1. Academic Validation
  2. The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs

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

  • J Autoimmun. 2016 Dec;75:105-117. doi: 10.1016/j.jaut.2016.07.011.
Cristian Doñas 1 Macarena Carrasco 1 Macarena Fritz 1 Carolina Prado 2 Gabriela Tejón 3 Francisco Osorio-Barrios 2 Valeria Manríquez 3 Paz Reyes 2 Rodrigo Pacheco 1 María Rosa Bono 3 Alejandra Loyola 2 Mario Rosemblatt 4
Affiliations

Affiliations

  • 1 Fundación Ciencia & Vida, Ñuñoa, 7780272, Santiago, Chile; Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andrés Bello, 8370146, Santiago, Chile.
  • 2 Fundación Ciencia & Vida, Ñuñoa, 7780272, Santiago, Chile.
  • 3 Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
  • 4 Fundación Ciencia & Vida, Ñuñoa, 7780272, Santiago, Chile; Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile; Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andrés Bello, 8370146, Santiago, Chile. Electronic address: mrosemblatt@cienciavida.org.
Abstract

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.

Keywords

Autoimmunity; DCs; GSK-J4; H3K27me3; JMJD3; Treg.

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