The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs

Cristian Doñas, Macarena Carrasco, Macarena Fritz, Carolina Prado, Gabriela Tejón, Francisco Osorio-Barrios, Valeria Manríquez, Paz Reyes, Rodrigo Pacheco, María Rosa Bono, Alejandra Loyola, Mario Rosemblatt

Resultado de la investigación: Contribución a una revistaArtículo

30 Citas (Scopus)

Resumen

As it has been established that demethylation of lysine 27 of histone H3 by the lysine-specific demethylase 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-β1, and reduced secretion of proinflammatory cytokines IL-6, IFN-γ, 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 CD4+ 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.

Idioma originalInglés
Páginas (desde-hasta)105-117
Número de páginas13
PublicaciónJournal of Autoimmunity
Volumen75
DOI
EstadoPublicada - 1 dic 2016

Áreas temáticas de ASJC Scopus

  • Inmulogía y alergología
  • Inmunología

Huella Profundice en los temas de investigación de 'The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs'. En conjunto forman una huella única.

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    Doñas, C., Carrasco, M., Fritz, M., Prado, C., Tejón, G., Osorio-Barrios, F., Manríquez, V., Reyes, P., Pacheco, R., Bono, M. R., Loyola, A., & Rosemblatt, M. (2016). The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs. Journal of Autoimmunity, 75, 105-117. https://doi.org/10.1016/j.jaut.2016.07.011