Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

C/EBPdelta-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9.

Abstract

The proinflammatory alarmins S100A8 and S100A9 are among the most abundant proteins in neutrophils and monocytes but are completely silenced after differentiation to macrophages. The molecular mechanisms of the extraordinarily dynamic transcriptional regulation of S100a8 and S100a9 genes, however, are only barely understood. Using an unbiased genome-wide CRISPR/Cas9 knockout based screening approach in immortalized murine monocytes we identified the transcription factor C/EBPdelta as a central regulator of S100a8 and S100a9 expression. We showed that S100A8/A9 expression and thereby neutrophil recruitment and cytokine release were decreased in C/EBPdelta KO mice in a mouse model of acute lung inflammation. S100a8 and S100a9 expression was further controlled by the C/EBPdelta-antagonists ATF3 and FBXW7. We confirmed the clinical relevance of this regulatory network in subpopulations of human monocytes in a clinical cohort of cardiovascular patients. Moreover, we identified specific C/EBPdelta-binding sites within S100a8 and S100a9 promoter regions, and demonstrated that C/EBPdelta-dependent JMJD3-mediated demethylation of H3K27me3 is indispensable for their expression. Overall, our work uncovered C/EBPdelta as a novel regulator of S100a8 and S100a9 expression. Therefore, C/EBPdelta represents a promising target for modulation of inflammatory conditions that are characterised by S100a8 and S100a9 overexpression.