Abstract: The underlying mechanisms of the second leading cause of death among Werner syndrome (WS) patients, atherosclerosis, is not fully understood. Here, we established an in vitro co-culture system using macrophages (iMφs), vascular endothelial cells (iVECs), and vascular smooth muscle cells (iVSMCs) derived from induced pluripotent stem cells. WS-iMφs induced endothelial dysfunction and characteristics of phenotype switching in WS-iVECs and WS-iVSMCs, respectively. 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-iMφs. Furthermore, we found higher expression of retrotransposable elements in WS-iMφs and WS peripheral blood-derived-Mφs and evidence that retrotransposable element-derived dsRNA may activate the DHX58-dependent cytoplasmic RNA sensing pathway in WS-iMφs. Conversely, silencing type I interferon signaling in WS-iMφs suppressed cellular senescence and inflammation. These findings suggest that Mφ-specific inhibition of type I interferon signaling could be targeted to treat atherosclerosis in WS patients.
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