title: The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs.
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.
authors.affiliation: Fundación Ciencia & Vida, Ñuñoa, 7780272, Santiago, Chile; Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andrés Bello, 8370146, Santiago, Chile.
authors.forename: Cristian
authors.initials: C
authors.lastname: Doñas
authors.affiliation: Fundación Ciencia & Vida, Ñuñoa, 7780272, Santiago, Chile; Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andrés Bello, 8370146, Santiago, Chile.
authors.forename: Macarena
authors.initials: M
authors.lastname: Carrasco
authors.affiliation: Fundación Ciencia & Vida, Ñuñoa, 7780272, Santiago, Chile; Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andrés Bello, 8370146, Santiago, Chile.
authors.forename: Macarena
authors.initials: M
authors.lastname: Fritz
authors.affiliation: Fundación Ciencia & Vida, Ñuñoa, 7780272, Santiago, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Prado
authors.affiliation: Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Tejón
authors.affiliation: Fundación Ciencia & Vida, Ñuñoa, 7780272, Santiago, Chile.
authors.forename: Francisco
authors.initials: F
authors.lastname: Osorio-Barrios
authors.affiliation: Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Valeria
authors.initials: V
authors.lastname: Manríquez
authors.affiliation: Fundación Ciencia & Vida, Ñuñoa, 7780272, Santiago, Chile.
authors.forename: Paz
authors.initials: P
authors.lastname: Reyes
authors.affiliation: Fundación Ciencia & Vida, Ñuñoa, 7780272, Santiago, Chile; Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andrés Bello, 8370146, Santiago, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Pacheco
authors.affiliation: Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: María Rosa
authors.initials: MR
authors.lastname: Bono
authors.affiliation: Fundación Ciencia & Vida, Ñuñoa, 7780272, Santiago, Chile.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Loyola
authors.affiliation: 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.
authors.forename: Mario
authors.initials: M
authors.lastname: Rosemblatt
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism; D001552:Benzazepines / Q000494:pharmacology*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D039001:Integrin alpha Chains / Q000276:immunology / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D011743:Pyrimidines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D001552:Benzazepines; D016207:Cytokines; C000593030:GSK-J4; D018836:Inflammation Mediators; D039001:Integrin alpha Chains; D011743:Pyrimidines; D053773:Transforming Growth Factor beta1; C091367:alpha E integrins; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse
keywords: Autoimmunity; DCs; GSK-J4; H3K27me3; JMJD3; Treg