Histone demethylase Jumonji D3 (JMJD3/KDM6B) at the nexus of epigenetic regulation of inflammation and the aging process.

Histone methylation is involved in the epigenetic control of immune responses and cellular senescence. Jumonji domain-containing protein 3 (JMJD3), also called lysine-specific demethylase 6B (KDM6b), is an inducible histone demethylase which enhances immune responses and can trigger cellular senescence. JMJD3 potentiates gene expression by demethylating repressive H3K27me3 epigenetic marks in promoters and gene bodies. Moreover, JMJD3 also stimulates transcription in a demethylase-independent manner by mediating interactions between chromatin modifiers. JMJD3 can enhance both pro-inflammatory and anti-inflammatory responses by targeting distinct transcription factors in a context-dependent manner in gene promoters. For instance, JMJD3 can induce macrophage M2 polarization via STAT6 signaling. JMJD3 also interacts with T-bet factor and induces Th1 differentiation of CD4(+) T cells. Moreover, JMJD3 can activate TGF-β signaling through the SMAD3 pathway. Conversely, JMJD3 displaces polycomb complexes from the INK4 box, which induces the expression of INK4a and triggers cellular senescence. JMJD3 can also enhance the nuclear localization of p53 and thus regulate its function. The control of INK4 box and p53 is closely related to the regulation of the aging process. We will briefly review the inducible properties of JMJD3 expression and then focus on the role of JMJD3 in the regulation of inflammation and senescence through different signaling pathways. We emphasize that an inflammatory milieu and cellular stress can enhance immune responses and provoke cellular senescence via epigenetic regulation through JMJD3 activation.