Influência da prostaglandina E2 na plasticidade de linfócitos Th17/Th1 no contexto da encefalomielite autoimune experimental
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Data
2019-05-16
Autores
Bazzano, Júlia Miranda Ribeiro
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Universidade Estadual Paulista (Unesp)
Resumo
A prostaglandina E2 (PGE2) é um mediador lipídico que participa tanto na diferenciação como na expansão de linfócitos T helper (Th) Th1 e Th17. Esse prostanoide vem sendo descrito como um importante mediador envolvido no agravamento da Encefalomielite Autoimune Experimental (EAE). A EAE é uma doença mediada por células Th1/Th17 autorreativas, responsáveis pela intensa resposta inflamatória contra antígenos do sistema nervoso central (SNC). Alguns estudos descrevem que a inibição da síntese desse prostanoide, ou o bloqueio de seus receptores EP, reduzem os níveis de IL-17A e IFN- e atenuam drasticamente o desenvolvimento da doença. A coexistência de linfócitos Th1 e Th17 na EAE, assim como a presença de células Th17 produtoras de IFN-γ (Th1-like) no SNC sugerem uma possível plasticidade destas subpopulações de linfócitos. No entanto, até o momento, não há relatos na literatura se a presença de PGE2, presente no SNC, estaria envolvida na plasticidade de linfócitos Th17 em Th1 nessa autoimunidade. Portanto, a hipótese desse estudo é que as células Th17 migrariam para o SNC e desencadeariam o recrutamento de células inflamatórias e o aparecimento dos primeiros sinais clínicos da doença. A presença de PGE2, associado esse microambiente inflamatório, favoreceria a plasticidade das células Th17 para um padrão Th1, resultando na diferenciação de células T CD4+ patogênicas (IL17+IFN+) e células Th1-like. Os resultados obtidos demonstram que as células Th17, quando cultivadas em condições polarizantes para Th1, foram hábeis em se converterem em linfócitos Th1-like, porém, a presença de PGE2 aumenta a porcentagem de células T CD4+IFN-γ+, via EP4 e, possivelmente, pela via de adenilato ciclase/PKA. Além disso, o tratamento com indometacina, em animais Il17cre/mTmG imunizados com MOG, durante a fase aguda da doença, resultou na diminuição de células Th17 produtoras de IFN-γ no SNC de camundongos que desenvolveram a EAE, sem causar a alteração no score clínico da doença e no infiltrado celular.
Prostaglandin E2 (PGE2) is a lipid mediator which participates in both differentiation and expansion of T helper (Th) Th1 and Th17. This prostanoid has been described as an important mediator involved in the worsening of EAE, an experimental model for Multiple Sclerosis in humans. EAE is a disease mediated for autoreactive Th1/Th17 cells, responsible for an intense inflammatory response against central nervous system (CNS) antigens. Some studies have described that inhibition of PGE2 synthesis or blockage of its receptors decrease IL-17A and IFN- levels and attenuate drastically the disease development. The coexistence of Th17 and Th1 lymphocytes together with IFN-γ-producing Th17 cells (Th1-like) at CNS suggests a possible plasticity between these subtypes of lymphocytes in EAE. However, until now, there are no reports in the literature if the presence of PGE2 in the CNS could be involved in Th17 to Th1 plasticity during EAE. Therefore, the hypothesis of this study is that Th17 cells could migrate to the central nervous system and trigger the recruitment of inflammatory cells and the appearance of EAE first clinical symptoms. The presence of PGE2, associated with the inflammatory microenvironment, could induce Th17 plasticity to Th1 lymphocytes, resulting in the differentiation of pathogenic T CD4+ (IL17+IFN+) and Th1-like cells, responsible for tissue damage. Recent data from our research group showed that Th17 cells, when cultured in Th1 polarizing condition, were capable to differentiate into Th1-like lymphocytes, however, in the presence of PGE2, T CD4+IFN-γ+ cells percentage is increased, through EP4 signaling, possible through cyclase adenylate/PKA activation pathway. Furthermore, the treatment of Il17cre/mTmG mice immunized with MOG with indomethacin, during the acute phase of the disease, impairs IFN-γ producing Th17 cells inside the CNS of mice which developed EAE, however, no change in the clinical score of the disease and cellular infiltrate was observed.
Prostaglandin E2 (PGE2) is a lipid mediator which participates in both differentiation and expansion of T helper (Th) Th1 and Th17. This prostanoid has been described as an important mediator involved in the worsening of EAE, an experimental model for Multiple Sclerosis in humans. EAE is a disease mediated for autoreactive Th1/Th17 cells, responsible for an intense inflammatory response against central nervous system (CNS) antigens. Some studies have described that inhibition of PGE2 synthesis or blockage of its receptors decrease IL-17A and IFN- levels and attenuate drastically the disease development. The coexistence of Th17 and Th1 lymphocytes together with IFN-γ-producing Th17 cells (Th1-like) at CNS suggests a possible plasticity between these subtypes of lymphocytes in EAE. However, until now, there are no reports in the literature if the presence of PGE2 in the CNS could be involved in Th17 to Th1 plasticity during EAE. Therefore, the hypothesis of this study is that Th17 cells could migrate to the central nervous system and trigger the recruitment of inflammatory cells and the appearance of EAE first clinical symptoms. The presence of PGE2, associated with the inflammatory microenvironment, could induce Th17 plasticity to Th1 lymphocytes, resulting in the differentiation of pathogenic T CD4+ (IL17+IFN+) and Th1-like cells, responsible for tissue damage. Recent data from our research group showed that Th17 cells, when cultured in Th1 polarizing condition, were capable to differentiate into Th1-like lymphocytes, however, in the presence of PGE2, T CD4+IFN-γ+ cells percentage is increased, through EP4 signaling, possible through cyclase adenylate/PKA activation pathway. Furthermore, the treatment of Il17cre/mTmG mice immunized with MOG with indomethacin, during the acute phase of the disease, impairs IFN-γ producing Th17 cells inside the CNS of mice which developed EAE, however, no change in the clinical score of the disease and cellular infiltrate was observed.
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Palavras-chave
PGE2, Plasticidade, Th17/Th1, EAE