Rol del receptor tipo toll 3 en la vía de señalización interferon tipo I y su efecto en la capacidad inmunosupresora en células madre mesenquimales murinas
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Fecha
2016
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es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
Las células madre mesenquimales (MSCs) desde su descubrimiento, han sido foco de
varios estudios, primero por su amplia capacidad de regenerar tejidos y más
recientemente, por su reconocida capacidad de modular la respuesta inflamatoria. Es
por ello que actualmente las MSCs han sido consideradas como una alternativa
terapéutica para el tratamiento de enfermedades autoinmunes, como lupus, esclerosis
múltiple y artritis reumatoide, entre otras. Es así entonces como las MSCs se han
descrito como células inmunosupresoras, inhibiendo la proliferación y activación de la
mayoría de los componentes del sistema inmune, no obstante, existen estudios que han
demostrado que en ciertos casos pueden ser inmuno-estimuladoras. El mecanismo,
tanto celular como molecular por el cual se produce esta “plasticidad” en su capacidad
inmunomoduladora, es desconocido. Se ha propuesto que los receptores tipo-toll
podrían estar involucrados en esta regulación. Estudios in vitro, utilizando diversos estímulos o drogas para estos receptores, han observado que utilizando un mismo
estímulo a diferentes concentraciones y tiempos, es posible obtener un desbalance de
liberación de citoquinas que favorecen una respuesta pro o anti inflamatoria.
En base a estos antecedentes, es que se utilizó un mismo estímulo, poly (I:C), agonista
del receptor tipo-toll 3, a distintos tiempos de estimulación en MSCs. Se determinó la
expresión génica, encontrándose que la mayoría de los genes tienen dos respuestas,
una previa a las 4 horas de estimulación: IFNβ, IRF3, TLR3 y RANTES y una expresión
posterior a 4 horas de otros genes presentes en la vía como TRIF, IFNaR1, IL8, IL1β e
IFNα seguido de una liberación tardía de IL6. En conjunto con el estudio de la expresión
génica, se observó un incremento de la proteína IRF3 fosforilada previo a las 4 horas
de estimulación manteniéndose en el tiempo y NFκB fosforilado, posterior a las 4 horas.
Según lo descrito, se propone que la respuesta diferencial obtenida en la capacidad inmunosupresora de las MSCs es dependiente del tiempo de estimulación y que el
desbalance en la liberación y producción de los genes involucrados tanto en la vía de
TLR3 como IFN tipo I influyen directamente en esta respuesta. Estos innovadores
hallazgos de modulación de las vías de señalización de las MSCs mediante un mismo
estímulo, dependiendo del tiempo de exposición, podrían aportar en nuevas terapias
para enfermedades pro-inflamatorias y/o autoinmunes.
Mesenchymal stem cells (MSCs) since their discovery have been the focus of several studies, first because of their extensive ability to regenerate tissues and more recently because of their recognized ability to modulate the inflammatory response. This is why MSCs have now been considered as a therapeutic alternative for the treatment of autoimmune diseases, such as lupus, multiple sclerosis and rheumatoid arthritis, among others. Although, MSCs have been described as immunosuppressive cells, inhibiting the proliferation and activation of most components of the immune system, there are studies that have shown that in some cases they may be immunostimulatory. The mechanism, both cellular and molecular, by which this "plasticity" occurs in its immunomodulatory capacity, is unknown. It has been proposed that Toll-Like Receptors could be involved in this regulation. In vitro studies, using various stimuli or drugs for these receptors, have observed that using the same stimulus at different concentrations and times, it is possible to obtain an imbalance of the cytokine release that favors a pro or anti inflammatory response. Based on this background, the same stimulus, poly (I:C), agonist of Toll-Like Receptor 3, was used at different stimulation times in MSCs. Gene expression was determined, with most genes having two responses, one prior to the 4-6 hour stimulation: IFNβ, IRF3, TLR3 and RANTES and a late expression after 4-6 hours of stimulation of other genes present in the pathway, like TRIF, IFNaR1, IL8, IL1β and IFNα followed by late release of IL6. Together with the study of gene expression, an increase of the phosphorylated IRF3 protein was observed prior to the 4 hours of stimulation being maintained in time and phosphorylated NFκB, after 4 hours. As described, it is proposed that the differential response obtained in the immunosuppressive capacity of MSCs is dependent on the time of stimulation and that this imbalance in the release and production of the genes involved in both TLR3 and IFN type I pathways directly influence this answer. These innovative findings of modulating MSC signaling pathways by the same stimulus, depending on the time of exposure, could contribute in new therapies for pro-inflammatory and/or autoimmune diseases.
Mesenchymal stem cells (MSCs) since their discovery have been the focus of several studies, first because of their extensive ability to regenerate tissues and more recently because of their recognized ability to modulate the inflammatory response. This is why MSCs have now been considered as a therapeutic alternative for the treatment of autoimmune diseases, such as lupus, multiple sclerosis and rheumatoid arthritis, among others. Although, MSCs have been described as immunosuppressive cells, inhibiting the proliferation and activation of most components of the immune system, there are studies that have shown that in some cases they may be immunostimulatory. The mechanism, both cellular and molecular, by which this "plasticity" occurs in its immunomodulatory capacity, is unknown. It has been proposed that Toll-Like Receptors could be involved in this regulation. In vitro studies, using various stimuli or drugs for these receptors, have observed that using the same stimulus at different concentrations and times, it is possible to obtain an imbalance of the cytokine release that favors a pro or anti inflammatory response. Based on this background, the same stimulus, poly (I:C), agonist of Toll-Like Receptor 3, was used at different stimulation times in MSCs. Gene expression was determined, with most genes having two responses, one prior to the 4-6 hour stimulation: IFNβ, IRF3, TLR3 and RANTES and a late expression after 4-6 hours of stimulation of other genes present in the pathway, like TRIF, IFNaR1, IL8, IL1β and IFNα followed by late release of IL6. Together with the study of gene expression, an increase of the phosphorylated IRF3 protein was observed prior to the 4 hours of stimulation being maintained in time and phosphorylated NFκB, after 4 hours. As described, it is proposed that the differential response obtained in the immunosuppressive capacity of MSCs is dependent on the time of stimulation and that this imbalance in the release and production of the genes involved in both TLR3 and IFN type I pathways directly influence this answer. These innovative findings of modulating MSC signaling pathways by the same stimulus, depending on the time of exposure, could contribute in new therapies for pro-inflammatory and/or autoimmune diseases.
Notas
Tesis (Magíster en Biotecnología)
Palabras clave
Células Madre, Agentes Inmunosupresores