Jmjd3-mediated epigenetic regulation of inflammatory cytokine gene expression in serum amyloid A-stimulated macrophages

Abstract

Serum amyloid A (SAA), a major acute-phase protein, has potent cytokine-like activities in isolated phagocytes and synovial fibroblasts. SAA-induced proinflammatory cytokine gene expression requires transcription factors such as NF-κB; however, the associated epigenetic regulatory mechanism remains unclear. Here we report that Jmjd3, a histone H3 lysine 27 (H3K27) demethylase, is highly inducible in SAA-stimulated macrophages and plays an important role in the induction of inflammatory cytokine genes. SAA-induced Jmjd3 expression leads to reduced H3K27 trimethylation. Silencing of Jmjd3 expression significantly inhibited SAA-induced expression of proinflammatory cytokines including IL-23p19, G-CSF and TREM-1, along with up-regulation of H3K27 trimethylation levels on their promoters. Depletion of Jmjd3 expression also attenuated the release of proinflammatory cytokine genes in a peritonitis model and ameliorated neutrophilia in SAA-stimulated mice. Finally, we observed that Jmjd3 is essential for SAA-enhanced macrophage foam cell formation by oxidized LDL. Taken together, these results illustrate a Jmjd3-dependent epigenetic regulatory mechanism for proinflammatory cytokine gene expression in SAA-stimulate macrophages. This mechanism may be subject to therapeutic intervention for sterile inflammation and atherosclerosis.

JMJD3 as an epigenetic regulator in development and disease

“…SAA-stimulation of macrophages leads to increased Jmjd3 expression, which is associated with reduced H3K27me3 marks, allowing for gene expression (Yan et al, 2014). Furthermore, Jmjd3 silencing and depletion inhibits macrophage pro-inflammatory cytokine secretion, and Jmjd3 is essential for SAA-induced foam cell formation (Yan et al, 2014), suggesting a possible therapeutic role in atherosclerosis. In wound healing, specifically in patients with Type 2 Diabetes (T2D), macrophages of the pro-inflammatory M1 phenotype mediate chronic inflammation.…”

TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis

“…Considering that oxLDL represented a potential non-microbial factor capable of upregulating TREM-1 (ref. 50, 51), we next addressed whether oxLDL and HFCD serum-derived factors could synergize with TREM-1-mediated signals to amplify production of pro-atherogenic cytokines, analogous to the well-established synergistic effects of TREM-1 with LPS27. Incubation of monocytes with oxLDL or HFCD serum alone did not induce substantial secretion of IL-1α, IL-1β or TNFα, whereas anti-TREM-1 stimulation in the absence of other factors distinctly increased the production of TNFα but not of IL-1 cytokines (Fig.…”

Epigenetic pathways in macrophages emerge as novel targets in atherosclerosis

“…These findings are factual for macrophage differentiation, but might also illuminate the critical role of Jmjd3 during seemingly heterogeneous modes of macrophage activation described above. Overall, Jmjd3 is needed to permit several responses to distinct external stimuli including LPS, SAA, IL-4, RANKL and M-CSF, and Jmjd3 activity thus is not associated with one particular macrophage activation status (Chen et al, 2012a;De Santa et al, 2009Ishii et al, 2009;Kruidenier et al, 2012;Satoh et al, 2010;Yan et al, 2014;Yasui et al, 2011) (Fig. 3).…”

“…Accordingly, also inflammatory cytokine induction by the acute-phase protein serum amyloid A (SAA) depends on Jmjd3 activity (Yan et al, 2014). Removal of repressive H3K27me3 marks by Jmjd3 is not only required for the pro-inflammatory response, but is also induced by and needed for IL-4 signalling in M2 macrophages (Ishii et al, 2009) during helminth infection and responses to chitin (Satoh et al, 2010).…”