitos T/inmunología
11.
Biochem Biophys Res Commun ; 529(2): 296-302, 2020 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-32703426

RESUMEN

Dedicator of cytokinesis 2 (DOCK2) is essential for the B cell differentiation, BCR signaling and humoral immune response. However, the role of DOCK2 in the memory response of B cell is unknown. By using two DOCK2 deficient patients, we found that the memory B cells were decreased and the early activation of DOCK2 deficient memory B cells was abolished to the degree of naïve B cells due to the decreased expression of CD19 and CD21 mechanistically. Interestingly the expression of LEF-1, a negative regulator of CD21, was increased in DOCK2 deficient B cells. This was linked to the increased expression of HIF-1α and cell metabolism, which in turn affected the ER structure. Finally, the reduction of memory B cells in DOCK2 patients was due to the increased apoptosis, which might be related with the increased metabolism.


Asunto(s)
Linfocitos B/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Diferenciación Celular , Células Cultivadas , Femenino , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/inmunología , Eliminación de Gen , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/inmunología , Humanos , Inmunidad Humoral , Memoria Inmunológica , Factor de Unión 1 al Potenciador Linfoide/genética , Factor de Unión 1 al Potenciador Linfoide/inmunología , Masculino , Ratones Noqueados , Mutación Puntual , Transducción de Señal
12.
Lymphat Res Biol ; 18(2): 136-145, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31429621

RESUMEN

Background: Early lymphedema detection may reduce the symptoms and improve clinical outcomes. However, the lack of reliable serum biomarkers capable of predicting lymphedema development is a current medical problem. In this study, we investigated if serum levels of hyaluronic acid (HA) and leukotriene B4 (LTB4), two molecules involved in lymphedema development, may work as predictors of this condition. Methods and Results: A mouse model of acquired lymphedema was generated through ablation of tail dermal lymphatic network. Tail diameter was measured daily, and HA and LTB4 serum levels were analyzed before and during the development of lymphedema. We found increased serum levels of HA and reduced levels of LTB4 at early days before the appearance of lymphedema signs. Similar results were observed in the lymphedema tissue. Increased local and systemic inflammation was also detected at early time points. Moreover, the ratio LTB4/HA arises as the strongest predictor for lymphedema development. In fact, we found an inverse correlation in our model, where reduced LTB4/HA levels showed increased lymphedema signs. Conclusions: These findings suggest that serum ratio of LTB4/HA may be a useful biomarker to predict acquired lymphedema development, with potential to be used in clinical conditions such as breast cancer patients.


Asunto(s)
Ácido Hialurónico/sangre , Leucotrieno B4/sangre , Linfedema , Animales , Biomarcadores/sangre , Modelos Animales de Enfermedad , Humanos , Linfedema/diagnóstico , Ratones
13.
Int J Mol Sci ; 20(23)2019 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-31810225

RESUMEN

Incidence and mortality of gastric cancer is increasing worldwide, in part, because of the lack of new therapeutic targets to treat this disease. Different types of ion channels participate in the hallmarks of cancer. In this context, ion channels are known to exert control over the cell cycle, mechanisms that support survival, angiogenesis, migration, and cell invasion. In particular, TASK-3 (KCNK9), a member of the K2P potassium channel family, has attracted much interest because of its oncogenic properties. However, despite multiple lines of evidence linking TASK-3 to tumorigenesis in various types of cancer, its relationship with gastric cancer has not been fully examined. Therefore, we set out to assess the effect of TASK-3 gene knockdown on KATO III and MKN-45 human gastric adenocarcinoma cell lines by using a short hairpin RNA (shRNA)-mediated knockdown. Our results demonstrate that knocking down TASK-3 reduces cell proliferation and viability because of an increase in apoptosis without an apparent effect on cell cycle checkpoints. In addition, cell migration and invasion are reduced after knocking down TASK-3 in these cell lines. The present study highlights TASK-3 as a key protein involved in migration and cell survival in gastric cancer and corroborates its potential as a therapeutic target for gastric cancer treatment.


Asunto(s)
Adenocarcinoma/genética , Neovascularización Patológica/genética , Canales de Potasio de Dominio Poro en Tándem/genética , Neoplasias Gástricas/genética , Adenocarcinoma/patología , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Supervivencia Celular/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Neovascularización Patológica/patología , Neoplasias Gástricas/patología
14.
Front Immunol ; 10: 772, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31037070

RESUMEN

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies against nuclear antigens, immune complex deposition, and tissue damage in the kidneys, skin, heart and lung. Because of the pathogenic role of antinuclear antibodies and autoreactive T cells in SLE, extensive efforts have been made to demonstrate how B cells act as antibody-producing or as antigen-presenting cells that can prime autoreactive T cell activation. With the discovery of new innate immune cells and inflammatory mediators, innate immunity is emerging as a key player in disease pathologies. Recent work over the last decade has highlighted the importance of innate immune cells and molecules in promoting and potentiating SLE. In this review, we discuss recent evidence of the involvement of different innate immune cells and pathways in the pathogenesis of SLE. We also discuss new therapeutics targets directed against innate immune components as potential novel therapies in SLE.


Asunto(s)
Inmunidad Innata/inmunología , Lupus Eritematoso Sistémico/inmunología , Animales , Humanos
15.
Nature ; 565(7737): 101-105, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30568299

RESUMEN

A defining feature of adaptive immunity is the development of long-lived memory T cells to curtail infection. Recent studies have identified a unique stem-like T-cell subset amongst exhausted CD8-positive T cells in chronic infection1-3, but it remains unclear whether CD4-positive T-cell subsets with similar features exist in chronic inflammatory conditions. Amongst helper T cells, TH17 cells have prominent roles in autoimmunity and tissue inflammation and are characterized by inherent plasticity4-7, although how such plasticity is regulated is poorly understood. Here we demonstrate that TH17 cells in a mouse model of autoimmune disease are functionally and metabolically heterogeneous; they contain a subset with stemness-associated features but lower anabolic metabolism, and a reciprocal subset with higher metabolic activity that supports transdifferentiation into TH1-like cells. These two TH17-cell subsets are defined by selective expression of the transcription factors TCF-1 and T-bet, and by discrete levels of CD27 expression. We also identify signalling via the kinase complex mTORC1 as a central regulator of TH17-cell fate decisions by coordinating metabolic and transcriptional programmes. TH17 cells with disrupted mTORC1 signalling or anabolic metabolism fail to induce autoimmune neuroinflammation or to develop into TH1-like cells, but instead upregulate TCF-1 expression and acquire stemness-associated features. Single-cell RNA sequencing and experimental validation reveal heterogeneity in fate-mapped TH17 cells, and a developmental arrest in the TH1 transdifferentiation trajectory upon loss of mTORC1 activity or metabolic perturbation. Our results establish that the dichotomy of stemness and effector function underlies the heterogeneous TH17 responses and autoimmune pathogenesis, and point to previously unappreciated metabolic control of plasticity in helper T cells.


Asunto(s)
Transdiferenciación Celular , Células Madre/citología , Células Madre/metabolismo , Células Th17/citología , Células Th17/metabolismo , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Modelos Animales de Enfermedad , Femenino , Memoria Inmunológica/inmunología , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Proteína Reguladora Asociada a mTOR/deficiencia , Proteína Reguladora Asociada a mTOR/genética , Análisis de Secuencia de ARN , Transducción de Señal , Análisis de la Célula Individual , Células Madre/inmunología , Factor 1 de Transcripción de Linfocitos T/biosíntesis , Factor 1 de Transcripción de Linfocitos T/metabolismo , Proteínas de Dominio T Box/biosíntesis , Proteínas de Dominio T Box/metabolismo , Células Th17/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo
16.
J Exp Med ; 214(9): 2629-2647, 2017 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-28784627

RESUMEN

Myelopoiesis is necessary for the generation of mature myeloid cells during homeostatic turnover and immunological insults; however, the metabolic requirements for this process remain poorly defined. Here, we demonstrate that myelopoiesis, including monocyte and macrophage differentiation, requires mechanistic target of rapamycin complex 1 (mTORC1) signaling and anabolic metabolism. Loss of mTORC1 impaired myelopoiesis under steady state and dampened innate immune responses against Listeria monocytogenes infection. Stimulation of hematopoietic progenitors with macrophage colony-stimulating factor (M-CSF) resulted in mTORC1-dependent anabolic metabolism, which in turn promoted expression of M-CSF receptor and transcription factors PU.1 and IRF8, thereby constituting a feed-forward loop for myelopoiesis. Mechanistically, mTORC1 engaged glucose metabolism and initiated a transcriptional program involving Myc activation and sterol biosynthesis after M-CSF stimulation. Perturbation of glucose metabolism or disruption of Myc function or sterol biosynthesis impaired myeloid differentiation. Integrative metabolomic and genomic profiling further identified one-carbon metabolism as a central node in mTORC1-dependent myelopoiesis. Therefore, the interplay between mTORC1 signaling and metabolic reprogramming underlies M-CSF-induced myelopoiesis.


Asunto(s)
Factor Estimulante de Colonias de Macrófagos/fisiología , Complejos Multiproteicos/fisiología , Mielopoyesis/fisiología , Serina-Treonina Quinasas TOR/fisiología , Proteínas Adaptadoras Transductoras de Señales/fisiología , Animales , Proteínas Portadoras/fisiología , Técnicas de Sustitución del Gen , Glucosa/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , Metabolómica , Ratones , Ratones Endogámicos C57BL , Proteína Asociada al mTOR Insensible a la Rapamicina , Proteína Reguladora Asociada a mTOR , Transducción de Señal/fisiología
17.
Vaccines (Basel) ; 5(2)2017 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-28556800

RESUMEN

The lethality of infectious diseases has decreased due to the implementation of crucial sanitary procedures such as vaccination. However, the resurgence of pathogenic diseases in different parts of the world has revealed the importance of identifying novel, rapid, and concrete solutions for control and prevention. Edible vaccines pose an interesting alternative that could overcome some of the constraints of traditional vaccines. The term "edible vaccine" refers to the use of edible parts of a plant that has been genetically modified to produce specific components of a particular pathogen to generate protection against a disease. The aim of this review is to present and critically examine "edible vaccines" as an option for global immunization against pathogenic diseases and their outbreaks and to discuss the necessary steps for their production and control and the list of plants that may already be used as edible vaccines. Additionally, this review discusses the required standards and ethical regulations as well as the advantages and disadvantages associated with this powerful biotechnology tool.

18.
Hypertension ; 63(4): 797-803, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24420551

RESUMEN

Adaptive immune response has been implicated in inflammation and fibrosis as a result of exposure to mineralocorticoids and a high-salt diet. We hypothesized that in mineralocorticoid-salt-induced hypertension, activation of the mineralocorticoid receptor alters the T-helper 17 lymphocyte (Th17)/regulatory T-lymphocyte/interleukin-17 (IL-17) pathway, contributing to cardiac and renal damage. We studied the inflammatory response and tissue damage in rats treated with deoxycorticosterone acetate and high-salt diet (DOCA-salt), with or without mineralocorticoid receptor inhibition by spironolactone. To determine whether Th17 differentiation in DOCA-salt rats is caused by hypertension per se, DOCA-salt rats received antihypertensive therapy. In addition, to evaluate the pathogenic role of IL-17 in hypertension and tissue damage, we studied the effect of IL-17 blockade with a specific antibody (anti-IL-17). We found activation of Th17 cells and downregulation of forkhead box P3 mRNA in peripheral tissues, heart, and kidneys of DOCA-salt-treated rats. Spironolactone treatment prevented Th17 cell activation and increased numbers of forkhead box P3-positive cells relative to DOCA-salt rats. Antihypertensive therapy did not ameliorate Th17 activation in rats. Treatment of DOCA-salt rats with anti-IL-17 significantly reduced arterial hypertension as well as expression of profibrotic and proinflammatory mediators and collagen deposits in the heart and kidney. We conclude that mineralocorticoid receptor activation alters the Th17/regulatory T-lymphocyte/IL-17 pathway in mineralocorticoid-dependent hypertension as part of an inflammatory mechanism contributing to fibrosis.


Asunto(s)
Acetato de Desoxicorticosterona/efectos adversos , Cardiopatías/prevención & control , Hipertensión/inducido químicamente , Enfermedades Renales/prevención & control , Espironolactona/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Animales , Anticuerpos/inmunología , Anticuerpos/farmacología , Acetato de Desoxicorticosterona/farmacología , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Factores de Transcripción Forkhead/efectos de los fármacos , Factores de Transcripción Forkhead/fisiología , Cardiopatías/etiología , Cardiopatías/fisiopatología , Hipertensión/complicaciones , Hipertensión/fisiopatología , Interleucina-17/antagonistas & inhibidores , Interleucina-17/inmunología , Interleucina-17/fisiología , Enfermedades Renales/etiología , Enfermedades Renales/fisiopatología , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Linfocitos T Reguladores/patología , Células Th17/patología
19.
Hum Vaccin Immunother ; 8(11): 1682-93, 2012 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-23111166

RESUMEN

DNA vaccines have emerged as an attractive strategy to promote protective cellular and humoral immunity against the encoded antigen. DNA vaccines are easy to generate, inexpensive to produce and purify at large-scale, highly stable and safe. In addition, plasmids used for DNA vaccines act as powerful "danger signals" by stimulating several DNA-sensing innate immune receptors that promote the induction of protective adaptive immunity. The induction of tumor-specific immune responses represents a major challenge for DNA vaccines because most of tumor-associated antigens are normal non-mutated self-antigens. As a consequence, induction of potentially self-reactive T cell responses against such poorly immunogenic antigens is controlled by mechanisms of central and peripheral tolerance as well as tumor-induced immunosuppression. Although several DNA vaccines against cancer have reached clinical testing, disappointing results have been observed. Therefore, the development of new adjuvants that strongly stimulate the induction of antitumor T cell immunity and counteract immune-suppressive regulation is an attractive approach to enhance the potency of DNA vaccines and overcome tumor-associated tolerance. Understanding the DNA-sensing signaling pathways of innate immunity that mediate the induction of T cell responses elicited by DNA vaccines represents a unique opportunity to develop novel adjuvants that enhance vaccine potency. The advance of DNA adjuvants needs to be complemented with the development of potent delivery systems, in order to step toward successful clinical application. Here, we briefly discuss recent evidence showing how to harness DNA-induced immune response to improve the potency of cancer vaccines and counteract tumor-associated tolerance.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Vacunas de ADN/inmunología , Inmunidad Adaptativa/inmunología , Animales , Vacunas contra el Cáncer/uso terapéutico , Humanos , Inmunidad Innata/inmunología , Vacunas de ADN/uso terapéutico
20.
Immunology ; 136(4): 414-24, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22587389

RESUMEN

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple functional alterations affecting immune cells, such as B cells, T cells, dendritic cells (DCs) and monocytes. During SLE, the immunogenicity of monocytes and DCs is significantly up-regulated, promoting the activation of self-reactive T cells. Accordingly, it is important to understand the contribution of these cells to the pathogenesis of SLE and the mechanisms responsible for their altered functionality during disease. One of the key enzymes that control monocyte and DC function is haem oxygenase-1 (HO-1), which catalyses the degradation of the haem group into biliverdin, carbon monoxide and free iron. These products possess immunosuppressive and anti-inflammatory capacities. The main goal of this work was to determine HO-1 expression in monocytes and DCs from patients with SLE and healthy controls. Hence, peripheral blood mononuclear cells were obtained from 43 patients with SLE and 30 healthy controls. CD14(+) monocytes and CD4(+) T cells were sorted by FACS and HO-1 expression was measured by RT-PCR. In addition, HO-1 protein expression was determined by FACS. HO-1 levels in monocytes were significantly reduced in patients with SLE compared with healthy controls. These results were confirmed by flow cytometry. No differences were observed in other cell types, such as DCs or CD4(+) T cells, although decreased MHC-II levels were observed in DCs from patients with SLE. In conclusion, we found a significant decrease in HO-1 expression, specifically in monocytes from patients with SLE, suggesting that an imbalance of monocyte function could be partly the result of a decrease in HO-1 expression.


Asunto(s)
Células Dendríticas/enzimología , Hemo-Oxigenasa 1/metabolismo , Lupus Eritematoso Sistémico/enzimología , Lupus Eritematoso Sistémico/inmunología , Monocitos/enzimología , Adulto , Animales , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Linfocitos T CD4-Positivos/enzimología , Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Femenino , Humanos , Receptores de Lipopolisacáridos/biosíntesis , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Monocitos/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de IgG/genética , Receptores de IgG/inmunología , Adulto Joven
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