Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model [iPS ATAC-seq]
The underlying mechanisms of atherosclerosis, the second leading cause of death among Werner syndrome (WS) patients, is not fully understood. Here, we established an in vitro co-culture system using macrophages (iMfs), vascular endothelial cells (iVECs), and vascular smooth muscle cells (iVSMCs) derived from induced pluripotent stem cells. In co-culture, WS-iMfs induced endothelial dysfunction in WS-iVECs and characteristics of the synthetic phenotype in WS-iVSMCs. RNA-seq and ATAC-seq revealed accelerated activation of type I interferon signaling and reduced chromatin accessibility of several transcriptional binding sites required for cellular homeostasis in WS-iMfs. Furthermore, the reduced H3K9me3 levels showed inverse correlation with retrotransposable elements, and retrotransposable element-derived dsRNA activated the DHX58-dependent cytoplasmic RNA sensing pathway in WS-iMfs. Conversely, silencing type I interferon signaling in WS-iMfs rescued cell proliferation and suppressed cellular senescence and inflammation. These findings suggest that Mf-specific inhibition of type I interferon signaling could be targeted to treat atherosclerosis in WS patients. Overall design: Assay for transposase-accessible chromatin with sequencing (ATAC-Seq)