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.

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

“…Moreover, GSK‐J4 modifies the H3K27me3 and H3K4me3 levels on specific gene promoters in dendritic cells, which prevents autoimmune encephalomyelitis (Donas et al . ). In the present study, we demonstrated that UTX, especially its enzyme activity, is involved in the regulation of inflammation in cultured renal cells and in db/db mice (Figs , and ).…”

Chemical probes targeting epigenetic proteins: Applications beyond oncology

“…Promotion of a more tolerant profile was characterized by reduced expression of co-stimulatory molecules CD80/CD86, an increased expression of tolerogenic molecules CD103 and TGF-β1, and reduced secretion of pro-inflammatory cytokines IL-6, IFN-γ, and TNFα. The effect was accompanied by increased generation, stability, and activity of Treg cells but not Th1 or Th17 cells 72 . Inhibition of JMJD3 may also be beneficial in the treatment of osteoarthritis.…”

Emerging Role for Methylation in Multiple Sclerosis: Beyond DNA

“…Moreover, betaine treatment during oxidative stress restored H3K4me3 levels and improved mitochondrial respiration in human neurons [22], a response that could potentially prevent susceptibility to axonal degeneration in MS. A potent inhibitor of H3K27 demethylases, GSK-J4, ameliorated EAE disease in mice, which could be attributed to a tolerogenic DC phenotype, but likely affects other cell types [87]. Although the observation that Jmjd3 deficiency can suppresses Th17 responses and EAE is in agreement [84], other studies suggest however, that Jmjd3 deficient mice in a colitis model have enhanced Th2 and Th17 responses in the small intestine and colon, and suppressed Th1 responses in the small intestine and spleen [85].…”