Examinando por Autor "Bono, María Rosa"

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    Adoptive transfer of autoimmune splenic dendritic cells to lupus-prone mice triggers a B lymphocyte humoral response
    (Humana Press Inc., 2017-08) Sauma, Daniela; Crisóstomo, Natalia; Fuentes, Camila; Gleisner, María Alejandra; Hidalgo, Yessia; Fuenzalida, María José; Rosemblatt, Mario; Bono, María Rosa
    Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by increased autoantibody production that leads to multiple tissue injuries. Dendritic cells (DCs) are important orchestrators of immune responses and key components in fine-tuning the balance between tolerance and immunity. However, their role in autoimmune disorders such as SLE remains uncertain. We analyzed the contribution of DCs in triggering SLE by adoptively transferring splenic DCs from aged autoimmune [NZB×NZW]F1 (BWF1) mice to young healthy BWF1 mice. We observed that the transfer of DCs from autoimmune mice to pre-autoimmune mice induced high autoantibody titers in the serum of recipient mice. Moreover, autoimmune DCs from aged BWF1 mice were crucial for the expansion and differentiation of plasmablasts and CD5+ B cells or B1-like cells in the peripheral blood, and spleen of recipient BWF1 mice, a phenomenon that is observed in autoimmune BWF1 mice. On the other hand, DCs from aged BWF1 mice participated in the expansion and differentiation of DCs and IFN-γ-producing T cells. These results reveal that DCs from autoimmune BWF1 mice exhibit functional and phenotypic characteristics that allow them to trigger B cell hyperactivation, as well as DC and T cell expansion and differentiation, thereby promoting an exacerbated humoral response in lupus-prone mice. © 2017, The Author(s).
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    CD73 and CD39 ectonucleotidases in T cell differentiation: Beyond immunosuppression
    (Elsevier B.V., 2015-07) Bono, María Rosa; Fernández, Dominique; Flores-Santibáñez, Felipe; Rosemblatt, Mario; Sauma, Daniela
    Extracellular ATP is a danger signal released by dying and damaged cells, and it functions as an immunostimulatory signal that promotes inflammation. However, extracellular adenosine acts as an immunoregulatory signal that modulates the function of several cellular components of the adaptive and innate immune response. Consequently, the balance between ATP and adenosine concentration is crucial in immune homeostasis. CD39 and CD73 are two ectonucleotidases that cooperate in the generation of extracellular adenosine through ATP hydrolysis, thus tilting the balance towards immunosuppressive microenvironments. Extracellular adenosine can prevent activation, proliferation, cytokine production and cytotoxicity in T cells through the stimulation of the A2A receptor; however, recent evidence has shown that adenosine may also affect other processes in T-cell biology. In this review, we discuss evidence that supports a role of CD73 and CD39 ectonucleotidases in controlling naive T-cell homeostasis and memory cell survival through adenosine production. Finally, we propose a novel hypothesis of a possible role of these ectonucleotidases and autocrine adenosine signaling in controlling T-cell differentiation. © 2015 The Authors. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.
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    CD73 Ectonucleotidase Restrains CD8+ T Cell Metabolic Fitness and Anti-tumoral Activity
    (Frontiers Media S.A., 2021-02) Briceño, Pedro; Rivas-Yañez, Elizabeth; Rosemblatt, Mariana V.; Parra-Tello, Brian; Farías, Paula; Vargas, Leonardo; Simon, Valeska; Cárdenas, César; Lladser, Alvaro; Salazar-Onfray, Flavio; Elorza, Alvaro A.; Rosemblatt, Mario; Bono, María Rosa; Sauma, Daniela
    CD39 and CD73 are ectoenzymes that dephosphorylate ATP into its metabolites; ADP, AMP, and adenosine, and thus are considered instrumental in the development of immunosuppressive microenvironments. We have previously shown that within the CD8+ T cell population, naïve and memory cells express the CD73 ectonucleotidase, while terminally differentiated effector cells are devoid of this enzyme. This evidence suggests that adenosine might exert an autocrine effect on CD8+ T cells during T cell differentiation. To study the possible role of CD73 and adenosine during this process, we compared the expression of the adenosinergic signaling components, the phenotype, and the functional properties between CD73-deficient and WT CD8+ T cells. Upon activation, we observed an upregulation of CD73 expression in CD8+ T cells along with an upregulation of the adenosine A2A receptor. Interestingly, when we differentiated CD8+ T cells to Tc1 cells in vitro, we observed that these cells produce adenosine and that CD73-deficient cells present a higher cytotoxic potential evidenced by an increase in IFN-γ, TNF-α, and granzyme B production. Moreover, CD73-deficient cells presented a increased glucose uptake and higher mitochondrial respiration, indicating that this ectonucleotidase restrict the mitochondrial capacity in CD8+ T cells. In agreement, when adoptively transferred, antigen-specific CD73-deficient CD8+ T cells were more effective in reducing the tumor burden in B16.OVA melanoma-bearing mice and presented lower levels of exhaustion markers than wild type cells. All these data suggest an autocrine effect of CD73-mediated adenosine production, limiting differentiation and cytotoxic T cells’ metabolic fitness. © Copyright © 2021 Briceño, Rivas-Yañez, Rosemblatt, Parra-Tello, Farías, Vargas, Simon, Cárdenas, Lladser, Salazar-Onfray, Elorza, Rosemblatt, Bono and Sauma.
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    CD73-mediated adenosine production promotes stem cell-like properties in mouse Tc17 cells
    (Blackwell Publishing Ltd, 2015-12) Flores-Santibáñez, Felipe; Fernández, Dominique; Meza, Daniel; Tejón, Gabriela; Vargas, Leonardo; Varela-Nallar, Lorena; Arredondo, Sebastián; Guixé, Victoria; Rosemblatt, Mario; Bono, María Rosa; Sauma, Daniela
    The CD73 ectonucleotidase catalyses the hydrolysis of AMP to adenosine, an immunosuppressive molecule. Recent evidence has demonstrated that this ectonucleotidase is up-regulated in T helper type 17 cells when generated in the presence of transforming growth factor-β (TGF-β), and hence CD73 expression is related to the acquisition of immunosuppressive potential by these cells. TGF-β is also able to induce CD73 expression in CD8+ T cells but the function of this ectonucleotidase in CD8+ T cells is still unknown. Here, we show that Tc17 cells present high levels of the CD73 ectonucleotidase and produce adenosine; however, they do not suppress the proliferation of CD4+ T cells. Interestingly, we report that adenosine signalling through A2A receptor favours interleukin-17 production and the expression of stem cell-associated transcription factors such as tcf-7 and lef-1 but restrains the acquisition of Tc1-related effector molecules such as interferon-γ and Granzyme B by Tc17 cells. Within the tumour microenvironment, CD73 is highly expressed in CD62L+ CD127+ CD8+ T cells (memory T cells) and is down-regulated in GZMB+ KLRG1+ CD8+ T cells (terminally differentiated T cells), demonstrating that CD73 is expressed in memory/naive cells and is down-regulated during differentiation. These data reveal a novel function of CD73 ectonucleotidase in arresting CD8+ T-cell differentiation and support the idea that CD73-driven adenosine production by Tc17 cells may promote stem cell-like properties in Tc17 cells.
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    Dopamine receptor D3 signalling in astrocytes promotes neuroinflammation
    (BioMed Central Ltd., 2019-12) Montoya, Andro; Elgueta, Daniela; Campos, Javier; Chovar, Ornella; Falcón, Paulina; Matus, Soledad; Alfaro, Iván; Bono, María Rosa; Pacheco, Rodrigo
    Background: Neuroinflammation constitutes a pathogenic process leading to neurodegeneration in several disorders, including Alzheimer's disease, Parkinson's disease (PD) and sepsis. Despite microglial cells being the central players in neuroinflammation, astrocytes play a key regulatory role in this process. Our previous results indicated that pharmacologic-Antagonism or genetic deficiency of dopamine receptor D3 (DRD3) attenuated neuroinflammation and neurodegeneration in two mouse models of PD. Here, we studied how DRD3-signalling affects the dynamic of activation of microglia and astrocyte in the context of systemic inflammation. Methods: Neuroinflammation was induced by intraperitoneal administration of LPS. The effect of genetic DRD3-deficiency or pharmacologic DRD3-Antagonism in the functional phenotype of astrocytes and microglia was determined by immunohistochemistry and flow cytometry at different time-points. Results: Our results show that DRD3 was expressed in astrocytes, but not in microglial cells. DRD3 deficiency resulted in unresponsiveness of astrocytes and in attenuated microglial activation upon systemic inflammation. Furthermore, similar alterations in the functional phenotypes of glial cells were observed by DRD3 antagonism and genetic deficiency of DRD3 upon LPS challenge. Mechanistic analyses show that DRD3 deficiency resulted in exacerbated expression of the anti-inflammatory protein Fizz1 in glial cells both in vitro and in vivo. Conclusions: These results suggest that DRD3 signalling regulates the dynamic of the acquisition of pro-inflammatory and anti-inflammatory features by astrocytes and microglia, finally favouring microglial activation and promoting neuroinflammation. © 2019 The Author(s).
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    Papel del microambiente linfoide en el desarrollo del Luipes Eritematoso Sistémico
    (Universidad Andrés Bello, 2011) Reyes Zúñiga, Paz Alejandra; Rosemblatt Silber, Mario; Bono, María Rosa
    El lupus eritematoso sistémico es una enfermedad autoimmune de etiología desconocida que afecta diversos órganos y se caracteriza principalmente por la producción de anticuerpos anti-antígenos nucleares. Utilizando ratones BWF1 provenientes de la cruza New Zealand White con New Zealand Black como modelo de la enfermedad, analizamos un aspecto esencial de la respuesta inmune adquirida, esto es la distribución de las células reguladoras y las células dendríticas en algunos de los sitios donde se inicia la respuesta inmune y demostramos que los ratones lúpicos presentan una disminución en el porcentaje de linfocitos T reguladores en sangre periférica y medula ósea, pero un incremento de esta población celular en el bazo. Al mismo tiempo, observamos un incremento del porcentaje de células dendríticas en el bazo, sangre periférica y en el linfonodo mesentérico de ratones lúpicos comparado con ratones control y prelúpicos. Además, demostramos mediante ensayos de homing, que las células dendríticas lúpicas y prelúpicas migran preferencialmente al bazo comparado con células dendríticas control. Establecimos que los linfocitos T reguladores lúpicos tienen una capacidad supresora normal, ya que suprimen normalmente la proliferación de los linfocitos T CD4+ control, mientras que suprimen débilmente, a los linfocitos T CD4+ lúpicos. Al evaluar la participación de las células dendríticas en la activación de los linfocitos T CD4+ demostramos que tanto las células dendríticas lúpicas como las controles son capaces de activar a los linfocitos T CD4+ provenientes de ratones normales, sin embargo, los linfocitos T CD4+ lúpicos proliferan notablemente menos comparado con los linfocitos T CD4+ control. Determinamos que los linfocitos T CD4+ lúpicos provenientes del bazo se encuentran basalmente activados. El conjunto de estos datos sugiere que los linfocitos T CD4+ lúpicos, dado su fenotipo activado y su disminuida capacidad de proliferar, son resistentes a la supresión. Con el fin de examinar los posibles mecanismos involucrados en el comportamiento de los linfocitos T CD4+ analizamos el efecto del microambiente celular sobre los linfocitos T reguladores y las células dendríticas durante el desarrollo de la enfermedad. Puesto que es en el bazo donde encontramos las mayores diferencias en cuanto a localización celular evaluamos mediante PCR array los niveles de expresión de un conjunto de quimioquinas y de receptores de quimioquinas en células obtenidas del bazo de ratones cursando diferentes etapas de la enfermedad. Nuestros datos muestran que las células estromales de bazo de ratones lúpicos presentan un patrón de expresión de genes de quimioquinas y sus receptores diferente al de las células estromales de bazo de ratones control y prelúpicos, lo cual podría explicar la mayor atracción y permanencia de las células dendríticas y de linfocitos T reguladores en este órgano. En resumen, nuestros resultados muestran que el microambiente del bazo de ratones lúpicos atrae a las células dendríticas en mayor proporción que el microambiente del bazo de ratones control, lo cual puede contribuir al desarrollo de la enfermedad.
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    The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs
    (Academic Press, 2016-12) Doñas, Cristian; Carrasco, Macarena; Fritz, Macarena; Prado, Carolina; Tejón, Gabriela; Osorio-Barrios, Francisco; Manríquez, Valeria; Reyes, Paz; Pacheco, Rodrigo; Bono, María Rosa; Loyola, Alejandra; Rosemblatt, Mario
    As it has been established that demethylation of lysine 27 of histone H3 by the lysine-specific deme thylase JMJD3 increases immune responses and thus elicits inflammation, we hypothesize that inhibition of JMJD3 may attenuate autoimmune disorders. We found that in vivo administration of GSK-J4, a selective inhibitor of JMJD3 and UTX, ameliorates the severity of experimental autoimmune encephalomyelitis (EAE). In vitro experiments revealed that the anti-inflammatory effect of GSK-J4 was exerted through an effect on dendritic cells (DCs), promoting a tolerogenic profile characterized by reduced expression of costimulatory molecules CD80/CD86, an increased expression of tolerogenic molecules CD103 and TGF-b1, and reduced secretion of proin flammatory cytokines IL-6, IFN-g, and TNF. Adoptive transfer of GSK-J4-treated DCs into EAE mice reduced the clinical manifestation of the disease and decreased the extent of inflammatory CD4þ T cells infiltrating the central nervous system. Notably, Treg generation, stability, and suppressive activity were all exacerbated by GSK-J4-treated DCs without affecting Th1 and Th17 cell production. Our data show that GSK-J4-mediated modulation of inflammation is achieved by a direct effect on DCs and that systemic treatment with GSK-J4 or adoptive transfer of GSK-J4-treated DCs ex vivo may be promising approaches for the treatment of inflammatory and autoimmune disorders. © 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).